**FDA/NIH Joint Symposium on Diabetes**

**Targeting Safe and Effective Prevention and Treatment**

May 13-14, 2004

National Institutes of Health

Natcher Conference Center

Main Auditorium

NIH Campus

Bethesda, Maryland

**[Day 1: Major Challenges to Development of New Therapeutics and
Diagnostics]{.smallcaps}**

***Welcome***

Dr. David G. Orloff, Director, Division of Metabolic and Endocrine Drug
Products, Center for Drug Evaluation and Research (CDER), Food and Drug
Administration (FDA), U.S. Department of Health and Human Services
(DHHS), opened the symposium by noting that this meeting was bringing
together world leaders in the study of diabetes, from basic scientists
to clinical researchers, to epidemiologists, to those directly involved
in commercial therapeutics, devices, and diagnostic tools. Dr. Orloff
thanked those present for their willingness to assist the FDA and the
National Institutes of Health (NIH) in identifying therapeutic gaps and
challenges for the safe and effective prevention and management of
diabetes, both type 1 and type 2. Dr. Orloff was hopeful that together
they could find the most appropriate and expeditious paths to improve
public health in this area.

This symposium was sponsored by the FDA's Center for Biologics
Evaluation and Research, the Center for Devices and Radiological Health,
CDER, and the Office of the Commissioner and by NIH's National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Orloff
announced speaker and panel member changes in the agenda and called the
participants' attention to items in their meeting packets and program
booklets, including speaker biographies; copies of previously submitted
PowerPoint presentations; speaker, panel member, and participant lists;
and a handout from the Juvenile Diabetes Research Foundation
International (JDRF). Dr. Orloff then introduced Dr. Allen M. Spiegel,
Director of NIDDK.

Dr. Spiegel welcomed the attendees and thanked Dr. Orloff and Dr. Robert
Meyer, Director, Division of Metabolic and Endocrine Drugs, of the FDA
and Dr. Judith Fradkin, Director, Division of Diabetes, Endocrinology,
and Metabolic Diseases (DDEM) , NIDDK, and Dr. Sanford Garfield, Senior
Advisor for Biometry and Behavioral Research Program, DDEM, NIDDK, and
other members of FDA and NIDDK for their efforts in organizing the
meeting. Dr. Spiegel stated that a number of NIH institutes and offices
are working together to foster research in type 1 and type 2 diabetes.
They have created consortia and clinical trial networks to further
progress in prevention and intervention in diabetes. For example, for
type 1 diabetes, there is a schema of natural history, partially
developed by one of the day's speakers, Dr. George S. Eisenbarth, that
clearly shows that type 1 diabetes is a slowly progressive, autoimmune
illness beginning with a genetic susceptibility and followed by
environmental triggers or other inciting events and a period of "silent
β-cell loss," largely because we do not yet know how to functionally
monitor β-cell mass in a non-invasive way. Dr. Spiegel stressed that
being able to do so is an important goal of NIH-supported research
through the Beta Cell Biology Consortium, as this would provide an
enormously important biomarker. Following this silent β-cell loss, the
overt onset of diabetes occurs and, in some instances, what is termed
"brittle diabetes," as a function of complete loss of β-cell reserve.

Dr. Spiegel highlighted several current trans-NIH initiatives in type 1
diabetes including the following:

-   Type 1 Diabetes Genetics Consortium (T1D GC), an international
    consortium to identify the additional genes that are known to
    underlie susceptibility.

-   Environmental Determinants of Diabetes in the Young (TEDDY), a
    consortium that will follow the prenatal and postnatal development
    of children to try to determine the environmental triggers that
    remain unknown.

-   TrialNet, a network of regional cooperative clinical groups for
    prevention and reversal of recent onset type 1 diabetes in
    partnership with the Immune Tolerance Network (ITN), which looks at
    the mechanistic aspects of monitoring T-cell function.

-   A new islet transplant consortium that will be launched in the fall
    of 2004.

-   DirecNet (Diabetes Research in Children Network), a pediatric
    network to look at non-invasive glucose monitoring.

In presenting a slide depicting the natural history of type 2 diabetes,
Dr. Spiegel showed that the disease follows a similar course to that of
type 1. There is a genetic susceptibility, along with an environmental
trigger, which, for type 2, is well known. This slide was developed by
another speaker, Dr. David Nathan, and his colleagues, and was also
based on years of study of the Pima Indians in Phoenix, Arizona, by
NIDDK's intramural branch. Although Dr. Francis Collins of the National
Human Genome Project has explained that everyone has some "misspellings"
in their genome, the natural history of type 2 diabetes follows a
spectrum from what is termed "normal" to a state now identified as
pre-diabetes, due to the stress of obesity and factors that impinge on β
cells.

Dr. Spiegel stated that based on new American Diabetes Association
criteria, there may be as many as 40 million individuals in the United
States with pre-diabetes, *twice the amount previously estimated*. Their
overt β-cell failure can lead to overt type 2 diabetes. Many of these
individuals are undiagnosed because, unlike type 1, type 2 diabetes is
an insidious disease. He added that the landmark Diabetes Control and
Complications Trial (DCCT) demonstrated that macrovascular complications
(such as cardiovascular disease) ensue as a function of poor glycemic
control and ultimately lead to disability and death.

Dr. Spiegel listed the following major NIH type 2 diabetes studies:

-   BARI2D (Bypass Angioplasty Revascularization Investigation 2
    Diabetes) study, which is primarily supported by the National Heart,
    Lung and Blood Institute (NHLBI), but NIDDK is involved.

-   ACCORD (Action to Control Cardiovascular Disease Risk in Diabetes)
    and LookAHEAD (Action for Health in Diabetes) studies, which are
    examining various measures of glycemic, weight, blood pressure, and
    lipid control, as a way of converting cardiovascular complications
    in established type 2 diabetes.

-   Diabetes Prevention Program (DPP) and the observational cohort
    follow-on DPPOS (Diabetes Prevention Program Outcome Study); DPP
    showed that an intensive lifestyle intervention or metformin could
    reduce the incidence of development of overt type 2 diabetes in
    those with so-called pre-diabetes.

-   STOPP-T2D (Studies to Treat or Prevent Pediatric Type 2 Diabetes), a
    pediatric effort in children and adolescents for treatment of type 2
    diabetes in those in whom it is established and an interventional
    study to prevent the markers of pre-diabetes in middle-school
    children.

In summary, Dr. Spiegel stated that NIH is making major investments and
taking a proactive role at every stage of the spectrum, focusing on
primary prevention wherever possible, because that is cost-effective,
but also working to ensure that its research investment is fully
translated. He emphasized that basic science studies have to be
translated for the development of new therapeutics and new devices and
efficacy trials have to be translated to show effectiveness in the
community. To accomplish this requires partnerships with other agencies
and organizations, as demonstrated by this FDA/NIH meeting. Dr. Spiegel
then introduced Dr. Janet Woodcock, FDA's Acting Deputy Commissioner.

Dr. Woodcock welcomed the group and reminded them that the impending
burden of diabetes is not just a national public health problem but also
a personal one since nearly everyone has a relative or friend affected
by this disorder. She explained that the focus of this conference is on
state-of-the-art prevention and treatment interventions for diabetes.
Dr. Woodcock agreed with Dr. Spiegel that there is a growing recognition
that biomedical research needs an increased focus on translating new
scientific knowledge into new therapies, as reflected in NIH's Roadmap
Initiative that was launched 6 months ago. In recognition of this need,
FDA is partnering more directly with NIH and is sponsoring several new
initiatives to facilitate the movement of innovative science into the
clinic. The Innovations in Medicine Initiative, launched about a year
ago, has as a goal to write new guidance on diabetes trials and
development of new anti-diabetes products. Dr. Woodcock expected this
symposium to assist the FDA with that activity.

Recently, FDA produced a report called, "Innovation or Stagnation:
Challenges on the Critical Path to New Medical Technologies." The
central thesis of this report reflected FDA's belief that, in addition
to the basic sciences, more emphasis is needed on product development
science and on new evaluative tools that will move new therapies more
quickly into the clinic. Dr. Woodcock noted that this thesis is very
relevant to the current meeting, since new tools are needed for drug,
biologic, and device development and evaluation. For example, the
meeting program calls for discussion of cellular therapies, such as use
of islet cells and so forth, topics that have been a dream for a long
time in this field. FDA has identified a broad series of challenges
about the use of cell therapies, not strictly related to islet cells,
but any type of cellular therapy. Dr. Woodcock listed a few of these.
For example, what tools exist to characterize these cells? When
interventions are studied in the laboratory, there is a controlled
environment. However, a very different set of challenges present
themselves when trying to control the cells and keep them stable in a
mass production environment. New genomics and proteomics tools must be
developed to evaluate characterization of cells in a production
environment and help developers produce stable products with predictable
characteristics. Dr. Woodcock said that FDA is working to develop and
introduce genomics and proteomics, now prominent in the basic science
realm, as new fields in industrial production.

Dr. Woodcock stated that medical devices are going to play an
increasingly important role in the therapy of diabetes as drug delivery
systems, as well as probably in the treatment of complications. FDA's
Center for Devices and Radiological Health (CDRH) has identified a need
for new computer tools to accomplish this. The medical device industry
is continuously pursuing engineering type activities to alter devices
and improve their performance. Computer models are needed to evaluate
the impact of incremental changes on a device's performance, rather than
the present method of evaluating these changes through costly and
time-consuming clinical trials. Otherwise, clinical use of these
improvements falls several cycles behind the engineers' developments.
This delay also creates a barrier to innovation in this area.

According to Dr. Woodcock a range of issues need to be addressed in the
area of drug therapies. For example, hepatotoxicity is a major barrier
to drug development. Better predictive tools to identify hepatotoxicity
and remove drugs earlier from the production pipeline or to predict who
would be at risk if exposed to the drug would greatly enhance drug
development by saving the billions of dollars of investment in drugs
that, either late in clinical evaluation or once out in the market, are
found to have serious hepatotoxicity. Another opportunity for improving
drug development would be to decrease the cost of clinical trials,
another large barrier, by developing improved clinical trial designs.

As part of FDA's Critical Path initiative, Dr. Woodcock said the agency
is meeting with many people during the spring and summer of 2004 to
identify opportunities for improving development processes, such as
learning what new scientific tools are needed to assist the development
pathways for various medical products. In the fall of 2004, FDA will
publish a list of the outstanding opportunities and enlist support in
putting scientific effort behind solving these challenges. Given the
challenges the Nation's healthcare system faces, Dr. Woodcock emphasized
that meetings like this symposium were essential to help generate ideas
and identify the kinds of problems that have to be addressed to
accelerate the pace of innovation in diabetes, as well as in other
serious diseases.

The agenda for the 1-1/2 day symposium addressed major challenges to
development of new therapeutics and diagnostics for diabetes and
perspectives on the future of prevention and therapy. Presentations
covered the following topics:

-   Overview of diabetes mellitus and vascular disease outcomes.

-   New molecular targets in type 2 diabetes and immunomodulation in
    type 1 diabetes.

-   Beta cell preservation in type 1 and type 2 diabetes.

-   Islet transplantation.

-   Glucose monitoring devices and insulin pumps.

-   Prevention of type 2 diabetes including new perspectives on the
    metabolic syndrome and findings of the Diabetes Prevention Program.

-   Industry and advocacy perspectives.

Speakers and symposium attendees participated in discussion periods
throughout the meeting, concluding with a panel and participant
discussion on targeting safe and effective prevention and treatment
steps as FDA and NIH move forward in bringing research findings to the
primary practitioner's office. Copies of Dr. Spiegel's slides and the
speakers' slides used in the following presentations are available at
<http://www.niddk.nih.gov/fund/other/conferences-arch.htm>. The
conference program book containing the agenda, speaker abstracts, and
speaker and participant contact lists is also available at that URL.

**Session I: Overview/Setting the Stage**

*Moderator: David Orloff, MD, Director, Division of Metabolic and
Endocrine Drug Products, Center for Drug Evaluation, FDA*

**Diabetes Mellitus 2004: Biomarkers and the Development of New
Therapeutics and Diagnostics**

***David M. Nathan, MD**, Director, General Clinical Research Center,
Diabetes Center, Massachusetts General Hospital; Professor of Medicine,
Harvard Medical School, Boston*

Dr. Nathan presented information predominantly from clinical trials
about the role of biomarkers or surrogates in understanding the clinical
course of diabetes mellitus and in the development of new therapeutics.

Dr. Nathan defined diabetes mellitus as a chronic disease characterized
by abnormal metabolism of glucose, as well as other nutrients such as
protein and fat, and accompanied by the risk of long-term complications
specific to diabetes that affect the eye, kidney, and nervous system.
Both type 1 and type 2 diabetes begin with a pre-diabetic phase.
Diabetes is usually clinically diagnosed on the basis of hyperglycemia.
Glycemia is a recurring theme in discussing diabetes and is, in a sense,
a biomarker. There is a latent period, during which the disease or the
condition is present but before the patient develops either early or
late complications that ultimately lead to morbidity and mortality. Dr.
Nathan discussed some of the surrogates or biomarkers for different
stages of the disease.

A surrogate is a predictor, or early warning sign, or marker of a
phenomenon present before the disease occurs. Dr. Nathan explained that
one of the inevitable questions during the development of clinical
trials is always, "We want to measure heart disease, but could we
reliably measure something that is not quite a heart attack? Something
that precedes or predicts a heart attack? Wouldn't that be more
efficient and potentially increase the power of a study?" This question
leads to "What would be an acceptable substitute for a specific
outcome?" In such discussions, the term "biomarker" has come into common
use and been used instead of surrogate as an indicator of the outcome.

Dr. Nathan presented the interesting fact that dictionaries did not list
"biomarker" as a word until very recently, yet there are more than a
quarter of a million citations in PubMed (more than 3,000 since the
beginning of 2004). Dr. Nathan searched Medline for "biomarker" and
"diabetes" in 2004 and found 10 citations, including coronary
calcification, CVD (cardiovascular disease), inflammatory markers,
oxidative stress, proteomics, periodontal disease and CVD risk, and
urinary isoprostanes. For the purposes of the meeting, Dr. Nathan
defined a biomarker as a "biological process or biochemical indicator
that precedes the development of disease and is usually indicative of
the future development or progression of the disease, and as such can be
used to measure the effects of treatment."

**Primary Prevention---Type 1 Diabetes**. Using Dr. Eisenbarth's concept
of the natural history of type 1 diabetes, Dr. Nathan listed specific
analytes that accompany the different stages: first, genotyping looking
at cytotoxic T-cells and autoimmune T-cell profiles; antibody generation
during the developmental stages; then, later on, abnormal insulin
secretion that can eventually be measured with a stress test such as an
intravenous glucose tolerance test; and finally, relatively late,
abnormal glycemia. For primary prevention, an important question is
whether any of these would substitute as an indicator for the actual
development of hyperglycemia, which is a rather late phenomenon. As an
example, since the generation of antibodies, and especially multiple
antibodies, is quite a good indicator of who is going to develop type 1
diabetes, would preventing antibody generation be an acceptable
biomarker for prevention of type 1 diabetes?

In the Diabetes Prevention Trial--1 (DPT--1), the outcome was
hyperglycemia detected by oral glucose tolerance testing. The study
demonstrated a high level of accuracy in predicting the development of
diabetes. Dr. Nathan asked if some of the analytes from that trial could
be used as biomarkers for new prevention studies. Dr. Nathan noted that
several studies have used biomarkers, such as C-peptide secretion, but
most investigators have considered these not reliable enough; however,
as stated in the DPT--1 report, increased "understanding of development
of diabetes may refine predictive markers" and result in alternative
outcomes for future intervention studies.

**Primary Prevention---Type 2 Diabetes**. Dr. Nathan presented the
pathophysiology of type 2 diabetes as beginning with insulin resistance,
mediated by obesity, genetics, and other endocrine disorders, which
leads to progressive postprandial hyperglycemia, then to impaired
glucose tolerance and to fasting hyperglycemia, and finally to type 2
diabetes. He said there may actually be two different subpopulations of
type 2---those who get fasting hyperglycemia may actually be different
than those who progress through the postprandial route. Downstream of
all of these stages are the duration-dependent complications.

Dr. Nathan referred to the "wounded" β-cell and resultant cyclic
decrease in insulin secretion as the important players in the
progression of this disorder that finally leads to glucose toxicity. The
various measurements used to chart the course of the disease
process---from clamp, HOMA, and minimod to the oral glucose tolerance
test (OGTT) and finally fasting glucose and hemoglobin A1c
(HbA1c)---could be used as biomarkers in prevention studies if
investigators were convinced that changes in the results of these
measurements at the various stages in disease progression would equate
to a decrease in the risk of developing type 2 diabetes.

Dr. Nathan pointed out that all of the studies for prevention of type 2
diabetes---DPP, the Finnish Diabetes Study, the Da Qing Study, and the
STOPP-T2D---have used development of diabetes based on fasting or
glucose tolerance testing, indicating general acceptance of diabetes as
a disorder of hyperglycemia. Dr. Nathan suggested that other potential
biomarkers could include lesser degrees of glucose intolerance. Changes
in insulin resistance and other metabolic changes such as changes in
free fatty acids might also be used as markers. He added that the
importance of looking at different levels of hyperglycemia or insulin
resistance goes beyond the issue of diabetes. Affecting sub-diabetic
levels of hyperglycemia may have a benefit in and of itself. For
instance, glucose intolerance and insulin resistance are components of
the metabolic syndrome, which is a risk indicator for cardiovascular
disease (CVD) as well as diabetes.

To illustrate the relationship of glycemia to the metabolic syndrome and
CVD risk, Dr. Nathan presented data from the Framingham Offspring Study,
a population-based study of the children and spouses of the children of
the original Framingham cohort. During the fourth 4-year cycle of the
offspring study, the participants were given glucose tolerance tests and
then divided into normal, impaired glucose tolerance (IGT), and diabetic
groups. The normal glucose tolerance group was divided into quintiles.
The curves showing the level of glucose tolerance in these groups
relative to elements of the metabolic syndrome, such as hypertension and
hyperlipidemia, and the presence of the metabolic syndrome itself (which
requires a grouping of factors), showed levels increasing along with
glycemia. Dr. Nathan stressed the continuous risk function based on
glycemia in the sub-diabetic range for both men and women for all of the
elements of the metabolic syndrome. Every one of the elements of
cardiovascular disease risk goes up continuously in the sub-diabetic,
and even in the sub-pre-diabetic range, which indicates that rising
glucose levels, perhaps mediated by increasing insulin resistance and by
other factors, play a role here. Thus, examining glycemia as a biomarker
of cardiovascular disease risk may be of benefit. Other biomarkers, such
as inflammatory and hemorheologic abnormalities, followed the same trend
across all quintiles.

Dr. Nathan noted that the Diabetes Prevention Program also had the goal
of determining whether the interventions would decrease cardiovascular
disease, cardiovascular disease risk factors, or biomarkers for
cardiovascular disease. He offered data currently in press that was
presented at the American Diabetes Association meetings in 2003. Year
one mean change in t-PA, a biochemical risk factor (or a biomarker) for
CVD, was reduced in the intensive lifestyle group and in the metformin
group, compared with the placebo group. Similarly, CRP (C-reactive
protein) was significantly lower in the female population in both the
intensive lifestyle and the metformin groups.

**Secondary Intervention**. Dr. Nathan presented possible surrogates or
biomarkers used in the Diabetes Control and Complications Trial (DCCT)
and the United Kingdom Prospective Diabetes Study (UKPDS). In DCCT and
most studies of diabetes, HbA1c is used as an index of chronic glycemia
and as the usual surrogate for chronic glycemia. Dr. Nathan presented
data showing that it has been known for some time that there is an
association between glycemia and complications, such as retinopathy and
kidney disease. For example in DCCT, a 10-percent reduction in HbA1c
through intensive glycemic control resulted in a 43-percent reduction in
risk for retinopathy. Retinopathy was tested using fundus photography
that assessed changes in the vasculature of the eye. Since the tight
relationship of HbA1c and the biomarker for pre-retinopathy (changes in
the eye associated with development of vision loss, not actual vision
loss) was demonstrated strongly in DCCT and in a 4-year follow-up, Dr.
Nathan suggested that pre-disease levels of retinopathy or HbA1c could
be used as biomarkers in primary and secondary intervention trials for
type 1 diabetes. DCCT also showed decreases in kidney disease
(predominantly microalbuminuria, another biomarker) associated with
decreased HbA1c; thus decreases in HbA1c could be used as a biomarker in
clinical trials of therapies and interventions to prevent nephropathy.

Since the incidence of CVD events in the DCCT was too low to determine
if intensive therapy reduced cardiovascular disease, Dr. Nathan said
that it was decided in the Epidemiology of Diabetes Interventions and
Complications (EDIC) study, the follow-up to the DCCT, to look at
biomarkers of CVD such as atherosclerosis measured by carotid
ultrasonography. EDIC showed that in the DCCT cohort, intensive therapy,
compared with conventional therapy, significantly decreased the rate of
progression of thickening in the common carotid and in the internal
carotid arteries. Other studies have demonstrated that IMT (intimal
medial thickness) of the carotid artery may be a good biomarker for
cardiovascular disease. Thus, biomarkers of CVD, such as measures of
atherosclerosis as IMT and coronary calcification, have been shown to be
sensitive to glycemic intervention. Further follow-up may demonstrate a
benefit of intensive therapy on the CVD events. If further follow-up
shows a correlation between the measures of atherosclerosis and CVD
events, then Dr. Nathan would urge the use of these measurements in
secondary prevention trials as substitutes for actual hard clinical
events.

**Tertiary Intervention**. Until the past 10 years or so, this is the
area (decrease in mortality or severe morbidity) that received the most
attention. Dr. Nathan stated that there are a lot of interventional data
available. By this late stage of disease progression, lipids and blood
pressure, rather than glycemia, are probably the important targets for
cardiovascular events. Dr. Nathan noted that the next speaker, Dr. Peter
Wilson, would be discussing the possible biomarkers for this stage.

Dr. Nathan concluded by stressing that diabetes represents a chronic,
long-term, degenerative disease for which there are numerous potential
targets with regard to the biology of disease. Use of these targets can
certainly increase the efficiency of future interventional trials.

**Diabetes Mellitus and Vascular Disease Outcomes**

***Peter Wilson, MD**, Professor of Medicine, Section on Endocrinology,
Diabetes, and Medical Genetics, and Program Director, General Clinical
Research Center; Medical University of South Carolina, Charleston*

Dr. Wilson began his presentation by stressing that the United States
has an epidemic in diabetes, with obesity contributing to the increasing
numbers of adults with type 2 diabetes, of whom two-thirds will have a
cardiovascular outcome as cause of death. Virtually every obese diabetic
will have CVD before they die. Dr. Wilson also offered data showing that
diabetes, along with hypertension, are the two primary causes of
end-stage renal disease (ESRD), another major reason to be concerned
about the diabetes and obesity epidemics. Type 1 diabetes also leads to
kidney failure, coronary artery disease, and other complications of
diabetes such as infections; approximately a third of type 1 diabetics
eventually die from CVD. The DCCT showed that with tight glycemic
control, microvascular events could be reduced but, as Dr. Nathan had
said, the number of macrovascular events was too small for tight
glycemic control to be predictive of these.

From NHANES III data (M. Harris, Diabetes Care, 23:754, 2000), Dr.
Wilson showed that of persons with type 2 diabetes in 1994, 45 percent
had a body mass index (BMI) greater than 30 (i.e., obese), 63 percent
had hypertension, and 58 percent had HbAlc greater than 7 percent, all
risk factors for complications. Dr. Wilson's data from the Framingham
cohort indicated that for younger persons (ages 35-64), diabetes doubles
their risk for CVD and stroke for men and triples it for women. In the
older age group (65-94), diabetes doubles the risk for men and women,
except for heart failure and stroke, where the risk is higher. Dr.
Wilson stressed that older persons with diabetes and hypertension tend
to slip into heart failure post-heart attack.

Dr. Wilson presented data from Dr. Steve Haffner and the Finnish
East-West study that indicated a non-diabetic was at lowest risk for a
second heart attack. Those at the highest risk were diabetics who had
had a prior myocardial infarction (MI). At equal risk were non-diabetics
with a prior MI and diabetics with no prior MI, which shows that having
diabetes puts a person at equal risk of a heart attack with a person who
has already had a heart attack. Dr. Wilson said this is why NHLBI and
other groups recommend treating diabetics as aggressively as one treats
people with known coronary events. The Nurses Health Study demonstrated
that, like microvascular disease in type 1 diabetes, the longer the
duration of type 2 diabetes, the greater the risk for macrovascular
disease.

**Glycemia and Vascular Risk**. Observational data on hyperglycemia in
middle-age adults and risk for vascular complications in type 2 diabetes
from the Wisconsin Epidemiology Study of Diabetic Retinopathy (WESDR)
showed a higher risk for retinopathy than for cardiovascular disease. As
with the lower hyperglycemia in middle age adults with type 2 diabetes
in WESDR, DCCT showed that tight glucose control affected progression of
small vessel disease in the eye in type 1 diabetes and also decreased
microalbuminuria and macroalbuminuria.

Dr. Wilson noted that the UKPDS was largely about glucose control but
also had a hypertension arm. This 10-year study included nearly 4,000
newly diagnosed non-obese type 2 diabetics whose median age was 54 at
onset of the trial, of whom approximately one-third were treated with a
conventional therapy and diet, receiving drugs if needed, and two-thirds
received intensive treatment with oral agents or insulin. Dr. Wilson
stressed that 10-year studies are no longer an option in this field
because answers are needed sooner and therapies are changing very fast.
For instance, today blood pressure treatment is two generations beyond
what was used in the UKPDS hypertension arm. Intensive glucose control
in NKPDS showed a strong decrease in microvascular endpoints. For
coronary artery disease (CAD), decreases in HbA1c and systolic blood
pressure and increases in HDL cholesterol decreased risk by 11 to 15
percent. A 39 mg/dl decrease in LDL cholesterol decreased risk by 57
percent. Dr. Wilson pointed out that the focus on multiple interventions
probably produced better results than focusing on just one intervention
does. He added that until recently, diabetics were often excluded from
blood pressure trials.

**Blood Pressure and Vascular Risk**. Dr. Wilson summarized the results
of the following studies that have included blood pressure and vascular
risk in diabetes:

-   WESDR: Some relationship of systolic pressure, but not diastolic, to
    progression of retinopathy in younger diabetics, but in older
    patients, the relationship to systolic and diastolic was about
    equal.

-   SHEP (Systolic Hypertension in the Elderly Program): Diabetics
    benefited nearly twice as much as non-diabetics from blood pressure
    treatment with chlorthialidone.

-   SYSEUR (Systolic Hypertension in Europe): Use of a calcium channel
    blocker was effective for stroke in both diabetics and
    non-diabetics, but less so for cardiac events.

-   HOT (Hypertension Optimal Treatment): This Scandinavian-led study
    produced lower levels of diastolic pressure in diabetics through
    aggressive treatment and led to new guidelines from the American
    Diabetes Association (ADA) (a diastolic of 80 for diabetics and 75
    for diabetics with kidney disease) and the National Cholesterol
    Education Program (NCEP).

-   HOPE (Heart Outcome Prevention Evaluation): A powerful angiotensin
    converting enzyme (ACE) inhibitor trial using ramipril showed that
    CVD risk could be reduced in high-risk patients, including those
    with diabetes.

-   UKPDS: Use of beta blockers for tight control of blood pressure
    indicated positive endpoint results in heart failure, stroke,
    diabetes death, and microvascular disease.

-   RENAAL (Reduction of Endpoints in NIDDM with Angio II Antag
    Losartan): Using an ARB (angiotensin receptor blocker) versus
    placebo, Dr. Barry Brenner and colleagues had positive results for
    diabetics in endpoint incidence of chronic kidney disease, ESRD, and
    death.

Dr. Wilson stated that the number of positive results from trials of
ACEs and ARBs is producing a strong message for guidelines to include
the use of these sooner rather than later in treating type 2 diabetes.

**Dyslipidemia and Vascular Risk**. Dr. Wilson explained that abnormal
LDLs are similar in diabetics and non-diabetics; however, in diabetics,
it is common for HDLs to be low and triglycerides to be high,
particularly in women, as shown by data from the Framingham Offspring
Study. In four secondary prevention trials to reduce CVD risk
(Scandinavian Simvastatin Survival Study (4S) and simvastatin, CARE and
pravostatin, LIPID and pravostatin, and the Veterans Affairs HDL
Cholesterol Intervention Trial (VA-HIT) and gemfibrozil), regardless of
the agent, except for simvastatin, or whether patients were diabetic or
non-diabetic, the results were similar in reducing relative risk in
high-risk patients. Dr. Wilson's main point was that these lipid
interventions work as well in diabetics as they do in non-diabetics. In
the ASCOT study, a joint Scandinavian and Great Britain trial using
atorvastatin, there were not enough diabetics in the group to get a
strong result versus non-diabetics.

**Multifactorial Issues**. Dr. Wilson presented data (Stamler, J.
Diabetes Care, 1993, 16:434-44) showing that having multiple risk
factors for coronary artery disease gradually increases risk of death in
non-diabetics, but doubles or triples the risk in diabetics. The Steno-2
study of 160 persons with type 2 diabetes, a mean age of 55, a
conventional diabetes treatment and intensive treatment group (80 in
each), with an 8-year follow-up, was a multifactorial intervention trial
that had as outcomes composite CVD death, nonfatal MI, nonfatal stroke,
revascularization, and amputation. The intensive treatment group
included total dietary fat and saturated fat restrictions of less than
30 percent and less than 10 percent, respectively; 30 minutes of
exercise 3 to 5 times each week; smoking cessation for those who smoked;
and treatments to reduce HbA1c, and lower blood pressure, elevated
cholesterol, and elevated triglycerides. With the exception of HbA1c,
the intensive group was very successful in reaching their goals. After 8
years, the outcome to prevent CVD was, in Dr. Wilson's words, "a real
win," with only about 20 percent of the intensive treatment group
developing CVD while nearly 60 percent of the conventional therapy group
had CVD. Dr. Wilson strongly recommended that the next generation of
aggressive trials build on the Steno-2 model by using multiple
interventions.

In summary, Dr. Wilson said that for microvascular disease such as
retinopathy and nephropathy, glycemic control is very important, blood
pressure control is a little less so, and lipids are the least important
in diabetes. Macrovascular disease in diabetes is more complicated.
Abnormal lipids double the risk in men and triple it in women,
especially for women in middle age. Unfortunately, after a
cardiovascular event, diabetics have a higher risk and a very poor
prognosis for outcomes. He highly recommended multifactorial
interventions to prevent macrovascular disease in diabetics, including
blood pressure therapy, treatment for abnormal lipids, diet and
exercise, and glycemic control for its mild effects on macrovascular
disease.

**Discussion**

Dr. Orloff led off the discussion by saying that in adding details to
our understanding of the step-wise progression to overt type 1 and type
2 diabetes, we have arbitrarily defined and redefined diabetes. He added
that we have increasingly accepted as valid certain biomarkers of the
pathogenic course of the disease that relate to chronic exposure to
glucose and metabolic abnormalities and the risks that accrue from
these, which have provided us with targets for prevention at a much
earlier stage of the disease. He asked if it should be conceded that our
definitions of diabetes have always been somewhat arbitrary, and, more
specifically, should FDA and NIH be thinking about standards of evidence
for safety of new interventions as we start to intervene earlier and
earlier in the course of the disease.

Dr. Nathan responded that since diabetes is a continuum of
pathophysiologic processes, we must be aware of the clinical trial
participants' or patients' stage in the continuum when testing or
recommending interventions. For example, more risk is taken in doing
stenting or angioplasty on a patient who has had or is close to having
an MI in order to prevent a heart attack than the risk in prescribing a
drug or lifestyle change for someone with high blood pressure. One is
usually willing to take a greater risk when the downstream outcome is
very near, whereas with a chronic, degenerative disorder, there is less
willingness to risk. An example would be questioning the use of
cyclosporin to prevent type 1 diabetes in pre-diabetic children. It is a
case-by-case decision on how close the patient is to a life-affecting
disease process as opposed to how early in the disease process the
patient is. Another example Dr. Nathan gave was the decision in DPP to
stop using troglitazone as the study group accumulated evidence that it
might be dangerous and DPP was working with high-risk, possibly
pre-diabetes, but non-diabetic patients. Later the drug was removed from
the market. The challenge with cardiovascular disease and
atherosclerosis is that this is a process that takes place over decades
and so one must decide when in the process it is most effective
clinically and economically to intervene and with which drugs. With
today's statins and blood pressure medicines, this is mostly a
cost-effectiveness issue. Still the questions are "Do we start treating
young men in their 20's to prevent an MI at age 50 or 60? And which
young men should be treated then?" This is more a health economics issue
than a safety issue. Dr. Nathan said that as we identify effective,
reliable preventive measures to apply early in the continuum, there will
have to be case-by-case decisions made.

Dr. Orloff remarked that the speakers' talks clearly showed that there
is a large amount of basic science data and clinical trial data
available and that thus we need to be careful in moving forward to not
address questions to which we already have the answers. On the issue of
treating asymptomatic disease or pre-clinical disease, this raises the
issue of whether we ought to, in some instances, be thinking not about
ultimate proof of effectiveness trials, but about safety trials. He
asked Drs. Nathan and Wilson what they saw as the highest priority
questions for clinical trials in prevention and management of type 1 and
type 2 diabetes to prevent sequelae.

Dr. Wilson recommended trials similar to that of Steno-2, which, since
it was a European trial, has not received much attention from the
average physician in North America. It was published in the *New England
Journal of Medicine* (Gaede. NEJM 348:383-393, 2003), so scientists in
diabetes and heart disease probably know about it, but again the problem
is translation to the average physician. A second issue is that it takes
a lot of time to care for someone with type 2 diabetes and for them to
get their protocols right. Most diabetics are on four to eight
medicines. Hypertension also is not a one-medication problem. British
literature has been discussing a "polypill" approach for prevention of
CVD in type 2 diabetes. A trial for this would not be simple because the
answer is not simple. Dr. Wilson therefore suggested trying to design
larger trials based on something simpler with still important outcomes.

Dr. Nathan felt that trials are large enough now and are designed with
safety considerations. For example, for the Diabetes Prevention
Trial-Type 1 (DPT-1), it was carefully considered whether giving insulin
parenterally would be dangerous; it turned out not to be and a much
larger study is not needed to pick up the half-a-percent or so who had
very low level complications. Dr. Nathan agreed with Dr. Orloff that we
have an enormous reservoir of information as to what we could be doing
in prevention but not enough studies like Steno-2 that show what might
happen with CVD if we applied what we know, even using old-fashioned
medications or diuretics. He suggested that what we need is
translational research on how to apply what we know, how to make the
therapies more accessible in order to stem the diabetes epidemic.

Dr. Simeon Taylor, Bristol-Myers Squibb Company, commented that just as
HbA1c was identified and accepted through epidemiological studies as a
valid biomarker for first one mechanism and then a number of mechanisms,
there are other biomarkers such as HDL that have been identified through
epidemiology. He asked how the scientific community and the regulatory
agencies go from a hypothesis or even validation for a single mechanism
to the next step where it is assumed that this represents a universal
truth for all mechanisms. Does the biomarker have to be validated for
each novel mechanism?

Dr. Nathan replied that although HbA1c was demonstrated in numerous
studies to be a concrete marker for glycemia and also a surrogate for
the glycemia component of microvascular and neurological complications,
the DCCT/EDIC also did a sub-study that showed that glycated dermal
collagen was even more directly related to a complication. Dr. Nathan's
point was that although a biomarker may be an excellent surrogate across
many mechanisms, there probably exist more direct measures downstream in
the pathogenesis of complications. He suggested the most direct way of
proving this is to ensure that there is enough stored tissue specimens
in the NIH repository so as new suggestions come up, associations can be
looked for to identify potential new biomarkers. He noted that there is
still a great deal to be explained in the pathogenesis of complications.

Dr. Wilson stated that most of the really good markers are now
standardized, such as cholesterol and blood pressure. C-reactive protein
is not yet standardized. Advanced glycosylated endproducts had great
promise but there were problems with measurement and standardization.
This is also true for some of the lipoproteins compared to standard
lipids. Standardization of new markers is therefore a key issue and
tends to be a tremendous problem with surrogate markers. For example,
carotid analysis is a highly advanced skill unlike testing for glucose.

Dr. Judith Fradkin, NIDDK, raised the issue of when a clinical trial
finding can be pronounced ready for translation to the community. For
example, NIH and the Centers for Disease Control and Prevention (CDC)
have developed the Small Steps initiative in the National Diabetes
Education Program (NDEP) to translate the DPP findings about early
intervention to protect loss of β-cell function before the β-cells are
severely wounded in those at risk for pre-diabetes. The DHHS Agency for
Healthcare Research and Quality, however, feels it has not been clearly
demonstrated to their satisfaction that we should be identifying people
with pre-diabetes or that it is cost-effective to intervene in that
situation. FDA will clearly be faced with this issue as other trials are
underway, looking at additional agents that might prevent progression.
Dr. Fradkin asked what should be the public health message from such
trials.

Dr. Nathan answered that in the past those who did clinical trials that
ultimately have public health implications have shied away from the
issue of the public health messages. The attitude has been "We did the
science. The message is up to someone else." This is changing. Dr. David
Marrero, who was a member of DPP, is very involved with NDEP and has
been very active in developing the Small Steps program. Dr. Nathan added
that every clinical trial today needs to be judged as to whether it is
translatable. There are very few large clinical trials these days that
do not have a health economics group working side-by-side with the
investigators. CDC has been partnering with DCCT/EDIC and with DPP for
more than a decade. Studies that use a lot of resources need to keep in
mind that ultimately there is going to be a translation message.

Dr. Nathan continued that it is not surprising that there are concerns
expressed by different agencies. Further follow-up may be needed to
convince agencies and other groups of the wisdom of the DPP message. For
example, the findings from DCCT that were accepted almost universally in
1993 have now been reinforced 10 years later by EDIC and shown to be a
very inexpensive intervention to prevent complications. The DPP
follow-up will hopefully do the same.

Dr. Wilson pointed out that about half of type 2 diabetes occurs after
age 65, at a time when persons are beginning to lose muscle mass and
brain mass and developing more adiposity and losing β-cell function, and
this will continue through the ensuing aging years. From Dr. Wilson's
perspective, the time to head off the diabetes problem is therefore
earlier, between 35 and 65.

Dr. Nathan agreed by emphasizing that it was critical to shift the focus
from treating disease to preventing disease if we are to stem the
epidemic. If not, there will be so much disease around that the entire
healthcare budget and all the limited resources that exist will have to
be spent on late-stage, tertiary prevention of complications in a
growing population of 800,000 to 1.2 million new diabetic patients per
year. There will not be enough resources to take care of the kidney
disease, the heart disease, and everything else that will occur.

In response to a question from Dr. Richard Pratley, University of
Vermont, regarding the validity of HbA1c as a marker for microvascular
disease in type 2 diabetes and cardiovascular disease, Dr. Nathan said
that the UKPDS tends to substantiate this but it was not a
Government-supported study and did not have the tight controls that DCCT
had; therefore, some of the evidence is not firmly established. It would
be a public policy issue as to how high a level of resources should be
invested in such an effort. He recommended again that trials be designed
so that samples exist in repositories and data is stored in a databank
in order to examine new biomarkers without the large investment of a
DCCT. With regard to CVD, Dr. Nathan said that clearly blood pressure
and lipids have a demonstrably greater effect than HbA1c does and there
is not convincing data to show that glycemic intervention itself lowers
the risk of CVD. The ACCORD study is examining that.

An issue of discussion was that given that a primary care physician has
approximately 7 minutes per patient to treat the illness or condition
with which the patient is presenting at this appointment, there is
little opportunity to diagnose type 2 diabetes or hypertension in the
early stages nor are there protocols for treating the possibly
pre-diabetic patient. Although glucose and the components of metabolic
syndrome should not be ignored over time, there are no obvious
short-term benefits for the doctor or the patient in dealing with them
immediately since the patient is then asymptomatic. Dr. Wilson noted
that there are important issues, pro and con, in performing early
intervention with drugs. Dr. Nathan added that currently we are
initially dealing with sub-clinical events as we face chronic disease
management for the next millennia. In terms of immediate, short-term
benefit, he agreed one may have to balance the possible benefit against
the side effects of the medication. This is the difference between
trying to prevent and initial MI, rather than treating an already
existing condition. Whereas, with regard to the silent epidemic of all
the cardiovascular disease risk factors and diabetes, there is no
penalty, there is no motivation, necessarily, to address these factors
right then, and unfortunately, they tend to "float on." Dr. Nathan's
preference would be to aggressively treat all risk factors.

Dr. Harold Lebovitz, State University of New York, stated that he felt
early diagnosis and intervention for hyperglycemia was important since
hyperglycemia causes structural damage and most people, by the time they
are diagnosed with diabetes, already have complications or sub-clinical
complications, not just risk factors. Dr. Lebovitz asked about the issue
of obesity in diabetics. Dr. Wilson stated obesity is the determinant
for type 2 diabetes. Diabetologists recognize the need for the patient
to lose weight; now they are concerned with the metabolic syndrome as a
risk factor.

Dr. Jorge Plutzky, Harvard Medical School, emphasized that there needs
to be outreach to the internist and the family practitioner to identify
early on those 1.5 million Americans who die from their first cardiac
event, of whom a large percentage are pre-diabetic or have the metabolic
syndrome and could have had a different outcome if there had been an
intervention. In patients with late-stage disease, there has to be a lot
of "catch-up" for disease that is too advanced, so that even if trials
show relative risk is low, persons with pre-diabetes or the metabolic
syndrome would benefit from earlier treatment.

Dr. Plutzky asked what happens when an unexpected outcome from a seeming
surrogate occurs, as when an ACE inhibitor decreases convergence to
diabetes. He also asked what is necessary to indicate use of a drug to
prevent or delay convergence to diabetes.

Dr. Nathan responded that several studies, one of which is HOPE, have
suggested that ACE inhibition or a statin may play a role in diabetes
prevention. Most of these studies were not designed primarily to study
diabetes prevention, and bias of ascertainment may play a role in some
of them. However, the HOPE study has performed detailed secondary
analyses that suggest a beneficial effect of ACE-inhibition. Several
ongoing clinical trials are examining whether ACE-inhibition is
effective in diabetes prevention. Dr. Nathan said he doubted that the
currently available data would affect labeling of ACE inhibitors, which
he feels are not being used enough. Without adding diabetes to the list
of indications, ACE-inhibitors are already indicated for the treatment
of hypertension, and are beneficial for cardio-protection and renal
protection. He thought it was important to use ACE-inhibition more
frequently for its current, well-established indications. If future
studies show that ACE-inhibition (or receptor blockade) helps prevent
diabetes, it would be an important development. However, no convincing
data currently demonstrate this.

Dr. Plutzky summarized that an internist, recognizing the importance of
ACE inhibitors and seeing a metabolic syndrome patient would then say to
him/herself "Blood pressure is 135 and the patient is thick around the
waist so, based on the choices available to me, I am going to take
advantage of an approved indication for an ACE inhibitor, not only to
improve this person's blood pressure, but possibly also to influence
convergence to diabetes or to delay it." Dr. Plutzky said that those
looking for insulin sensitizers might ask themselves "When can I do the
same thing with metformin?" based on DPP data.

Dr. Nathan applauded the emphasis on prevention issues and reminded the
group that even people with recognized cardiovascular disease and its
risk factors in diabetes are currently undertreated, a barrier that
needs to be overcome.

**Session II: New Targets of Intervention**

*Moderator: Judith Fradkin, MD, Director, Division of Diabetes,
Endocrinology, and Metabolic Diseases, NIDDK*

**New Molecular Targets in Type 2 Diabetes Mellitus**

***Nancy A. Thornberry,** Senior Director, Department of Metabolic
Disorders, Merck Research Laboratories, Merck and Company, Inc., Rahway,
New Jersey*

To set the stage for her review of the molecular targets that have the
most potential within the next 10 years, Dr. Thornberry briefly reviewed
the pathogenic defects that result in hyperglycemia--hepatic glucose
overproduction, insulin resistance, and insulin secretory dysfunction.
She stated these defects are thus the primary targets for current and
future therapies to treat elevated blood glucose. There are three major
classes of oral antihyperglycemic agents (AHAs):

-   Sulfonylureas that stimulate insulin secretion in the pancreas, but
    may increase risk of hypoglycemia, cause drug interactions, exhaust
    β cells, or cause weight gain.

-   Metformin and PPARs that lower glucose overproduction in the liver;
    metformin may have gastrointestinal side effects and cause lactic
    acidosis; PPARs also may have drug interactions, increase weight
    gain, or cause edema.

-   PPARs that improve insulin resistance in muscle, but have the
    possible side effects listed above.

Dr. Thornberry stated that future potential therapeutic classes will
include these three major classes of insulin sensitizers, insulin
secretagogues, and mediators of hepatic glucose output. She presented
the rationales and key issues for various therapeutic agents in each of
these classes.

**Insulin Sensitizers: PPARα and PPARγ Agonists**. PPARs are
ligand-modulated transcription factors. Dr. Thornberry explained that
the PPAR is a nuclear hormone receptor involved in differentiation and
function of fat cells; ligands bind to the nuclear receptor but the
downstream mechanism is not fully understood. PPARα agonists target
dyslipidemia and atherosclerosis by correcting lipid abnormalities.
PPARγ agonists are a target for type 2 diabetes to correct insulin
resistance. The rationale for using these as dual activators is to
improve and simplify treatment of diabetes patients while decreasing
cardiovascular risk. There is preclinical proof in animal studies of the
efficacy of using them as dual agonists. Key issues are their combined
adverse effects. For PPARα, this includes myopathy and a potential for
hepatotoxicity. Adverse effects for PPARγ are weight gain, edema, mild
anemia, mild leucopenia, and the potential for increased risk of heart
failure.

**Insulin Sensitizers: SPPARγMs**. Dr. Thornberry said that safety
concerns are a key barrier in widespread use of PPARγ full agonists such
as thiazolidinediones (TZDs), which has led to the selective PPARγ
modulator (SPPARγM) hypothesis. SPPARγMs are potent ligands but only
partial agonists. Unlike full agonists, their alternative binding motifs
produce differential coactivator associations and the restricted gene
expression changes profiles, so they may retain efficacy but have
reduced toxicity, as was demonstrated in the db/db mouse study that
compared rosiglitazone, a full agonist, and a partial "relative" of
rosiglitazone that still retained full efficacy. Rodent studies also
showed that the partial agonist caused only modest cardiac effects
compared to the rosiglitazone. Key issues include whether or not the
SPPARγMs will equal the efficacy of current TZD full agonists while
avoiding the safety concerns and adverse effects of TZDs. If they are
safer, then there would be an option to test higher doses.

Summarizing, Dr. Thornberry said the dual PPARα/γ agents have the
potential to act on co-morbidities but may have the same safety and
tolerability liabilities as individual PPARs. The SPPARγMs have a safer
profile and may ultimately allow for treatment at earlier stages of
diseases. She told the audience that there is a lot of effort going on
in developing the next-generation insulin sensitizers with a focus on a
non-PPAR mechanism, enhanced efficacy, and improved safety and
tolerability.

**Insulin Secretagogues: Glucagon-like Peptide 1 (GLP-1) Analogs**. The
analogs are one of two GLP-1 based therapies being studied. The other is
dipeptidyl peptidase IV (DP-IV) inhibitors. Dr. Thornberry described
GLP-1 as a peptide secreted from the stomach in response to food intake
that has been shown in humans to have a number of beneficial effects,
including stimulation of glucose-dependent insulin biosynthesis and
secretion, inhibition of glucagon secretion, and slowing of gastric
emptying resulting in a feeling of satiety and thus reducing appetite.
In fact, modest body weight loss has been observed with GLP-1 analogs.
She added that there is very intriguing data in rodents to indicate that
GLP-1 may have a potential for regulating islet growth and survival.

Dr. Thornberry cited a study by Dr. Holst and colleagues (Holst et al.
Lancet 359, 2002) in Copenhagen that demonstrated that as soon as 1 week
after continuous infusion of GLP-1 in humans there were excellent
effects on both postprandial and fasting glucose compared to saline
infusion and these effects were maintained over a 6-week period. Dr.
Alain Baron has reported the results of a 5-month open-label study with
Exenatide (exendin-4) in 155 patients failing metformin and
sulfonylureas in which the interim analysis showed reductions in HbA1c
and positive effects on body weight. There were some safety and
tolerability issues such as antibody titers and nausea and vomiting that
is observed with all GLP-1 analogs; however, there was decreased
incidence of the stomach upset with repeated dosing, the antibody titers
apparently did not impact efficacy, and there were no safety
liabilities.

According to Dr. Thornberry, the vision for GLP-1 analogs is sustained
efficacy, good durability, and the potential to stabilize β-cell
function. GLP-1 analogs do not have any of the adverse effects
associated with current agents---there is no or a low risk of
hypoglycemia, no weight gain or even body weight loss, and no edema.
They offer an excellent potential for use in combination with other
agents for the pathology such as insulin sensitizers and mediators of
hepatic glucose output. Dr. Thornberry cited rodent data showing a
potential for β-cell regeneration, an attribute that, if it extends to
humans, Dr. Thornberry compared to finding a "holy grail" that could
lead to improvement over time in glycemic control and even reverse
β-cell loss.

Key issues for GLP-1 analogs are that injections are required with the
current agents in development; patients experience nausea due to delayed
gastric emptying, although this may not be a issue in the long run; and
the β-cell effects have not been demonstrated in humans.

**Insulin Secretagogues: DP-IV inhibitors**. Dr. Thornberry explained
that DP-IV inhibitors are essentially an oral approach to GLP-1 therapy.
DP-IV is the key enzyme involved in the regulation of GLP-1, which, like
other peptides, is very rapidly degraded *in vivo*, with a half-life of
less than 1 minute, so that inhibition of DP-IV results in raising the
endogenous level of GLP-1. Proof-of-concept was provided by Dr. Holst
and his colleagues in 1998. Several compounds are in clinical
development. A study with a Novartis compound (Arhen et al., 2002,
Diabetes Care 35) in which 93 patients were treated for 4 weeks
demonstrated the compound was well tolerated and had statistically
significant effects on fasting, postprandial, and 24-hour glucose.

Dr. Thornberry described the vision for DP-IV inhibitors also sustained
efficacy and good durability in stabilizing β-cell function; tolerance
and a good safety profile; oral therapy (versus the GLP-1 injections)
and the potential for once-daily dosing; excellent potential for use in
combination with other therapeutic agents; and the potential for β-cell
regeneration.

The key issues are the unknown extent of the efficacy with 24-hour,
chronic DP-IV inhibition; the potential that the therapy would have to
be limited to mild diabetes with intact β-cell function; ability to be
used in combination (likely synergistic with PPAR and metformin but may
be difficult to predict efficacy with sulfonylureas and insulin);
whether it will have the potential β-cell preservation and/or
regeneration benefit in humans; and determination of safety and
tolerability. Dr. Thornberry said that the enzyme, in addition to its
role in GLP-1, has been implicated in a number of different functions,
including T-cell activation and immune function, and there are a variety
of substrates other than GLP-1 that are cleaved *in vitro* by this
enzyme, which is true of subsurface peptidases in general. Their *in
vivo* significance and whether or not they are regulated *in vivo* is
very difficult to establish, which means data is needed on its long-term
safety and tolerability. In addition to establishing safety and
tolerability, Dr. Thornberrry said the focus for future agents should be
glucose-stimulated insulin secretion, as this is the mechanism by which
DP-IV inhibitors work; greater efficacy; and trying to understand what
is indeed responsible for β-cell degradation so that can be targeted in
a more rational way. Overall, these agents are expected to present many
benefits.

**Mediators of Hepatic Glucose Output**. Dr. Thornberry highlighted
these because there is some human validation for both glucokinase
activators and glucagons receptor antagonists. **Glucokinase (GK)** is a
key enzyme involved in the metabolism of glucose, catalyzing the
phosphorylation to glucose-6 phosphate in both the liver and in the
pancreas, where it is predominantly expressed. It is a member of the
hexokinase family and a rate-limiting step of glucose metabolism. Dr.
Thornberry remarked that the rationale for this target is clearly the
anticipation that dietary glucose would be absorbed and converted to
glucose-6 phosphate, resulting in enhanced hepatic glucose uptake and
decreased glucose production. Glucokinase plays a key role in the
glucose sensing in the pancreas that results in insulin secretion;
therefore, GK activation should result in production of insulin. In
summary, the combined hepatic and pancreatic effects may translate into
improved efficacy over current agents.

Dr. Thornberry stated that human validation has been provided in the way
of genetic validation. Approximately 150 mutations have been identified
in GK. Fifty percent of GK function has been observed in MODY (maturity
onset diabetes of the young) and gestational diabetes. One hundred
percent loss of GK results in neonatal diabetes, and activating mutants
have been identified by Dr. Franz Matschinsky (Matschinsky, FM. Diabetes
51:S394-404, 2002) and a number of other investigators showing increases
in fasting and 2-hour glucose in subjects with GK mutations as opposed
to their unaffected relatives. Dr. Thornberry said that it has been
demonstrated that only modest activation of GK is required to produce
beneficial effects in rodents. A two-fold increase in messenger RNA in
the liver of rodents lowered glucose and improved glucose tolerance.
Roche published data in 2003 that demonstrated pharmacological
proof-of-concept for GK activators (Grimsby et al. 2003, *Science* 301,
370).

Potential attributes and advantages listed by Dr. Thornberry included
considering GK activators as a single-agent combination therapy
affecting both the β-cell and the liver, so it could potentially be
applied to a broad range of type 2 diabetic patients with both insulin
resistance and impaired insulin secretion. It is also predicted to have
a good safety and tolerability profile and the potential to be used in
combination with insulin sensitizers, DP IV inhibitors, and metformin.

Key issues for this target are hypoglycemia and the potential for lipid
accumulation in the liver, as with all gluconeogenesis targets.

Dr. Thornberry said those present were well familiar with the following
rationale for **glucagon receptor antagonists**: glucagons have a very
important role in maintaining glucose homeostasis. Being secreted by the
α-cells in response to falling glucose, glucagons activate the hepatic
glucagon receptor, which in turn results in glycogen breakdown and
gluconeogenesis, which elevates blood glucose. Some limited
proof-of-concept in humans has been provided in a study done by Bayer
with a glucagon antagonist that demonstrated it blocked exogenous
glucagon effect in dogs and rhesus, and in man. Dr. Thornberry gave as
potential attributes and advantages that the glucagons receptor
antagonist is predicted to decrease both fasting and postprandial
hyperglycemia; is anticipated to have a relatively clean safety profile;
is an oral agent; and has good potential for use in combination. The key
issue is its potential for hypoglycemia.

In summary, Dr. Thornberry said the agents furthest along in development
are the dual PPARα/γ agonists, the GLP-1 analogs, and the DP-IV
inhibitors. There are a variety of other mechanisms that either are or
may be in early development, including SPPARγMs, GK activators, glycogen
phosphorylase inhibitors, SGLT (sodium-glucose cotransporter)
inhibitors, glucagon antagonists, fructose 1,6 bis-phosphatase
inhibitors. The insulin receptor phosphatase looks like an attractive
target, the issue being whether or not one can truly make a phosphatase
inhibitor that has suitable properties for use *in vivo*. Dr. Thornberry
stated that chemical tractability is a big issue here, so there are
companies that instead are pursuing an antisense approach to PTPIB
(protein-tyrosine phosphatase 1B). She concluded by noting that she may
have missed some others in development, but in any event, there are a
number of promising therapies emerging.

**Immunomodulation in Type 1 Diabetes**

***George Eisenbarth, MD, PhD**, Executive Director, Barbara Davis
Center for Childhood Diabetes; Professor of Pediatrics, Medicine, and
Immunology, University of Colorado, Denver*

Dr. Eisenbarth noted that we are at a somewhat unusual era in type 1
diabetes: We can predict the disease, we can prevent it in animal
models, but we do not know how to intervene yet in the disease in man.
The next decade will focus on taking therapies studied in the animal
models and applying them to humans---a major undertaking.

Dr. Eisenbarth stated that immunomodulation of type 1 diabetes is a
broad topic and referred the audience to the Barbara Davis Center's
website
([www.barbaradaviscenter.org](http://www.barbaradaviscenter.org/)) where
a book on the immunology of diabetes with teaching slides provides more
detail than he would cover in his presentation. He stressed the
importance of weighing the benefits of prevention and treatment of a
disease against potential side effects of the therapies being
considered, especially some of the immunologic therapies for diseases
like rheumatoid arthritis or multiple sclerosis. This perspective is
also critical in type 1 diabetes.

Data from the British Diabetes Association Cohort Study (1972-93), cited
by Dr. Eisenbarth, indicated almost a 3 percent excess mortality in
these young individuals ages 1 through 29, compared with the general
population. Primarily these are metabolic deaths, not renal or
cardiovascular disease. Dr. Eisenbarth's point was that the immunologic
therapies thus need to be weighed against current problems with therapy,
but hopefully, other therapies such as continuous glucose monitoring,
will make inroads into these metabolic problems.

Dr. Eisenbarth stated that it is crucial in developing therapies to
understand that type 1 diabetes pathogenesis is basically a balance
between pathogenic T-cells and regulatory T-cells as illustrated by Dr.
Aldo Rossini's teeter-totter schema. Regulatory T-cells used to be
called suppressor T-cells; but now it is clear that there are regulatory
T-cells that are essential for immunoregulation in humans. Dr.
Eisenbarth gave as an example a mutation of the FOXP-3 gene that removes
a major subset of regulatory T-cells. Infants with this rare syndrome
die, often in the first months of life, with overwhelming autoimmunity
and can develop diabetes at age 2 to 3 days. Introduction of that FOXP-3
gene into a regular T-cell turns it into a regulatory T-cell.

Dr. Eisenbarth presented a more complex slide from Dr. Len Chess that
depicted many of the players in the development of β-cell destruction,
in particular, the antigen-presenting cells, with their HLA molecule
that present peptides to CD4 regulatory T-cells. Cytotoxic T-cells can
directly destroy β-cells or influence other portions of the innate
immune system that can produce cytokines that destroy β-cells. Dr.
Eisenbarth pointed out there are many therapeutic opportunities in the
immunopathophysiology of diabetes, and drugs are being developed for
many of the specific molecules of this immune regulatory system.

In summarizing the general paradigm for prevention and treatment of type
1 diabetes, Dr. Eisenbarth listed the major steps as:

-   Identify genetic susceptibility.

-   Detect initial presence of autoantibodies.

-   Monitor metabolic decompensation.

-   Treat overt disease prior to morbidity and mortality.

-   Pursue basic and clinical research to develop prevention
    interventions.

**Genetic Susceptibility**. At the first stage of genetic
susceptibility, the major determinant currently known is genes within
the major histocompatibility (MHC) complex. Alleles of these genes make
up about 50 percent of the familial risk of type 1 diabetes. Explaining
the nomenclature, used in describing the complex, Dr. Eisenbarth said
each different polymorphic HLA molecule is given a number that
represents the amino acid sequence of that molecule. Risk can be
ascribed to a given allele, like DR4, but on that same chromosome, right
next to DR4, there is DQ8; these molecules present peptide antigens and
one forms a high-risk haplotype. What really determines risk of type 1
diabetes in this region is a person's genotype, the chromosomes
inherited, one from each parent. The highest risk genotype for type 1
diabetes in the United States is a DR3/4 heterozygous individual with
DQ8/2. With a different DR4 subtype, for instance, DRB1\*0403, Dr.
Eisenbarth explained that about three or four amino acids would be
changed, thus greatly reducing risk.

Studies based on this genetic susceptibility information include the
Diabetes Autoimmunity Study in the Young (DAISY) in Denver, BabyDiab in
Germany, Diabetes Prediction and Prevention (DIPP) in Finland, and now
NIDDK/CDC's The Environmental Determinants of Diabetes in the Young
(TEDDY). From DAISY, Dr. Eisenbarth spoke of identifying at-risk
children at birth by determining HLA genotypes from umbilical cord
blood. The highest risk genotype (DR3/4) is present in about 2.4 percent
of children, of whom 1 of 15 will develop type 1 diabetes, approximately
half of all children in Denver developing type 1 before the age of 5.
The genotype also decreases the age at which the disorder manifests. In
DAISY, first-degree relatives of a sibling or offspring of a parent with
type 1 diabetes are also followed from birth.

**Autoantibodies**. A series of semi-automated assays for
anti-autoantibodies are now available. Some are in a modified ELISA
format, but most are high-sensitivity and high- specificity assays.
Dr. Eisenbarth listed the three autoantibodies that are primarily
measured as insulin, glutamic acid decarboxylase, and ICA512 (IA-2)
autoantibodies.

Development of autobodies can be followed in the at-risk children
identified at birth. Dr. Eisenbarth said insulin autoantibodies can be
present at 9 months of age---or first develop at 40 years of age. He
added that the practical utilization of this information is limited,
because we do not have the ability currently to prevent type 1 diabetes.
However, at-risk children in a close follow-up study as in DAISY do not
present with classical ketoacidosis. For the children in the DAISY study
versus a control population, 1 out of 30 children needed to be
hospitalized at the onset of diabetes because of ketoacidosis or some
other major metabolic problem versus about 40 percent of the general
population.

The DPT-1, in which close to 100,000 relatives were screened and
autoantibodies measured, clearly illustrated that progression to
diabetes can be predicted based on the number of autoantibodies
expressed. Dr. Eisenbarth emphasized that the DPT-1 data show that risk
can be identified and thus we can do trials for prevention in such a
cohort. He added that DPT-1 also revealed that, even given the presence
of autoantibodies, there are also HLA alleles that prevent the
development of diabetes. For example, DQB1\*0602, DR2, even when it's
combined with the highest risk alleles, like DR4, has a very low
progression to diabetes amongst antibody-positive individuals.

Dr. Eisenbarth next referred to the best studied animal model in type 1
diabetes, the NOD (non-obese diabetic mouse). NOD mice, just like young
children, make insulin autoantibodies, beginning somewhere between 4 and
8 weeks of age. The insulin autoantibodies actually peak and go down,
and then the blood glucose rises; thus the autoantibodies are a
predictor and a surrogate, although obviously not perfect as shown by an
NOD mouse that never expressed insulin autoantibodies but did progress
to diabetes.

Target antigens have been identified in humans and in animal models,
especially at the T-cell level. Dr. Eisenbarth stated that it is
reasonably clear that autoantibodies per se are not the direct cause of
type 1 diabetes, since T-cells and T-cell clones can transfer the
disease. Among the autoantigens in the NOD mouse, insulin is prominent.
Dr. Eisenbarth gave the example of a peptide of the insulin molecule
recognized by pre-diabetic, diabetogenic T-cells in the NOD, the B:9
through 23 sequence, that can be used to prevent diabetes or to induce
diabetes. He added that a difficulty with the NOD mouse is that it is
perhaps too easy to prevent diabetes given more than 100 reported
preventive therapies., For instance a single injection of the B:9-23
insulin peptide at 4 weeks of age prevents diabetes in 90 percent of the
mice. Dr. Eisenbarth recommended that more robust models be developed
such as an insulin-2 knockout, in which the insulin gene expression
within the thymus is removed creating a more robust, more diabetogenic
NOD mouse. In contrast to prevention of diabetes, Dr. Eisenbarth said
that giving the same B:9-23 peptide to a normal BALB/c mouse induced
insulin autoantibodies within weeks. The antibodies reacted with insulin
and not with the inducing peptide, suggesting that, given the genetics
of a normal BALB/c mouse, the mouse is ready to begin part of the
process that leads to type 1 diabetes, and with genetic tricks, a mouse
is produced that responds to the peptide by developing diabetes.
Dr. Eisenbarth cautioned that in the area of immunologic vaccination
there is much to be learned.

**What Is Missing?** Dr. Eisenbarth repeated his earlier statement that
we can now predict type 1 diabetes, but we do not have therapies to
prevent the disorder as illustrated by the parenteral study of DPT-1,
where the prediction was accurate, but there was no effect on delaying
the disease.

Dr. Eisenbarth stated the main thing missing today is an assay for
pathogenic T-cells. There are several assays being developed---tetramer,
ELISPOT. He cited a study from Drs. Trudeau, Tan, and Santamaria (JCI,
111:217-223 2003) indicating a T-cell assay that would help in
predicting diabetes. Basically, a tetramer takes the MHC molecule,
places a peptide in it, and then it binds to the T-cell receptor, so
T-cells can be quantitated and the specific autoantigenic peptide can be
seen. In this study, the NOD mice that went on to diabetes had T-cells
reacting with the peptide of an islet-specific molecule called IGRP
(islet glucose-related phosphatase), whereas the NOD mice that did not
progress to diabetes did not have those circulating cells. Dr.
Eisenbarth thought that, eventually, the same peptide cellular
reactivity needs to be defined in the human, which is a very difficult
area of research. He suggested that the T-cells will have to be found in
the pancreas because it is too hard to find them in the peripheral blood
due to their extremely small numbers. One possible source of these
disease-causing T-cells might be from programs that screen cadaveric
donors for autoantibodies to obtain a pancreas. Then the peptides the
T-cells recognize must be defined and assays developed for those
T-cells.

Dr. Eisenbarth presented guidelines from the Immunology of Diabetes
Society for designing trials for each stage of the development of type 1
diabetes and suggested it would be helpful if trials were designed based
on specific guidelines, even though arbitrary, in order to better
compare data across trials and have more confidence in the results of
the trials. Dr. Eisenbarth said a key factor would be the use of
C-peptide as a marker of loss of β-cells, since loss of β-cells is
primary in this immune-mediated disorder.

Noting that there are many in process trials of non-antigen-specific
immunotherapies, Dr. Eisenbarth said the furthest advanced probably is
the anti-CD3 trials of Dr. K. Herold and Dr. L. Chatenoud. The anti-CD3
antibodies are, at this point, thought to work not simply by depleting
T-cells, which has the effect of clearing the insulitis, but of
stimulating regulatory T-cells, in particular T-cells that are making a
cytokine TGF-β. There are also trials in newborns, with dietary
interventions, that are underway or about to occur. Results of these
non-antigen-specific therapies are still forthcoming.

Listing some of the trials for antigen-specific therapies, Dr.
Eisenbarth mentioned the parenteral insulin trial that had no effect and
the DPT-1 oral insulin trial, which overall had no effect, although a
subgroup analysis of those individuals with the highest levels of
insulin autoantibodies suggested the possibility of an effect that the
TrialNet group will follow up. There is a trial at the Joslin Diabetes
Center of the insulin B chain; also altered peptide ligands in the B9
through 23 peptide; trials of hGAD from Diamyd;, and trials of heat
shock protein peptides. There are a lot of potential agents to be
evaluated. Dr. Eisenbarth particularly noted that to have an immunologic
vaccination that prevents or delays diabetes would be a remarkable
accomplishment. Multiple sclerosis is the only disease having an
FDA-approved therapy in this realm with an unusual peptide.

In summary, Dr. Eisenbarth stressed that prevention of diabetes and
prevention of β-cell loss after the onset of type 1 diabetes is very
important. Predicting high risk is, in quotes, "easy." Although it can
be debated that not everyone who has a single autoantibody progresses to
diabetes and probably not everyone with multiple autoantibodies will
develop diabetes, the probability is over 90 percent. There are multiple
therapies in animal models. There is an explosion of immunotherapies in
man. Dr. Eisenbarth pointed out the tremendous change in comparing the
PDR (*Physicians Desk Reference*) listing for therapies for immunologic
disorders from 20 years ago to what is in the PDR now and what will be
in the PDR within the next 10 years. He believes it is only a matter of
time before there is an immunotherapy for chronic active insulitis, just
as there is now a therapy for chronic active hepatitis. People with
chronic active hepatitis do not have overt disease, but they are likely
to develop overt disease. As outcomes, Dr. Eisenbarth listed overt
diabetes and C-peptide and suggested that a short-term outcome of
prevention of hypo- and severe hyperglycemia will be available within a
2-year trial because of improvement in continuous glucose monitoring. He
commended the international collaboration represented by the ITN and
TrialNet and the public support provided by NIH.

**Discussion**

Dr. Fradkin, NIDDK, asked Dr. Thornberry and Dr. Eisenbarth to suggest
how NIH could best foster bench-to-bedside translation of basic
discoveries of NIH-supported scientists into development of
therapeutics. Dr. Thornberry replied that continuing support for basic
research in β-cell dysfunction and support of academic endeavors to
identify next generation targets would be extremely helpful. Most
pharmaceutical companies increasingly have collaborations with external
academic investigators in order to exploit the genomic revolution and
proteomics and better understand new targets for insulin sensitization
and preservation of β-cell function.

Dr. Eisenbarth responded that he understood that NIH, and particularly
NIDDK and the National Cancer Institute (NCI), had developed a mechanism
to further pharmaceutical drug development, including animal toxicity
testing, which is not easily done in an academic laboratory. He added
that partnering with the pharmaceutical industry is helpful but
sometimes their priorities differ with those of the academic researcher.
The availability of a parallel system to facilitate development of a
drug without pharmaceutical support is, therefore, very useful.

Dr. Fradkin explained that Dr. Eisenbarth was referring to a newly
developed program (T1D-RAID) in which NIDDK is partnering with NCI to
use a mechanism the institute had developed for cancer---rapid access to
intervention development---and to make those resources available for
type 1 diabetes, particularly because type 1 is a smaller market than
type 2 and thus commands less industry interest and resources in
developing therapeutic agents.

In response to a request from Dr. Laura Shawver, Phenomix Corporation,
about other DP-IV family members, Dr. Thornberry said DP-IV, a member of
an emerging protease family, is the only enzyme for which function is
well understood. There is no clear evidence that any of the other
enzymes play a role in glucose control. The issue of selectivity is an
open one right now, and one that Merck and others are working very hard
to resolve.

Dr. Nathan asked Dr. Eisenbarth to answer an either-or situation. Given
that type 1 diabetes evolves over time, screening is difficult, and only
a small percent of those at risk develop the disease, but the major
burden for those who do lasts over a lifetime, would Dr. Eisenbarth
choose to address the disease during its early development, pre-clinical
stage or reverse it at a later stage?

Dr. Eisenbarth said he preferred to do both because there are therapies
that work only in the pre-diabetic phase and therapies that work in the
new-onset phase, which is a tremendous spectrum. Although called
new-onset diabetes, studies like DAISY suggest that people have had
their diabetes for 6 months to 1 year before identified. People vary
greatly in the amount of C-peptide that remains. There are times to
intervene even in the genetically susceptible by simply changing the
diet. He agreed that screening solely for type 1 diabetes on a
population level would be expensive; however, in the future it will
probably fall into a category of many other immune-mediated diseases
that would be screened for at the same time. For example, as a public
health measure, Colorado screens newborns for more than 20 different
disorders. As this public health policy and practice develops, the
screening cost per disease will come down, because of the package
approach.

Dr. Amy Rosenberg, FDA, asked Dr. Thornberry if the to GLP-1 analogs
were neutralizing and also what the normal circulating levels of GLP-1
are and do they fluctuate. Dr. Thornberry answered that she understood
they had no effect on efficacy and there were no safety concerns thus
far. Secreted in response to food intake, GLP-1 circulates at very low
levels. Total GLP-1 postprandially is about 20 to 25 picomolar, and a
large amount is degraded peptide, so at any given time, perhaps only 20
percent is actually active. Fasting levels are closer to 5 picomolar or
less. Dr. Rosenberg commented that this probably would explain the low
level of immunologic tolerance.

In reply to Dr. Rosenberg's request to comment on the finding that
T-regulatory cells are CD25 positive, and antibody to CD25 is actually
salutary for transplant rejection, Dr. Eisenbarth said there are many
different subsets of T-regulatory cells and we do not have great markers
for them nor understand what some of our therapies are doing,
particularly antibodies to CD25 cells. There are CD4+ and a CD25+
regulatory cell that is extremely important, but T-cells, as they become
activated, also express the CD25 marker. Since there is efficacy of
those markers, Dr. Eisenbarth suggested they are probably not doing
anything near like what a FOXP-3 gene knockout does.

Dr. Thornberry responded to a question from Dr. David Karph, Metabolex,
Inc. and Stanford University, that she had no specific data suggesting a
differential role for partial PPARγ agonists in the efficacy side on
lipid parameters or on inflammatory markers of cardiovascular disease.
Based on pre-clinical data, she thought that, at least in rodents, one
could anticipate achieving efficacy comparable to that of full agonists
with respect to glucose for partial γ agonists, but she could not
comment on the lipid effects.

Dr. Simeon Taylor, Bristol-Myers Squibb, commented that currently there
are at least five approved mechanisms for treatment of type 2 diabetes
in many compounds and from Dr. Thornberry's presentation, there could be
10 or 15 more approved over the next few years. He wondered how
physicians were going to decide on the best way of treating patients. He
asked if Dr. Thornberry envisioned a time when there would be either
pharmacogenomics or biomarkers or some other scientific evidence-based
way to select who was more or less likely to benefit or to have toxicity
from a particular mechanism. She said that was one of the promises of
microarrays, for example. Scientists are trying to use microarrays to
categorize various subsets of diabetics and pre-clinically to look at
whether or not there are markers to anticipate potential toxicities. It
remains to be seen if ultimately we can predict responders and
non-responders.

Dr. Fradkin offered the idea that, potentially, some of the samples
being sent to repositories from clinical trials can subsequently be used
to examine those kinds of questions after the potential predictors are
identified. She noted this concept has been very exciting in the cancer
field recently.

Dr. Louis Herlands, Chief Operating Officer, DARA Biosciences, Inc.,
asked Dr. Eisenbarth what the potential therapeutic implications were of
a prevalent population of CD8+ T-cells in the NOD mouse---possibly
amounting to as much as 40 percent of the CD8+ T-cells in the islets,
possibly more---recognizing IGRP. Dr. Eisenbarth answered that this is
crucial to the antigens to which the dominant immune response is
directed and raises several questions. For instance, if you knock out
the IGRP gene, which is doable, and a number of groups are in the
process of doing it, will that completely prevent the development of
diabetes? Knocking out the insulin-1 gene reduces the development of
diabetes by almost 90 percent. A major question is, "Is it multiple
different antigens that are all crucial, or is it just one antigen whose
recognition is crucial to the disease, whereas other reactivities mirror
the disease as it is occurring?" Obviously, IGRP is a very important
target to look at in the human. Thus far, there are no autoantibodies to
IGRP, and T-cells are just being studied in relationship to the IGRP
molecule. Dr. Eisenbarth asked, "Will we be able to develop a predictive
assay with IGRP? Will creating tolerance to the IGRP molecule prevent
the disease?"

Dr. Jerry Palmer, University of Washington, commented that we normally
divide studies into classic type 1 and type 2 diabetes trials. He asked
how often does the type 1 autoimmune attack on the β-cell participate in
diabetes in general, both type 1 and type 2. This could potentially be
very important therapeutically. Dr. Eisenbarth noted that actually there
are good studies for latent autoimmune diabetes in adults (LADA).
Between 5 and 15 percent of individuals who are called type 2 diabetics
really have anti-islet autoantibodies, lose C-peptide faster, and, in
his opinion, their genetics reflect this and he would call them a type 1
diabetic. On the other side, insulin resistance is likely a key
determinant when someone presents with diabetes and is losing β cells.
In the DPT-1 study, some children who were becoming diabetic had fasting
insulins of 50 or 60; therefore, it might be possible to treat those
children with an oral agent for several years, even without affecting
their autoimmunity, which would be an advantage for those children. He
added that as Dr. Palmer had mentioned, we have classic diseases, but
there is no reason that they do not overlap.

Dr. Fred Murray, Aventis Pharmaceuticals, followed up Dr. Palmer's
remarks by saying if one takes the BB rat, which is an animal model with
type 1 diabetes, and breed it with the Zucker rat, which is an obese
animal model, the result is the BBZ rat that in the male has type 2
diabetes and in the female has impaired glucose tolerance. Dr. Murray
also presented the question: Since it is known or believed that type 2
diabetes and cardiovascular disease are both inflammatory diseases, and
some agents, like the PPARs, have anti-inflammatory effects as well as
insulin-sensitizing effects, are there inflammatory markers we can use
to identify a pre-diabetes condition that occurs before impaired glucose
tolerance? For instance, there are several ongoing trials to prevent
diabetes in those with impaired glucose tolerance. Some of the problems
there have to do with the hypoglycemia seen in type 1 diabetes. If there
were better biomarkers, perhaps cytokines, to identify early diabetes,
then trials and agents would be safer.

Dr. Eisenbarth replied that we have the techniques now to look across a
broad spectrum of cytokines for inflammatory changes in both type 1 and
type 2 diabetes and in the pre-diabetic group. Dr. Thornberry agreed
that there is a great deal going on in the inflammation arena about
which we need to be aware.

Dr. Alex Szidon, DARA Biosciences, commented that one of the issues with
type 2 diabetes is the number of target tissues for interventions to
regulate metabolism as a whole. For example, recently, there have been
findings regarding interventions at the hypothalamus actually affecting
both gluconeogenesis in the liver and food intake. He asked Dr.
Thornberry where she looked to affect metabolic change and what her
general sense was of intervening at targets in the hypothalamus to treat
multiple facets of the disease. Dr. Thornberry agreed that this was an
emerging area of interest and there is accumulating evidence that
lipogenic targets may indeed control effects such as feeding and glucose
metabolism via effects in the brain. AMPK, is a recent example that has
been implicated in controlling metabolism via its effects in the brain.
Dr. Thornberry felt that it is too early to know if there are going to
be good targets there and whether or not it will be consistent to target
them both in the periphery and in the brain.

Dr. Christopher Saudek, The Johns Hopkins University School of Medicine,
asked what the current thought was on the so-called 1B or non-autoimmune
type 1 diabetes. Dr. Eisenbarth said that, for the most part, if there
is not an identified genetic mutation, then the disorder is classified
either type 1A or type 1B. The trouble is, according to Dr. Eisenbarth,
that he is not sure just what he would classify as a type 1B diabetic.
Reports from Japan, where they have a low percentage overall of type 1
diabetes, report a significant percentage of patients with what they
call fulminant diabetes. These are patients, some of them adults, who
present with a normal HbA1c and an extremely elevated blood glucose,
which is rarely found in the United States. Originally, it was proposed
that they were an initial example of type 1B, but it turns out their HLA
reflects the HLA of high risk for type 1A diabetes in Japan and they
have infiltration, especially of the acinar pancreatic tissue by
lymphocytes. Dr. Eisenbarth said the question is whether these
individuals are a form of type 1A that is extremely fulminant and
without time to make the auto-antibodies. On the other hand, there are
other surprising results that have not been factored in yet, such as the
detection or evidence of chronic enteral viral infection within β-cells.

In response to the question of whether there is a role for antibodies
and their ability to cause epitope spreading and enhanced antigen
presentation in T cells and whether there might be a ping-ponging
effect, Dr. Eisenbarth said he thought both B-lymphocytes and antibodies
might well participate in the disease. There is good evidence in the NOD
mouse that antibodies are important to development of the disease. If
there are no transplacental antibodies, the incidence of diabetes goes
down by about 90 percent. Also, B-lymphocytes are potentially very
important for antigen presentation.

Dr. Jose Caro, Aventis Pharmaceuticals, asked about the relative
importance of different antibodies as predictors of type 1 diabetes
(i.e., is anti-GAD (glutamic acid decarboxylase) more important than
anti-islet). The response was that there are fine distinctions and
specific antibodies do make a difference. At first cut, probably the
number of auto-antibodies is very important. The IA2 auto-antibodies are
the most predictive. They are usually associated with the presence of
the other auto-antibodies and, in some ways, they are the easiest to
measure. This might depend on assay ability. The insulin auto-antibodies
are highest in the youngest children developing type 1 diabetes. There
is a very peculiar log inverse linear relationship. GAD, if anything, is
fairly flat and just the opposite and IA-2 is shallow. So the specific
antibodies make a difference.

Dr. Caro asked Dr. Eisenbarth if in the DAISY cohort, did they look at
the number of children who were antibody-negative initially and then
developed positive antibodies over time and ultimately developed
diabetes. Dr. Eisenbarth answered that, if you measure early enough, say
at 3 months, most are antibody-negative and then develop the antibody
later. As best as they could tell, children are not born with the
antibodies, although there is transplacental passage for a group that is
probably not pathogenic. He said that if the fundamental question was
what is the best timing for measuring antibodies, at what ages, this had
not absolutely been defined. Dr. Eisenbarth's guess was antibodies can
be picked up in the first 9 months of life, and in very young children,
an annual testing might be necessary.

In response to a question about investigation of altered antigen
presentation mechanisms in high-risk genotypes, Dr. Eisenbarth said
there is a debate in the field about whether or not there is less
stability in the highest risk genotypes, but he felt the bulk of the
data is that these HLA molecules are normal, even though they are
creating diabetes susceptibility. For instance, the haplotype that
prevents 98 percent of type 1 diabetes is the high risk haplotype for
multiple sclerosis. It appears that these HLA molecules are determining
which target antigen and thus which tissue, rather than being abnormal
in overall function.

Dr. Alain Baron, Amylin Pharmaceuticals, referred to the seriousness of
type 1 diabetes as evidenced by Dr. Eisenbarth's data on the high
mortality rate in patients between the ages of 20 and 30. This brings up
the risk benefit issue regarding novel therapies, when the only current
agent is insulin. He asked where Dr. Eisenbarth would rank type 1
diabetes on a scale of 1 to 10 with cancer ranking as a 7 or 8. Dr.
Eisenbarth said therapies needed to be weighed against problems with
diabetes from age 0 to 30, even before the chronic complications occur.
Type 1 diabetes is a difficult disease to treat. It completely changes
family members' lives. The risk of hypoglycemia is a major limitation as
efforts are made to lower blood sugar. The Barbara Davis Center cares
for about 3,000 children and 2,000 young adults. Over the past decade,
there have been at least 20 deaths in that cohort, so this is a very
serious disease for anyone. Dr. Eisenbarth stressed that if there was no
hypoglycemia and there was good metabolic control, the mortality rate
would change dramatically.

**Session III: Beta Cell Preservation**

*Moderator: Ilan Irony, MD, Medical Officer, Division of Therapeutic
Biological Internal Medicine Products, Center for Drug Evaluation and
Research, FDA*

**Assessment of Beta Cell Preservation in Type 1 Diabetes**

***Jerry P. Palmer, MD,** Professor of Medicine and Director of the
Diabetes Endocrinology Research Center, University of Washington,
Seattle; Director of Endocrinology, Metabolism, and Nutrition, Veterans
Affairs Puget Sound Health Care System, Seattle*

Dr. Palmer began by stressing that the target of the type 1 auto-immune
disease process is the pancreatic β-cell, so it makes excellent sense to
try to preserve the function of that target cell. Studies of the
preservation of β-cell function fall into two categories: intervention
studies with persons who already have type 1 diabetes and prevention
studies for those at risk.

Dr. Palmer noted that intervention studies have, with varying degrees of
success, tested azathioprine and steroids; cyclosporin; anti-CD3, an
antibody to T-cells; and DiaPep 277, a fragment of heat shock protein. A
trial of MMF (mycophenolate mofetil) and DZB has begun in TrialNet, and
a future trial of anti-CD20, a monoclonal antibody directed at β -cells,
is under consideration.

Of the many studies of cyclosporin, Dr. Palmer considers the
Canadian-Diabetes-France (Plus) Study to be the most important because
patients were randomized, received intensive therapy, and if patients
went into remission, rather than stop the cyclosporin, it was continued
until they again went out of remission. The results showed that
immunomodulatory therapy in type 1 diabetes can work. Almost 50 percent
of patients who received cyclosporin versus placebo went into remission,
defined as being insulin-free. Remissions also were longer in the
patients treated with cyclosporin versus placebo. Although these results
are remarkable, Dr. Palmer explained that the medical community has
essentially decided that cyclosporin therapy is too toxic a way to try
to alter the type 1 disease process.

As Dr. Nathan had said earlier, the DPT-1 prevention study showed that
parenteral insulin was not effective, nor was the overall trial for oral
insulin, although in a subset of persons with high auto-antibodies,
there may have been a treatment effect and that is being followed up. A
large-scale European trial of nicotinamide also was unsuccessful in
preventing type 1 diabetes. The large international Trial to Reduce the
Incidence of type 1 Diabetes in the Genetically at Risk (TRIGR), led by
the National Institute of Child Health and Human Development (NICHD), is
asking whether the first formula that an infant uses, whether
cow-milk-based or not, has an effect. The primary endpoint of TRIGR is
the development of antibodies and then over 10 years the development of
type 1 diabetes.

TrialNet, an NIDDK-led international network of 18 regional cooperative
clinical centers in the United States, Canada, Europe, and Australia,
has as its goal to alter the type 1 disease process in those who already
have disease, in relatives at risk of disease, and in those who have a
high genetic risk. It also will further define the epidemiology, natural
history, and risk factors of this disease. The network has a
coordinating center and core laboratories in genetics, immunology,
metabolism, biochemistry, and viral infections. Dr. Palmer heads up the
β-cell function core laboratory.

TrialNet selected measurement of C-peptide as the endpoint for its
intervention strategies. Dr. Palmer listed several of the advantages of
C-peptide as an endpoint. In the structure of the proinsulin molecule,
C-peptide connects the α- and the β- chains of insulin. There is a
one-to-one molar ratio of insulin to C-peptide in terms of secretion.
Insulin undergoes a variable and substantial first-pass extraction in
the liver of up to 50 percent but C-peptide does not. For a number of
years, there have been excellent assays that accurately measure the very
low levels of C-peptide in persons with type 1 diabetes. These assays
are effective even when treating the patient with insulin, and also the
insulin auto-antibodies that patients develop do not interfere with the
assays. TrialNet also is also planning to test omega-3 fatty acids,
GLP-1, and oral insulin.

Dr. Palmer explained that the literature can be confusing because there
are two major ways c-peptide is reported, either as ng/ml or nmol/l;
therefore, it is important to pay attention to which of the units the
reader is seeing. The detection limits of the standard assays is 0.1 ng
or 0.03 nmol/l. Dr. Palmer stressed that a very important point is that
the half-life for insulin and C-peptide are dramatically different,
which is important in interpreting C-peptide values. For insulin, it is
about 3 minutes; for C-peptide it is closer to 35 minutes.

Factors that affect residual β-cell function include age at diagnosis,
duration of diabetes, metabolic control, and marked inter-individual
variation. Dr. Palmer cited data from TrialNet showing that, in terms of
age at diagnosis, C-peptide is lower in those who are in the 12- to
17-year-old age group than in those over 18, and it is much lower in
those who were diagnosed prior to age 12.

C-peptide was an entry criteria for the DCCT with the cut-point for
entry being stimulated C-peptide of 0.5 nmol/l. Mixed meal tolerance
tests (MMTTs) were performed on 3,736 type 1 diabetic patients to
identify the 1,441 patients who ultimately participated in that study.
Dr. Palmer showed two slides that plotted the C-peptide levels in those
screened, one for those diagnosed over the age of 18 and one for those
diagnosed under the age of 18. He noted that a remarkably large
proportion of people (48 percent) who had type 1 diabetes for up to 5
years according to their physicians' diagnoses after the age of 18,
still had meaningful and biologically important C-peptide. For those
diagnosed under the age of 18, the values tended to be lower, although
again there were a lot of individuals with C-peptide above 0.2 nmol/l, a
level that has been shown in a number of studies to be associated with
better diabetes control and less complications.

In the DCCT, those individuals who had diabetes from 1 to 5 years and
C-peptides between 0.2 and 0 .5 nmol/l were brought back each year for a
follow-up mixed meal stimulation test. Dr. Palmer said the control in
the DCCT had a dramatic effect on C-peptide levels. For the 303
individuals meeting the criteria stated above and randomized to
intensive therapy versus conventional therapy, the intensive group had a
57 percent reduction in risk of C-peptide falling below 0.2. Dr. Palmer
emphasized that DCCT is the largest and best study showing that
intensive glycemic control is a powerful means to protect underlying
β-cell function.

In the feasibility stage of the DCCT, Dr. Palmer said one of the things
asked was, "How much C-peptide does it take to be important in terms of
metabolism?" At the time of screening, patients were divided into those
with very low C-peptides, those between 0.05 and 0.1, 0.1 to 0.2., and
above 0.2. Patients above 0.2 had substantially lower fasting glucose
and HbA1c levels. There was evidence for a dose-response curve, because
even though glycemic control becomes significantly better at 0.2 versus
0.1 nmol/l c-peptide,, it took less insulin to achieve the same degree
of control with stimulated c-peptide of 0.1 nmol/l. Similar data were
observed in a later stage of the DCCT. In intensively treated patients
who were defined as non-responders (i.e., with C-peptide less than 0.2)
or responders, the responders had lower HbA1c. Dr. Palmer described what
he called a virtuous cycle as opposed to a vicious cycle: Better
diabetes control leads to less β-cell damage, less β-cell damage
preserves β-cell function, which leads to better diabetes control.

Dr. Palmer presented DCCT data regarding the 3+ step change in
retinopathy progression that showed that the intensely treated
responders, who achieved β-cell preservation as measured by C-peptide
levels, had a dramatically greater risk reduction than the
non-responders. In another analysis of DCCT data, Dr. Palmer showed that
those who sustained their C-peptide levels from entry to 1 year at 0.21
to 0.5 had a 4.6 times difference in retinopathy and a 4.4 times
difference in albuminuria as a measure of nephropathy. Another
observation from the DCCT is that not only is there better HbA1c and
less complications when C-peptide is preserved (and thus β-cell
function), but the Achilles heel of intensive therapy, namely
hypoglycemia, is also helped. In the responders in the intensive
treatment group (those with C-peptide above 0.2), there was a 62-percent
risk reduction in hypoglycemia with coma and seizures.

Dr. Palmer said there is additional data (some of the best from Dr.
Christian Binder) that demonstrates that stimulated C-peptide around 0.2
is the level at which differences in ease of metabolic control and
improvement in complications are clearly seen. To show the relationship
between C-peptide and hypoglycemia, Dr. Palmer presented data from a
Japanese study (Diabetes 37:81-88, 1988) that used what the researchers
called a supersensitive assay, but was really an extraction method. The
study recruited patients who were C-peptide negative in a standard assay
and divided them into those who were responders and non-responders to
C-peptide with their supersensitive assay and induced hypoglycemia in
these individuals. They then measured glucose, glucagon, epinephrine,
nor-epinephrine, and cortisol. The responders had less severe
hypoglycemia but they also had better measurements for the
counter-regulatory hormones.

Dr. Palmer mentioned literature covering a variety of animal and human
studies with either acute or chronic administration of C-peptide showing
that the possible direct effects of C-peptide include lowering of
diabetes-induced increased blood flow; decreased microalbuminuria,
improvement in nerve conduction velocity and autonomic function, and
augmented glucose utilization. Thus, in addition to being a biomarker

Dr. Palmer's "take home" home messages about C-peptide were the
following:

-   Excellent assays are available.

-   C-peptide levels are higher than commonly assumed many years after
    diagnosis of type 1 diabetes, contrary to the textbooks that say
    C-peptide is undetectable 5 years after onset of type 1 diabetes.

-   Glycemic control preserves C-peptide.

-   Preserved C-peptide results in improved glycemic control.

-   Higher C-peptide results in less retinopathy and nephropathy.

-   Higher C-peptide results in less hypoglycemia.

-   C-peptide may have direct beneficial effects beyond being a
    biomarker for β-cell function.

In conclusion, Dr. Palmer listed several ongoing activities on C-peptide
as the primary outcome measure for type 1 diabetes clinical trials to
preserve β-cell function. The Immunology of Diabetes Society published
recommendations (Diabetes 52:1059-65, 2003). The report of an American
Diabetes Association-sponsored workshop on markers that could be used
for type 1 intervention studies was recently published (Diabetes
53:250-264, 2004). Currently there is a Wet Workshop coordinated by the
University of Missouri on the optimal assay for C-peptide and asking how
it can be standardized so that results are comparable from one lab to
another. There is an international program comparing the MMTT, the test
usually done on this side of the Atlantic versus the glucagon-stimulated
test (GST), the test done in Europe, to determine how comparable they
are and whether one test is preferable to the other.

**The Case for β-Cell Preservation in Type 2 Diabetes Mellitus**

***Steven Kahn, MB, ChB**, Professor of Medicine, Division of
Metabolism, Endocrinology, and Nutrition and Associate Director,
Diabetes Endocrinology Research Center, University of Washington,
Seattle; Director of Research and Development, Veterans Affairs Puget
Sound Health Care System, Seattle*

Dr. Kahn emphasized the importance of looking for markers to identify
persons early on in the development of type 2 diabetes in order to
preserve β cells and β-cell function. He also stressed the concept that
there are multiple factors that are responsible for the loss of β cells
in type 2 diabetes, which means that scientists need to start thinking
"outside the box" about how to handle the potential causes of reduction
in β-cell mass that occurs in type 2 diabetes.

Dr. Kahn cited data from the UKPDS showing that people with type 2
diabetes at time of entry into the study only had 50 percent of their
β-cell function remaining as measured by the HOMA method. During the
6-year follow-up, β-cell function continued to decline. Assuming that
the loss of β-cell function is linear, if one performed a linear
regression and extrapolated this data back, one could predict that
β-cell function was last normal over a decade prior to the presentation
and enrollment into the study. Mr. Kahn noted that data such as that
from the UKPDS and other studies is a basic reason for the increased
focus on β cells.

The acute insulin response to glucose, a measure of the ability of the β
cell to release insulin in response to an intravenous injection of
glucose was used to highlight the deficit in individuals with type 2
diabetes. Dr. Kahn demonstrated this with a slide showing the response
of a group of healthy control subjects and a group of persons with type
2 diabetes who were given a glucose injection. In the control group,
prior to the injection, plasma insulin concentration was stable; then
there was a brisk increase in the plasma concentration in what is called
first-phase response, and then a second-phase response of decreased
concentration. In individuals with type 2 diabetes, the first phase
response was essentially absent and the second-phase response was
dramatically reduced compared to the healthy controls, indicating
deficient insulin secretion. Dr. Kahn said that enhancing β-cell
function and lowering glucose in these patients clearly would be useful,
but it would be better to intervene prior to the stage of diabetes
progression of these individuals to try to preserve β-cell function and
insulin secretion in general.

Dr. Kahn stated that understanding what modulates the β cell is
necessary to address this issue. Clearly, the β cell is modulated by the
nature of the stimulus and the magnitude of the stimulus *and by other
factors*. For example, the first-phase response is markedly diminished
in patients with impaired glucose tolerance (IGT). On the other hand,
healthy individuals have a broad range of plasma insulin responses to
glucose, thus raising the question "Why?" Studies in the late 1980s and
early 1990s tried to look at the impact of insulin sensitivity on acute
insulin response. It was recognized that when the β cell is given a
stimulus, it secretes insulin, which then acts in a variety of tissues
that are sensitive to its effect, the major organ systems being the
liver, the muscle, and adipose tissue. Because the insulin response
seemed to be so well regulated in not only bringing the glucose levels
down to normal, but also shutting off appropriately to ensure
hypoglycemia does not occur after meals, it was thought that there must
be a feedback loop that controls the magnitude of the stimulus, either
through the bloodstream or through the brain, or potentially through
both systems.

In following up the concept of a feedback loop, investigators in Seattle
looked at data from healthy individuals. The investigators related the
acute insulin response to glucose as a measure of insulin response of
the β cell to insulin sensitivity quantified using the minimal model of
glucose kinetics. Using data from the 93 healthy subjects, males and
females, they were able to show mathematically that the relationship
between insulin sensitivity and insulin response is not a straight line,
as is commonly applied to biological assessments, but instead, it is a
curve, a hyperbolic relationship. Dr. Kahn explained that this
hyperbolic relationship means that insulin sensitivity and insulin
response are related in such a manner that the product of the
two---insulin sensitivity times the insulin response---is a constant. An
example would be that an individual who had an insulin sensitivity of 10
and fell on the line that represents the 50^th^ percentile or mean
relationship for the group, for that individual, the insulin response
would be about 250, giving a product of 2,500 (sensitivity index of 10
times a response of 250). An individual with an insulin sensitivity of 5
also would have a product of 2,500, because the insulin response would
be 500. Thus low sensitivity resulted in high responses. This study
supported the concept of a feedback loop and a regulated system that was
dependent on a *healthy* individual's insulin sensitivity being a
determinant of the magnitude of the person's insulin response, assuming
that the healthy person had normal β-cell function.

The study with the healthy subjects indicated that if there was insulin
resistance at the level of the insulin-sensitive tissue, because of the
feedback loop, either through the bloodstream or through the brain, the
islet senses that there is a change occurring at the site where insulin
is supposed to act, and it simply increases its insulin output in
response to the stimulus of the glucose injection. In type 2 diabetes,
Dr. Kahn said it is thought that what happens is either failure of the
islet to respond to the stimulus or failure of the feedback loop to be
operating normally. This failure results in a reduction in insulin
secretion and development of hyperglycemia in individuals who have
insulin resistance, as seen typically with obesity.

Dr. Kahn asked how this understanding could help researchers develop
approaches to identify persons at high risk for type 2 diabetes who
could then be the subjects of intervention trials using therapies and
compounds, other than those from DPP, at early stages. He also asked how
could biomarkers be identified, such as measures of secretion and
sensitivity, that could be used as endpoints instead of full-blown
diabetes, which would reduce the need for large-scale, expensive
clinical trials.

To address the questions he had raised, Dr. Kahn referred the audience
again to the data and curve from the study with the 93 healthy
individuals. Researchers calculated percentiles for the relationship
between insulin sensitivity and insulin secretion based on a pair of
numbers for those two variables for any individual. Based on these
percentile plots and data from other studies performed in Seattle and
studies by others, Dr. Kahn illustrated the concept that diabetes is a
disease where there is both insulin resistance and a loss of the insulin
response by showing that individuals developing type 2 diabetes and
those who are at high risk have reduced percentile values for the
relationship between insulin sensitivity and insulin secretion..

To illustrate how this measurement model and the calculated percentiles
could be used to identify those who are likely to progress to diabetes,
Dr. Kahn presented data from several studies. It was previously believed
that it was insulin resistance that begets type 2 diabetes and that
persons with impaired glucose tolerance did not have a β-cell defect
because they did produce insulin. Mr. Kahn offered data from a study at
Emory University of individuals with type 2 diabetes who had an insulin
sensitivity index of 1 and an insulin response of 150 picomoles/liter
and thus were very insulin deficient. He compared this study with a
study in Chicago with individuals with IGT who were as insulin resistant
as the group from Emory but had an insulin response of 500 (producing
only 20 percent of the normal product of 2,500). Based on their insulin
sensitivity index and their insulin response, the IGT persons already
had severe β-cell dysfunction and were headed towards developing type 2
diabetes. This was also true for a group of elderly subjects in Seattle
who had an insulin sensitivity of 3, an insulin response of 250, giving
a product of 750---again far below the norm of 2,500, placing them on
the 2^nd^ percentile in the hyperbolic relationship and thus progressing
in the direction of full-blown diabetes. Other groups recognized as
being at very high risk for type 2 diabetes are women with a history of
gestational diabetes (GDM), who convert to diabetes at a rate of
approximately 10 percent per year, and women with polycystic ovarian
syndrome. Studies with these groups and with a group of relatives of
individuals with type 2 diabetes placed them at the 5^th^ (GDMs), 17^th^
(polycystic ovarian syndrome), and 25^th^ (relatives) percentiles,
respectively, showing that each group was at risk for developing type 2
diabetes.

Another Seattle study of 34 first-degree relatives of persons with type
2 diabetes looked at a variety of parameters. At baseline in 1994, their
BMI put them in the overweight category. Over the 7 years of follow-up,
they gained weight and in 2001 were classified as being obese. This
weight gain appeared to be central; waist circumference increased but
hip circumference did not change significantly. Their fasting glucose
and fasting insulin concentrations also did not change dramatically.
Their fasting glucose was well below 100. Dr. Kahn noted that fasting
glucose and progression to diabetes is a late phenomenon; therefore,
other biomarkers, possibly 2-hour glucoses, are needed to diagnose
diabetes risk and progression earlier. Over the 7 years of the study,
the 34 subjects had a 7-percent reduction in insulin sensitivity and a
16-percent decrease in acute insulin response to glucose, placing them
at the 15^th^ percentile for relationship between insulin sensitivity
and insulin secretion, in keeping with the progressive loss of β-cell
function over the follow-up period. Over the 7 years, there was also
deterioration in glucose tolerance as measured by an oral glucose
tolerance test (OGTT). In 1994, approximately 50 percent had IGT and 50
percent normal glucose tolerance. In 2002, less than 50 percent were
normal and more than 20 percent had progressed to type 2 diabetes.

Further information gained from this study of first-degree relatives
showed that those who initially had normal glucose tolerance measured by
OGTT but did not maintain this over the 7 years also initially fell into
a lower percentile (based on insulin sensitivity and insulin response)
than those who maintained their normal glucose tolerance. In other
words, they already had an abnormality in β-cell function even with
normal glucose tolerance, a point in time when no one would have
considered intervening with them or testing them in a clinical trial to
prevent progression to impaired glucose tolerance and later diabetes. In
the group that maintained normal glucose tolerance for 7 years, β-cell
function barely changed according to their insulin sensitivity/insulin
response measurements and percentiles. Dr. Kahn suggested that in
finding biomarkers of β-cell function, there is a potential to identify
high-risk individuals much, much earlier than is done currently with IGT
and to intervene with them to try to preserve β cells and β-cell
function and thus hopefully prevent type 2 diabetes.

Dr. Kahn referred to a Pima Indian study (Weyer C. et. al. J Clin Invest
104:787-794; 1999) highlighting that pathophysiology of diabetes in
Native Americans is very similar to that of other U.S. population
groups. Insulin sensitivity was measured by the clamp technique.
Thirty-one persons maintained normal glucose tolerance over the 5 years
of follow-up, and although they became more insulin resistant over time,
their β cells simply increased insulin secretion to compensate, keeping
them on their curves and thus maintaining normal glucose tolerance. In
contrast, there were a group of individuals who progressed, over the 5
years of follow-up, from normal glucose tolerance to impaired glucose
tolerance, and then on to diabetes. These individuals had a fall in
insulin secretion over time resulting in a deterioration of glucose
tolerance and also development of diabetes. Again, these individuals at
baseline had a markedly disturbed relationship between their insulin
sensitivity and their insulin secretion, which Dr. Kahn believes
indicates the presence of β-cell dysfunction. He repeated that this
marker of insulin sensitivity related to insulin secretion could
therefore identify persons with normal glucose tolerance who actually
are at high risk and who could be recruited for prevention studies
investigating a variety of agents that might preserve β-cell function
*before* they reached the high-risk category of the DPP cohort who had
impaired glucose tolerance.

In discussing the problems with the OGTT, Dr. Kahn referred to data from
an American Diabetes Association study of first degree relatives of
persons with type 2 diabetes. Of these 513 people given an OGTT at
baseline, 100 were unaware that they already had diabetes, 191 had IGT,
and 240 had normal glucose tolerance. From the early insulin response
during the OGTT, it became evident that β-cell dysfunction was a
characteristic not only of type 2 diabetes but also of IGT. Based on
this and similar data, Dr. Kahn recommended using measures that are more
sophisticated than the OGTT in order to show subtle defects very early
on before hyperinsulinemia leads to β-cell failure.

Dr. Kahn listed glucotoxicity, lipotoxicity, and loss of β-cell mass as
possible causes of β-cell dysfunction in type 2 diabetes. A study of
autopsy samples of β-cell mass from non-diabetic obese individuals
(based on BMI criteria) and non-diabetic lean individuals (Butler, AE et
al. Diabetes 52:102-110, 2003) showed that the obese persons had
substantially greater β-cell volume compared to the lean persons,
possibly as a compensation mechanism by which the obese person increased
insulin response to insulin resistance. On the other hand, obese persons
with impaired fasting glucose had decreased β-cell volume compared to
those with normal glucose tolerance. Both the obese and the lean persons
with type 2 diabetes had β-cell volume lower than that of either group
of non-diabetic subjects, indicating that there is an association
between diabetes and β-cell mass.

Why does this reduction in β-cell mass occur? One hypothesis is that
islet amyloid deposits replace β-cells in persons with diabetes. In
Alzheimer's disease, deposition of amyloid in the brain is a cause of
the mental changes in the disease. The amyloid is deposited at a local
site where a unique peptide component for those deposits is produced.
Similarly, in type 2 diabetes, in the islet amyloid deposits is the
peptide islet amyloid polypeptide (IAPP), also known as amylin, which is
a unique 37 amino acid peptide. This peptide has a critical amino acid
sequence between amino acids 20 and 29 that gives it the amyloidogenic
potential in humans. Dr. Kahn said that a problem in studying diabetes
in animal models is that, in rodents, amino acid substitutions in the 20
and 29 amino acid region of the molecule result in an inability of the
IAPP or amylin molecule to form deposits; therefore, unless the animal
is transgenic, it never develops amyloid deposits as seen in humans with
type 2 diabetes. Dr. Kahn said another important answer to be found is
why the peptide forms deposits in diabetics and not in non-diabetics.

Dr. Kahn explained that his group has developed a microscope-based
system to quantify islet area, β-cell area, and amyloid area and also
developed measures to show how much amyloid is being deposited and how
much β-cell mass might be lost. Using these measures, they can quantify
for an individual the number of their islets that have amyloid deposits,
the amount of amyloid deposited in each islet, and thus the severity of
the amyloid deposition. Dr. Kahn said that the data generated (to be
shown at the ADA meeting in June) suggest that the development of
amyloid is a diffuse process that involves all islets, and as the degree
of the disease is progressing, the degree of amyloid deposition also
increases and β-cell mass decreases in a strong inverse relationship to
the severity of the amyloid deposition. Dr. Kahn explained that what is
not known is whether the decrease in β-cell mass occurs before or after
the amyloid development; however, studies in the transgenic mouse
strongly suggest that amyloid deposits develop long before
hyperglycemia, which indicates that amyloid may play a role in the loss
of islet β-cell function in type 2 diabetes.

In the transgenic mouse, as in humans, amyloid deposition occurs
profusely and involves nearly all the islets before it starts to become
severe and replaces β cells. Increasing dietary fat in these mice
increases amyloid deposition, an interesting observation since the
incidence of diabetes is increasing and is related, at least partially,
to the environment, decreased exercise, and increased fat consumption.
Dr. Kahn added that, unlike what has been suggested with Alzheimer's
disease and mouse models of Alzheimer's disease, apoE is not a critical
component required for amyloid deposition in islets in these mice.

Dr. Kahn said that studies with the transgenic mouse are very valuable
because equivalent studies in humans would be very difficult. Other
information derived from the studies includes that in the transgenic
mice that are getting amyloid deposits, there is an increased rate of
apoptosis and the magnitude of amyloid deposition is positively
correlated to the rate of β-cell death, suggesting strongly that amyloid
formation in islets increases apoptosis and β-cell death. The amyloid
deposition also suppresses the islet's normal regenerative response to
build β-cell mass in response to the apoptosis and β-cell death. Dr.
Kahn expects that these two effects of amyloid deposition---suppression
of regenerative response and β-cell death---also occur in human type 2
diabetes with, ultimately, loss of β-cell mass, which contributes to the
development of hyperglycemia.

Dr. Kahn reviewed information from another transgenic mouse study in
which there were three groups: a control group, a growth group given
rosiglitazone, and a group given metformin. The mice were fed high-fat
diets for a year. In the control mice, 32 percent had amyloid compared
to about 10 percent of the mice in the rosiglitazone and metformin
groups, indicating that the drugs did not prevent amyloid formation in
these mice but they did reduce it. Both of the drugs also had dramatic
effects on the severity of amyloid measured by the number of islets
containing amyloid deposits and the amount of amyloid within these
islets. Dr. Kahn recommended that these studies be followed up.

Dr. Kahn pointed out that one of the difficulties of studying amyloid in
models of type 2 diabetes is that such studies take a year to produce
data. Clearly, one wants to be able to test compounds that work earlier
in the diabetes cycle. As an example, he presented a slide from an in
vitro study in which an islet from an hlAPP transgenic mouse that had
been cultured in 16.7 mM glucose already showed amyloid deposition in
just 1 week. Using this system, Dr. Kahn's group was able to test an
agent that more or less obliterated amyloid formation. This compound, of
course, is no where close to being applied to type 2 diabetes. There is
still a great deal of work to be done both by the pharmaceutical
industry and those in academia to understand the β cell, why its
function declines, and how to preserve it. He suggested that amyloid
inhibition might be one of the possible approaches down the road.

In conclusion, Dr. Kahn acknowledged the work of outstanding
post-doctoral fellows and faculty members of the University of
Washington with whom he has collaborated, the researchers from around
the world for their contributions to the field, and those people who
participate in clinical trials. He expressed his appreciation to ADA for
their support and seed money for the transgenic mouse studies, without
which the field could not be where it is today. He also thanked NIDDK
for support for clinical studies and the amyloid studies; the VA for its
career development grants, and GlaxoSmithKline, which supported the
studies in rosiglitazone.

**Discussion**

To begin the discussion, Dr. Irony asked Dr. Palmer which he considered
the best approach to use to investigate products that would protect
β-cells in patients with type 1 diabetes---C-peptide with a mixed meal
tolerance test or a glucagon stimulation test. Dr. Palmer responded that
part of the reason for international collaboration being authorized as
part of TrialNet is to answer the crucial question of whether or not one
gets differences in C-peptide response with an MMTT versus a glucagon
stimulation test. The MMTT usually takes 2 hours, but can take 4 hours.
The glucagon stimulation test is classically done with a baseline
measurement and then one measurement 6 minutes later, after a 1mg dose
of intravenous glucagon. Thus the tests are dramatically different in
terms of how the β cells are stimulated. The small amount of data
available suggests that in normal controls the tests will give
comparable responses. What still needs to be asked is "What is the
difference in people with diabetes?" and "As people progress toward
diabetes, does one of the tests give you a different answer?"

Next Dr. Irony asked Dr. Kahn, "With regard to the continuum of impaired
glucose tolerance and impaired fasting glucose as an individual moves
toward type 2 diabetes and with the availability of potential treatments
in the future for earlier conditions of β-cell defects, will diabetes
again be redefined as tends to happen as treatments become available for
diseases?" Dr. Kahn answered that, in fact, there has recently been a
change in the criteria for impaired fasting glucose from 110 to 100,
which prompted that week's announcement about how many more people are
at risk for developing diabetes. During DPP, the definition of diabetes
as a fasting glucose level was reduced from 140 to 126, which was
clearly a challenge for a clinical trial, but showed the potential in a
clinical trial to adapt to changes occurring in the outside world.
Dr. Kahn felt this would continue to happen down the road as he thinks
the change in impaired fasting glucose was the first step and he
believes the criteria for diagnosing type 2 diabetes in terms of fasting
glucose is also going to be lowered, because there is a disconnect
between the fasting response and the 2-hour response. In part, this
change also will be driven by clinical trials. Dr. Kahn recommended that
clinicians and investigators work with FDA to ensure that some of the
treatments that are being defined for diabetes are not limited to
diabetes but are moved into the general public health arena. The
metformin results from DPP would be a good example as well as the
lifestyle changes.

Based on Dr. Palmer's presentation of C-peptide as a good reflection of
β-cell mass and Dr. Kahn's data that β-cell function is reflected by
dynamic tests of insulin secretion, the question was asked if it was
possible that in the DCCT, adolescents in whom C-peptide was present
were actually a subgroup of patients with a different disorder, such as
metabolic syndrome or type 2 diabetes presenting at a younger age. Or
conversely, can people with type 2 diabetes who progress to decreased
β-cell mass be reflected by studies of on Dr. Palmer's presentation of
C-peptide as a good reflection of β-cell mass and Dr. Kahn's data that β
function without measuring C-peptide?

Dr. Palmer replied that he would not want to leave the impression that
C-peptide is a good measure of β-cell mass, but rather that there is a
correlation between β-cell mass and all measures of β-cell function.
β-cell function is really what is being measured by C-peptide, which is
not equivalent to measuring β-cell mass. He stressed that for type 1
diabetes, and possibly also for type 2, part of the disease process is
damaged β cells, not necessarily dead β cells. In animal models and
increasingly in humans, with aggressive treatment, especially glycemic
treatment, but also with immunologic treatment in the animal models,
there is a surprising recovery of β-cell function

Dr. Kahn agreed that measuring β-cell function is difficult and that
C-peptide has become the best way to do so in type 1 diabetes because
those individuals are being treated with insulin. There are arguments to
use C-peptide in type 2 diabetes as well, since hepatic clearance, which
can be so variable, does not come into play. The problem is the expense.
It is easier to measure insulin, especially with ADA's move to have the
insulin assay standardized; therefore, it may be that insulin will be
used in most instances. Dr. Kahn also agreed that C-peptide is not truly
a measure of β-cell mass. Also, he did not wish to leave the impression
that β-cell mass is all that is wrong with type 2 diabetes. He suggested
there is a functional defect that might actually contribute to the
amyloid formation. Amyloid formation and loss of β-cell mass appear to
go hand-in-hand in contributing to the loss of insulin secretion.

Dr. Kahn continued that the issue of how best to assess this is a real
problem, because clearly the intravenous tests he described in his
presentation are not ones that can be done in the clinic in large-scale
clinical trials, whether they are NIH-based clinical trials or
pharmaceutical-based clinical trials. He did think that with the use of
more precise measures of β-cell function, the number of individuals
needed in some of these trials could be reduced and it may even be
possible to use some of these measures, rather than glucose, as
biomarkers when one is making assessments in clinical trials aimed at
preventing β-cell loss. By reducing the number of subjects in clinical
trials, Dr. Kahn believes more centers can do the studies, and,
hopefully, in time the FDA and other groups will look on tests and
approaches like this as ways to assess early disease and enable us to
develop interventions. He also felt that assessing interventions early
on in people with normal glucose tolerance to see if this would prevent
diabetes would require many years of follow-up, which would be extremely
difficult and expensive.

As an aside, Dr. Kahn noted that he and Dr. Harry Shamoon and Dr. Bill
Knowler have been involved in writing up the insulin secretion and
sensitivity data from the DPP and that data indicates that the lifestyle
intervention, which did best in preventing or delaying diabetes, also
had the most effect in improving **β**-cell function. OGTT-derived
measures were used to measure this and could certainly be used in
clinical trials to look at compounds and how they might change
sensitivity and β-cell function.

Dr. Alan Moses, Novo Nordisk Pharmaceuticals, commented that he agreed
about the need to do better in terms of assessing both β-cell mass and
function, particularly in looking to drugs to change the early natural
history of type 2 diabetes. He asked if the UKPDS curve based on the
HOMA method was a linear curve or was it a combination of lipotoxicity,
perhaps glucotoxicity, at very mild levels of hyperglycemia, and perhaps
amyloid accumulation that made it something other than a linear curve.
Dr. Kahn said that it was possible that it was linear at that point in
time. In more recent studies trying to measure secretory capacity by
raising the glucose to the maximum level (above 450 mg/dl) and then
giving a stimulus like arginine, to examine at β-cell secretory
capacity, it was found that the relationship between β-cell function and
hyperglycemia is a curve as well. Individuals can lose 75 percent or
more of β-cell function before developing hyperglycemia.

In response to a question about how the curves of insulin sensitivity
versus insulin secretion might vary for different categories of obesity
in early pre-diabetes and whether they would be shifted from those
observed in subjects with normal glucose tolerance, Dr. Kahn answered
that their data with people of varying BMIs indicated that in older
people and in those with impaired fasting glucose, the curves, and they
are definitely hyperbolic curves in these other groups, are shifted down
and to the left. Dr. Kahn felt these curves indicate that, in people at
very high risk, simply using the product of the two measures---insulin
sensitivity index and insulin secretion---as a measure of β-cell
function might be a way of following these individuals down the road.

The question was asked whether the subjects in UKPDS who developed
diabetes might actually never have had normal β-cell function and in
relation to islet volume measurements in those people who progressed to
diabetes versus those who did not, could the difference in the two
groups been a defect in β-cell volume to begin with in those who got
diabetes. Dr. Kahn replied that he believed that diabetes is certainly a
genetic *and* an environmental disease. If these subjects could have
been studied at 2 years of age, he thought that those who later
developed diabetes at 65 probably already had decreased secretion at 2.
In other words, there was probably a genetic component in those who
developed diabetes, but that increased dietary fat and other
environmental factors that contribute to obesity have a very deleterious
impact on insulin secretion and thus, it was the environment, in Dr.
Kahn's opinion, that was the major player in what happened to
individuals who were genetically predisposed to develop β-cell
dysfunction and diabetes.

With regard to islet mass, Dr. Kahn thought that islet mass might
genetically also be reduced. Most of the genes that have been identified
so far for diabetes appear to be transcription factors, such as PDX1,
which is a major player in terms of islet development. However these
people had not been studied in this regard. In animal studies using
systems with nuclear staining and counting cells and looking at islet
adaptation to higher fat diets and obesity, there is β-cell hyperplasia,
but not hypertrophy or much neogenesis. Based on these studies, it is
thought that there is replication occurring within the β cell. In mice,
a very strong linear relationship has been observed between the degree
of adiposity in the mice and the number of β cells. The question again
is that if this is a linear relationship, would it have been monolinear
up at the top in these animals? Dr. Kahn said they really do not know
what is normal. His guess would be that in humans β -cell mass might be
genetically determined in part and then the environment has a
detrimental effect, restricting complete β-cell adaptation, along with
other factors such as amyloids.

Dr Amy Rosenberg, FDA, asked Dr. Kahn if his group had dissected further
the amylin protein in the transgenic mice to target the particular amino
acids involved in the amyloid deposition. She also asked why he felt fat
per se results in lipotoxicity. If the mice had a high-fat diet but
calories were controlled, would there still be lipotoxicity and does the
kind of fat make a difference?

Dr. Kahn replied that in terms of the amino acid sequence in the
animals, the transgenic mouse was created because normal mice have
protein substitutions in their 20 to 29 amino acid sequence that appear
to be critical. Mice and rats never get amyloid. Monkeys, cats, and dogs
do get amyloid, so the sequence appears to be critical. His group has
not worked further with this subject. With regard to fats, *in vitro*
studies have clearly shown that fatty acids are deleterious in terms of
islet function and insulin secretion. This seems to vary a bit,
depending on the fatty acid employed. The high-fat diets in the
transgenic mice were the high-fat diets associated with obesity and what
was seen was that insulin secretion appeared to be disturbed. A similar
result was seen with dogs fed a high fat diet. These animals developed
obesity, insulin resistance, β-cell dysfunction, and thus glucose
intolerance. Dr. Kahn added that the mechanism by which the high-fat
diet is producing this effect *in vivo* is unclear and this is one of
the limitations of doing clinical physiology in humans or animals.

**Session IV: Islet Transplantation**

*Moderators: Cynthia Rask, MD, Division Director, Office of Cellular,
Tissue, and Gene Therapies, Center for Biologics Evaluation and
Research, and Richard McFarland, PhD, MD, Medical Officer, Office of
Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation
and Research, FDA*

**Islet Transplants: Past, Present, and Future**

***Bernard J. Hering, MD**, Director of the Islet Transplant Program,
Associate Director of the Diabetes Institute for Immunology and
Transplantation, and Associate Professor of Surgery, University of
Minnesota; Co-Director, JDRF Islet Transplant Center, University of
California/University of Minnesota*

Dr. Hering pointed out that it is important to recruit many more
investigators to capitalize on the current opportunities for developing
islet translation to a viable and widely available treatment option for
people with type 1 and type 2 diabetes. In the past, the challenge has
been to achieve and to restore insulin independence. The challenge now
is how to implement what we have accomplished. For the future,
innovation will be critically needed.

**The Past**. Dr. Hering listed three barriers in the past that
challenged achieving insulin independence: low engrafted islet mass,
high metabolic demand, and immunologic graft loss. It was felt that the
islet mass transplanted was inadequate, that the engraftment of islets
was impaired by hypoxia and immunity, and that the function of the
engrafted islet mass was compromised by insulin resistance and by
impaired insulin secretion caused by diabetogenic drugs and possibly by
underlying diabetes itself. At that time,

islets were subject to rejection and beta-cell toxic immunosuppressive
regimens..

Dr. Hering briefly reviewed the 30-year history of islet
transplantation:

-   **1974:** First transplant was performed by Drs. John Najarian and
    David Sutherland. Basic components of the 1974 protocol have
    remained much the same. Islets are still recovered from deceased
    donors, collagenase and density gradients are used, islets are
    infused into the portal vein, and anti-lymphocyte globulin or other
    T-cell antibodies are used for recipient treatment.

-   **Late 1980s**: Dr. Ricordi made a significant contribution by
    developing a new technique for islet isolation from the human
    pancreas.

-   **1990**: First, well-documented case of insulin independence was
    reported by Drs. David Scharp and Paul Lacy using islets prepared
    from two donor organs. The type 1 diabetes patient achieved insulin
    independence 10 days after transplantation and glucose control
    remained fairly stable.

-   **1990**: Pittsburgh group reported on nine simultaneous islet liver
    transplants in patients with surgical diabetes, using a
    prednisone-free protocol. Seven of nine patients became insulin
    independent, and at 1 year, five of the nine had remained insulin
    independent---a remarkable success rate in patients with surgical
    diabetes.

-   **1991 and 1992**: Edmonton group used islets from one fresh
    pancreas together with cryopreserved islets from four additional
    donors (10,000 islet equivalents per kilogram) and reported the
    first example of insulin independence and euglycemia for more than 1
    year duration after islet transplantation in Type 1 diabetes.

-   **1992:** Dr. Hering and others developed the Geissen protocol that
    successfully prevented islet graft failure in most of their
    patients. Outcome was measured in basal C-peptide levels exceeding 1
    nanogram per ml. Insulin independence was achieved in about
    one-third of patients treated with high-dose cyclosporin and
    prednisone after a single-donor islet transplantation.

-   **1993**: Dr. Paul Gores reported on insulin independence in type 1
    diabetes after a single donor transplantation using unpurified
    islets.

-   **1998**: First type 1 diabetic islet recipient remaining insulin
    independent for more than 5 years, was reported by Washington
    University, St. Louis.

-   **2000:** Dr. Shapiro reported an 85-percent success rate for
    insulin independence at 1 year post-transplant using a modified
    Edmonton protocol with a new streptomycin-based, steroid-free,
    immunosuppressive and islets from two to three donor organs.

Dr. Hering stated that the Edmonton protocol changed the field. He felt
the high rate of insulin independence achieved was probably due to the
increased islet mass engrafted, the lowering of metabolic demand, and
the new protocol's prevention of graft loss due to autoimmunity and
allo-immunity. More than 300 patients have received transplants
following the Edmonton protocol, with a number of groups achieving
success rates as high or nearly as high as at Edmonton.

**The Present**. Dr. Hering named several current concerns in making
successful islet transplantation available to more persons who suffer
from difficult-to-manage diabetes. These included the low efficiency of
the procedure, safety issues, limited availability, and uneven
integration of the procedure into the diabetes care community. Specific
questions within these concerns are: What is the cost utility, what is
the duration of successful islet transplants, do we need multiple
donors, is the academic setting adequate to deliver against demand, how
do we resolve the logistics of pancreas allocation, will third-party
reimbursement bear the cost, what are the risks of the procedure, and
importantly, what are the risks of long-term immunosuppression, are
those risks known, and what would be the most adequate approach? Dr.
Hering's priorities to address these issues were to focus on single
donor islet transplants, steroid- and calcineurin inhibitor-free
regimens, the FDA biologics license application, and randomized clinical
trials to determine when to use islet transplantation versus insulin
therapy.

***Single-Donor Islet Transplant Approaches***. Dr. Hering's rationale
for single-donor islet transplantation was based on the fact that a
second transplant increases cost by \$75,000, which cannot be handled
easily; single-donor transplants allow ultimate validation of islet
potency assays, which is important to move the field forward and to
improve islet processing techniques; and single-donor transplants
facilitate evaluation of immunotherapeutic protocols. He added that
adopting single-donor transplants will promote FDA approval and
insurance coverage, promote donor pancreas allocation to islet patients,
and therefore promote overall availability of islet transplantation.

A new approach and protocols have been developed by Dr. Hering and his
colleague, Dr. Jeffrey Bluestone, for successful transplantation of
cultured islets from two-layer, preserved pancreases with anti-CD3
antibody immunotherapy. Four of six recipients achieved and maintained
insulin independence after single-donor transplantation. The basic
approach uses maintenance treatment as described by the Edmonton
protocol. Dr. Hering used two additional protocols, one of which
involved the addition of a soluble TNF (tumor necrosis factor) receptor
blocker to mitigate early inflammatory responses to the transplant
islets and rabbit antithymocyte globulin (ATG). Dr. Hering stated that
immunotherapy with a new generation anti-CD3 antibody may facilitate
minimization of maintenance immunosuppression (Hering et al., Am J
Transplantation 4:390-401, 2004).

Patients with sustained insulin independence after single-donor islet
transplantation showed acceptable metabolic control with normal HbA1c
levels, normal OGT responses in 8 of 10 recipients, and acceptable acute
C-peptide and insulin responses to arginine and insulin. Hypoglycemia
was avoided in all recipients who suffered from recurrent episodes of
severe hypoglycemia pre-transplant. There were no prolonged serious
adverse events, procedural complications, or opportunistic infections.
Dr. Hering explained that studies indicate that different induction
protocols may produce a different engraftment index (i.e., the acute
C-peptide response to arginine, divided by the transplanted islet mass
per kilogram). Preliminary data suggest that the addition of soluble
TNF-receptor blockers could promote engraftment of transplanted islets.
Based on successful use of this protocol in a series of 20 recipients,
Dr. Hering believes it possible to build on the achievement and make it
available to more centers for single-donor transplants.

Dr. Hering suggested the following as other opportunities to achieve
single-donor success on a more consistent basis: improvement of islet
mass and potency by working on donor pre-treatment, pancreas
preservation, using recombinant enzymes, process engineering, and gene
transfer and protein transduction for the purpose of protecting islets
during processing. For example, in islet processing what will be
important is having a validated, reliable, preferably real-time assay of
islet β-cell mass and potency, which is an area in which Dr. Hering and
others have been working. Dr. Hering presented a slide showing there are
now real-time release assays that show very good correlation with
post-transplant function, the β-cell mass per kilogram, oxygen
consumption rate (OCR) per DNA, and ATP (adenosine triphosphate). His
example from work done by Drs. Papas, Koulmanda, Weir, Colton, Ikle, and
Nelson showed that in the rat-to-mouse model, the assay had a predictive
value of 89 percent, a sensitivity of 93 percent, and a specificity of
94 percent. By plotting OCR per DNA as a measure of the fraction of
viability of tissue and the implanted viable islet equivalents, then,
with a very low dose of islets, just 75 islet equivalents per mouse,
diabetes can be reversed with a high fraction of viability. As the
fraction of viability decreases, probability will decrease. The example
also showed that even a very high number of islets will not reverse
diabetes if the fraction of viability is below 75 nanomole per minute
per milligram DNA. Dr. Hering said there is more and more information
from human islet transplants and pig islet transplants suggesting that
this probability of transplant success based on OCR per DNA and viable
islet equivalents per kilogram is also present in pre-clinical and
clinical situations.

Dr. Hering suggested an islet engraftment can be optimized by targeting
immunity through developing new islet delivery techniques using
biodegradable scaffolds or using pro-angiogenic, anti-apoptotic,
anti-inflammatory, and immunoregulatory peptides. One islet implantation
site that his center has become interested in is the small intestine
subserosal space, a highly vascularized space. In a pig islet transplant
model, diabetes was reversed and outcomes were comparable with an
intraportal islet transplantation site. Local immunotherapy can possibly
be easily performed at this site and promote engraftment and survival.

***Steroid and CNI-Free Regimens***. According to Dr. Hering, lower
metabolic demand can be achieved by avoiding both corticosteroids and
calcineurin inhibitors. Two protocols have recently been developed: one
based on CD28 blockade using LEA29Y, a CTLA4 IG mutant, and a second one
based on FTY720. Compared with the Edmonton protocol, the protocol
published by the Emery group basically replaced the calcineurin
inhibitor, FK506, with LEA29Y. Work done at Dr. Hering's institution, in
collaboration with Miami, used FTY720 instead of FK506. This approach
lacked islet, kidney, and cardiovascular toxicity. The impact on
protective immunity is unknown, but Dr. Hering considers this a very
promising development. With LEA29Y, it was possible to reverse diabetes
and protect transplant islets, whereas in the control group, all animals
rejected the islets. With FDY720, basiliximab, and RAD (a rapamycin
derivative), again it was possible to prevent rejection in a non-human
primate transplant model. It was also possible to reverse diabetes with
a very low islet dose of 5,000 islet equivalents per kilogram, and
animals became insulin independent and remained euglycemic after
discontinuation of insulin, suggesting that avoiding calcineurin
inhibitors may promote engraftment and may improve insulin secretion.

***FDA Biologics Response Modifiers Advisory Committee***. In October
2003, FDA hosted a meeting focused on islet transplantation and
addressing manufacturing and clinical study design issues related to
clinical trials designed to support a biologics license for human
islets. The Biological Response Modifiers Advisory Committee was asked
to review the status of the field. Dr. Hering thought the consensus in
the field was that control and consistency of islet manufacturing has
progressed to the point that a license could possibly be considered.
More work will be necessary in the area of islet potency assays, and it
was unclear whether substantial evidence of safety and effectiveness are
available. A proposed indication on labeling also was discussed.
Restoring euglycemia in type 1 diabetes as a clinical endpoint was also
considered.

Dr. Hering emphasized that for a small subgroup of people with type 1
diabetes who suffer from recurrent episodes of severe hypoglycemia,
islet transplants can achieve remarkable improvement. He added this is
important in relationship to the DCCT findings that risk can be reduced
but not without increasing the rate of hypoglycemia. He presented
several slides supporting his statement.

***Randomized Trials and Islet Transplantation Vs. Insulin Therapy***.
Dr. Hering said the current overall question is whether the field has
developed to the point where randomized clinical trials should be
considered. Other questions include whether to focus on
hypoglycemia-associated autonomic failure, whether costs per
quality-adjusted life year can be approved, and whether to focus on
chronic complications and ask if microvascular lesions in type 1
diabetic patients with, for example, microalbuminuria treated with renin
angiotensin system blockers (RASB), will continue to progress if normal
glycemia is not restored. There is emerging consensus in the field that
randomized clinical trials are probably needed to document the benefits
of islet transplantation. Dr. Hering noted that a lot of support has
been provided by NIH and the field has clearly benefited from this
support and by FDA's interest. He felt additional Federal agencies will
need to be involved in the trials. Pancreas allocation and health
insurance coverage are two very important issues. In support of
initiating trials, Dr. Hering stressed that progress has been made in
islet transplantation; efficiency and safety have improved. He cited
integration and availability as important areas requiring further work.

**The Future**. Dr. Hering emphasized that innovation is needed, for
example to develop a state of immunologic tolerance and to provide an
unlimited β-cell source or possibly β-cell replication *in situ*.

***Immunologic Tolerance***. The current paradigm suggests depletion of
pathogenic T-cells and establishment of a state of regulation is
necessary to achieve stable and robust tolerance. This has become
possible, as reported by the Alabama group, with anti-CD3 immunotoxin
combined with deoxyspergualin (15-DSG), which inhibits allo-immunity,
dendritic cell maturation, and antigen presentation. Dr. Terry Strom's
group developed another apparently successful approach in a very
difficult NOD mouse model and also in non-human primates, involving
three different strategies---rapamycin, agonist interleukin 2, and
antagonist interleukin 15---promoting deletion and regulation.

With support provided by the Immune Tolerance Network, Dr. Hering's
group will begin testing anti-CD3 immunotherapy with rapamycin to see if
it can achieve tolerance in type 1 diabetic islet recipients. It has
been shown that this antibody can actually lead to a contraction of 8.5
to 0.1 percent of the anti-T-cell repertoire in the peripheral
circulation. A striking increase in the percentage of regulatory T-cells
after immunotherapy with this antibody has been noted, suggesting that
tolerance could possibly be accomplished. A paper published on-line
suggests a 40,000-fold expansion of CD25+CD4+ T-cells *ex vivo* over a
period of only 3 or 4 weeks.

***β-Cell Source***. A number of different strategies have been proposed
to develop a β-cell source including maximization of decreased donor
pancreas utilization, living donor islet transplants, xenogeneic islet
transplants, precursor cell-derived islet beta cell transplants, and
beta cell replication *in situ*. Dr. Hering believes β-cell mass and
supply for transplantation can be increased. Pig islets are already
being tested in animal studies.

In the area of xenotransplantation, Dr. Hering's center transplanted pig
islets into immunosuppressed diabetic monkeys and demonstrated reversal
of diabetes. Normal glycemia was achieved for more than 100 days. A
liver biopsy showed 90 percent of islets without any evidence of
infiltration. Dr. Hering stated a number of strategies are becoming
available to decrease immunosuppressive risks. It was his opinion that
adult stem cell-derived islets probably would not become a source. A
paper by Dr. Douglas Melton (Nature 429:41-46, 2004) suggested that new
β-cells are formed by self-duplication of pre-existing β-cells and are
not formed by stem or progenitor cells during adult life. Dr. Hering
thought the other important message from the paper is that there is a
very high proliferative capacity and turnover of terminally
differentiated β-cells. The question is, "Can this capacity be exploited
for expansion to a clinically useful mass?" Also, with respect to islet
transplantation, "Is the longevity of islet transplants determined by
the proliferative potential of transplanted β-cells?" Dr. Hering
continued that Dr. Peter Butler keeps reminding him that, based on
mathematical modeling, transplants can only last for 5 years, unless
there is replication of transplanted β-cells. Dr. Hering believes, from
clinical observations, that replication happens. He gave as an example
an islet auto-transplant patient with chronic pancreatitis who has been
insulin independent and normal glycemic for 20 years, suggesting islets
can survive long-term; this may also be evidence of intrahepatic islet
replication more than neogenesis.

In conclusion, Dr. Hering said cell-based therapeutics will soon play an
increasingly significant role in diabetes care, particularly if
documentation of benefits of islet transplants using clinically relevant
endpoints is possible. Considerable effort and new concepts will be
needed to overcome translational obstacles in the implementation and
integration of cell-based therapeutics into the healthcare system.

**Obstacles and Hurdles Facing the Clinical Application of Islet
Transplantation**

***Robert S. Sherwin, MD**, C.N.H. Long Professor of Medicine and
Director, Diabetes Endocrinology Research Center and General Clinical
Research Center, Yale University School of Medicine*

Dr. Sherwin explained that he became interested in the issues of islet
transplantation as a diabetologist and an *ad hoc* member of the
Biological Response Modifiers Advisory Committee. As Dr. Hering said,
the Edmonton study was the turning point in the story of islet
transplantation. Today there are remarkable improvements, but we still
cannot ensure normality for people with islet transplantation, only
about 50 percent of whom become insulin independent over the first year.
Although considered clinically successful, normal glucose tolerance is
extremely rare in these patients. About a third of the
insulin-independent patients resume insulin therapy within 2 years,
although they often require less insulin, have less hypoglycemia, and
are more stable metabolically. In other words, clinically they are
greatly improved. One can anticipate, given the numbers today, that
there are quite a few patients who will resume insulin over time.
However, the majority of transplant patients self- report improved
quality-of-life. At present there is little data regarding microvascular
and macrovascular complications in islet transplant patients.

Regarding the mechanism for the loss of β-cell function post-transplant
over time, Dr. Sherwin feels there are multiple factors involved.
Chronic rejection undoubtedly contributes, since it is unlikely that
there is no allo-response in these patients. In many cases, there is the
recurrence of autoimmunity, as demonstrated by the formation of
antibodies in some patients who required insulin. The immunosuppressive
drugs themselves have adverse effects on β-cells. Tacrolimus, which is
the part of the Edmonton protocol, clearly reduces β-cell function, and
rapamycin, another component, inhibits the mTOR signaling pathway
involved in protein synthesis and probably has a role in reduced β-cell
proliferation, which may be an important factor. An article in Diabetes
Care (Davidson, Diabetes Care 24; 2004) reported that there is a high
rate of incidence of diabetes with tacrolimus compared to cyclosporin,
which also had some adverse effects. In the best of circumstances, even
immediately after transplantation, there is probably only about 20 to 30
percent of β-cell mass present, thus only marginal β-cell function. One
thing that little is known about is whether there is insulin resistance,
a critical factor in β-cell function.

On the positive side, Dr. Sherwin reported pooled data compiled by Dr.
Hering showing that progress was being made. The pooled data on cultured
islet transplants from three centers where 75 patients received
transplants since 2000, showed that 74 of the 75 (99%) demonstrated
primary function based on C-peptide post-transplant, 72 (96%) were
C-peptide positive after 1 year, and 64 (85%) remained insulin
independent at 1 year.

Dr. Sherwin noted that there are complications associated with the
Edmonton experience, which is critical when asking FDA to consider
instituting this kind of therapy and licensing it. Safety is a key
element in such deliberations. The major acute islet-related
complication was bleeding, although generally it was modest (10 percent
incidence) but this often requires transfusion. There was also
occasional thrombosis at the injection site (4 percent incidence).
Chronic islet-related complications included fatty liver. A host of side
effects and drug-related complications also occur, some modest, some
significant. Certainly mouth ulcers are a problem for patients as well
as increased cholesterol, increased blood pressure, and diarrhea.

Dr. Sherwin reported that the major questions at the FDA meeting of the
Biological Modifiers Advisory Committee in October 2003 were "What
manufacturing requirements and clinical evidence should be needed for
FDA approval of allogeneic islets as type 1 diabetes treatment?" In Dr.
Sherwin's opinion, the outcome from the meeting was that there are still
many basic and clinical questions that need to be resolved. However,
some centers have made substantial progress and therefore may ultimately
be able to provide sufficient data for FDA approval for islets as a
licensed product.

Next Dr. Sherwin listed the following obstacles and hurdles to be
overcome for FDA approval, noting there are probably others he did not
list:

-   Islet procurement is a major problem. Islet transplantation centers
    have tremendous difficulty getting islets for islet transplantation.

-   Optimization of islet production and culture methods needs to be
    refined.

-   There needs to be development of islet viability and function tests
    *in vitro* that relate to clinical outcomes. Although there is
    progress in this area, there is not a gold standard yet.

-   Optimization of immunosuppressive regimens are needed.

-   The preferred site for islet engraftment needs to be studied and
    determined.

-   Methods to reduce implantation local phenomena, such as
    inflammation, clotting, and perfusion deficits need to be developed.

-   Appropriate clinical outcome measures must be defned.

-   Data is needed to assess the risk-benefit ratio for approval.

-   Methods to detect early islet rejection must be devised. This is a
    major problem, because currently rejection is detected by
    hyperglycemia, which is too late.

**Pancreas Allocation**. Dr. Sherwin pointed out that the pancreas
allocation process is an issue of importance and a major obstacle to
islet transplantation. The vast majority, probably over 95 percent, of
pancreas organs from obese and older (\>50 years of age) patients are
not used and yet they are not offered in a timely manner to the islet
transplant community. This is important since cold ischemic time is
highly critical for islet transplantation, much more critical than for
pancreas transplantation. Dr. Sherwin added that, surprisingly, the
United Network for Organ Sharing (UNOS) kidney-pancreas allocation
committee, which is not under FDA, has no representation from either the
islet transplant community or the diabetes community. Dr. Sherwin
recommended that the pancreas allocation policy be amended to include
(1) limiting time to less than 4 hours for offers for pancreas
transplantation or provide pancreases directly for islet transplantation
from donors with a BMI greater than 30 or older than 50 years of age;
and (2) involve the islet transplant and diabetes communities in the
pancreas allocation process.

**Clinical Outcome Measures**. The current clinical outcome measure for
successful islet transplantation is insulin independence. The criterion
for insulin independence is HbA1c less than 6.5 percent when off
insulin. Dr. Sherwin recognized that this means many of these
insulin-independent patients obviously have pre-diabetes or diabetes. He
suggested that although insulin independence is obviously important to
the patient, clinical outcomes would be better defined on the basis of
ADA criteria of glycemic control, such as normal glucose tolerance, IGT,
IFG, and non-insulin-requiring diabetes.

For partial success in islet transplantation, the current clinical
outcome is C-peptide secretion and reduction in insulin dose. Dr.
Sherwin said it is important to keep in mind that the studies of islet
function that are used in the transplant community are largely based on
arginine stimulation or mixed meal tolerance tests, rather than the gold
standard used by diabetologists to assess diabetic state, namely
glucose-stimulated insulin/C-peptide secretion.

Referring to the NIH Roadmap Initiative, Dr. Sherwin said that what was
needed to move forward is an in-depth assessment of islet
transplantation with multi-disciplinary centers such as General Clinical
Research Centers (GCRCs) able to conduct state-of-the-art physiological,
end organ, and behavioral outcomes studies on islet graft recipients,
who, he added, are not an enormous population.

**Clinical Assessment of β-cell Function, Glycemic Control,
Hypoglycemia, and Complications**. Dr. Sherwin presented two suggestions
for clinical assessment of β-cell function in islet transplant
patients---one for insulin-independent patients and one for
insulin-requiring patients. For him, the gold standard for the
insulin-independent patient is an oral glucose test, preferably OGTT,
with early insulin and C-peptide sampling to better characterize
secretory responses. Second, as a crude measure of β-cell mass, he
recommended stepped glucose infusion, possibly with arginine added.
Third, as a measure of insulin sensitivity to assess β-cell function
(insulin secretion data), he suggested the euglycemic insulin clamp.
Lastly, Dr. Sherwin said there needs to be more direct measures of islet
cell mass, which we do not have yet. Insulin-requiring patients will
obviously not have much glucose-stimulated β-cell function; therefore
Dr. Sherwin's suggestion for clinical assessment of them was mixed
meals, focusing on C-peptide; maybe a stepped glucose infusion with
arginine; and again, the β-cell mass.

For clinical assessment of glycemic control and hypoglycemia in islet
transplant patients, Dr. Sherwin would do an OGTT, with 24-hour glucose
monitoring in the hospital to monitor glucose excursions and
hypoglycemia, especially in the insulin-independent patients.
Additionally, he would want monthly profiles of these patients (pre- and
2-hour post meal, bedtime, and 3 a.m.), including glucose meter
measurements; a continuous glucose monitoring system (CGMS) for
postprandial hyperglycemia and lability; and a validated hypoglycemic
scoring system.

Dr. Sherwin proposed clinical assessment of complications in islet
transplant patients should include fundus photos and checks for
microalbumin excretion and glomerular filtration rate (GFR), essentially
as done in the DCCT; sensory testing, nerve conduction, RR interval;
endothelial function studies; carotid IMT and perhaps coronary perfusion
studies; measurement of hypoglycemic counterregulation and awareness;
and potential complications related to therapy.

**Risk-Benefit Assessment**. Dr. Sherwin stated a risk-benefit
assessment also is needed. On the benefit side would be insulin
independence, which is everyone's dream for patients with type 1
diabetes, or at least sufficient C-peptide secretion to make glucose
control easier without hypoglycemia and to have better glucose control
than is achievable with current methods. Another major benefit would be
the potential decrease in diabetic complications. On the risk side, Dr.
Sherwin identified the risk of acute complications of the procedure, the
side-effects of the anti-rejection regimens, and the potential for
neoplasia, infections, poor wound healing, pneumonitis, and so forth.
Remaining questions raised by Dr. Sherwin included uncertainty about the
diabetic nephropathy benefit; potential adverse effects with respect to
cardiovascular disease, since other kinds of transplantation clearly
accelerate cardiovascular disease and produce hypertension and
hypercholesterolemia; and uncertainty about the duration of islet
function with these grafts being sufficient to have a clinical long-term
outcome.

One of the key questions for Dr. Sherwin was, "Will islet
transplantation prevent or reverse nephropathy?" The pros are that the
University of Washington, Seattle, group showed reversal of mesangial
accumulation and base membrane thickening, 10 years after successful
pancreas transplantation (Robinson et al. NEJM, 2004). On the other
hand, in 2003 the *New England Journal of Medicine* reported development
of renal failure in 3 years in 17 percent of non-kidney graft recipients
(Ojo et al. NEJM, 2003). *Transplantation* (Majur et al.
Transplantation, 2004) reported a 38-percent decrease in GFR in patients
who had bladder drained pancreas transplants (one patient actually
required a kidney transplant); granted bladder drainage produces
dehydration, which probably contributed to this, but it is something to
consider. Dr. Sherwin also pointed out that pancreas transplantation
currently produces better and more sustained glycemic control than islet
transplantation.

Dr. Sherwin also cited the report of Dr. David Harlan (JAMA, 2003), who
looked retrospectively at studies. Using the UNOS database (1995 through
2000), Dr. Harlan divided patients according to procedure (pancreas
alone, pancreas after kidney, or simultaneous pancreas/kidney). He then
compared these patients to a control group, based on 4-year follow-up
period from the database. Dr. Sherwin admitted it could be argued that
those in the control group, such as people on a waiting list who did not
receive a pancreas, might not have been in as desperate circumstances as
those who did get pancreas grafts. Nevertheless, the data showed that
those who received simultaneous pancreas/kidney transplants clearly
benefited. However in the other categories, 4 years out, there was not
much benefit compared to the control group who received conventional
therapy. Dr. Sherwin concluded that, although retrospective studies that
compare different populations can be questionable, this one does raise
issues regarding the risk-benefit ratio.

**Islet Transplantation or Insulin Therapy?** Comparing intensive
insulin therapy in 2004 with islet transplantation, Dr. Sherwin scored
glycemic control generally better; hypoglycemia, much better; central
nervous system (CNS) function in patients who have severe hypoglycemia,
unknown; quality of life, most say better; retinopathy, probably better;
nephropathy, unknown; neuropathy, probably better; cardiovascular
disease; unknown; malignancy, probably worse; and long-term survival,
unknown. Based on his "scorecard," Dr. Sherwin concluded there are only
two current indications for islet transplantation: (1) patients with
severe recurrent hypoglycemia and hypoglycemia unawareness, which is the
major clinical problem encountered with insulin therapy in a subgroup of
type 1 diabetes patients; and (2) patients who have had a kidney
transplant and are already receiving steroid-free regimens that are like
the ones used for islet transplantation. Dr. Sherwin said that only
rarely should poorly controlled or labile type 1 diabetes patients be
considered for islet transplantation because these patients are doing
reasonably well today compared to the past. Survival and quality of life
have improved, largely due to DCCT/EDIC and to the newer insulins and
insulin delivery systems, the statins, lipid control, improved diets,
and so forth. Dr. Sherwin concluded that due to these improvements in
standard of care, judging the need for islet transplantation is
different today than it was 10 or 20 years ago.

Dr. Sherwin noted that severe hypoglycemia remains a problem and is far
more common than appreciated. Sympathoadrenal responses and cognitive
awareness are markedly reduced in these patients and 50 percent of
severe events occur while people are sleeping. In most patients treated
intensively, the fear of hypoglycemia exceeds their fear of
complications, which is anxiety promoting and leads to decreased
commitment to treatment in patients, their families, and their
physicians. Dr. Sherwin stated that patients with severe recurrent
hypoglycemia with unawareness, who fail to respond to modern multiple
injection and insulin pump therapy delivered by a diabetes specialist
for a period of time (and this is arbitrary) are very good candidates
for islet transplantation. He added that severe hypoglycemia and
unawareness needs to be well-defined and documented. Basically, it is
considered a history of two serious events a year such as coma,
hospitalization, or requiring help from another person, with documented
glucose meter readings and, ideally, hypoglycemia clamp studies or some
form of study to evaluate function. Dr. Sherwin said that these
measurements are important because sometimes improved management can
reduce iatrogenic hypoglycemia and improve responses, and although this
can be difficult and may not be practical in many settings, it s worth
considering prior to undergoing transplantation.

For Dr. Sherwin, an acceptable outcome in the patients with severe
hypoglycemia could be both insulin-independent and insulin-requiring,
C-peptide-positive patients, with insulin independence obviously more
acceptable. In patients receiving islet transplants after kidney
transplant, again, insulin independence and insulin requiring C-peptide
positive secretion would be acceptable outcomes because better control
would probably be achieved in those patients since they would be on the
same regimen. Dr. Sherwin questioned there being an acceptable outcome
in patients with impaired renal function, especially if they would be
insulin-requiring, C-peptide positive, given his concerns about
presently available regimens. He was uncertain about an acceptable
outcome for patients with poor control of their diabetes.

Cautioning that clinical trials are expensive, Dr. Sherwin recommended
the following kinds of clinical trials to further examine the potential
benefits of islet transplantation for certain patients with type 1
diabetes:

-   Patients with severe hypoglycemia: relatively short-term (1 to 2
    years) observational studies.

-   Patients for islet transplant after kidney transplant: matching of
    patients with historical controls and data with 2 or 3 years of
    follow-up.

-   Patients with poorly controlled labile diabetes: a 5-year, DCCT-type
    randomized trial to assess the long-term impact of this treatment.

    **Discussion**

In response to a question about the regulatory pathway to approval of
manufacturing of islets, Dr. McFarland said that there are nuances since
one islet preparation is not the same as another islet preparation;
however, the principle under which the Center for Biologics Evaluation
and Research (CBER) grants licenses, at least going back to the granting
of the first biologics license for monoclonal antibodies, is that
processes are very important in the development of the product. Islets
are regulated at the level of the cellular product, but the process to
make that product is evaluated as part of the application. This is also
true at the level of the investigational new drug (IND) applications for
investigational products. As islet technology improves and changes
occur, FDA will be informed and also will have bridging studies to show
that the lot release tests are similar and that the products are similar
in function.

Dr. David Marrero, Indiana University School of Medicine, Indianapolis,
stated that quality of life is a key phrase in considering the potential
for new treatments and targets for treatments. It is important to
consider a patient's quality of life and the trade-offs that are
involved with decisions to invoke certain treatment, not only for
transplantation, but for virtually anything, be it a drug or device, or
whatever the technology under discussion. Dr. Sherwin said that for
patients and their families, severe hypoglycemia is a dominant player.
Avoiding this phenomenon has an enormous impact on quality of life for
that group. One of the purposes of islet transplantation is to improve
quality of life and if there is anybody whose quality of life is going
to be improved the most, it will be the patient with severe
hypoglycemia, provided that the side effects of the drugs are minimal.
Given the fact of very limited resources, Dr. Sherwin would give
priority to the patient with recurrent severe hypoglycemia.

Dr. Marrero, a type 1 diabetes patient of 26 years, followed up by
saying that what was of interest to him about hypoglycemia was that many
of the therapies that have evolved in his lifetime have a dual-edged
component, where initially there is an increased risk but over time or
exposure or experience with the treatment, the results become better. He
said FDA and NIH may need to plan on how to balance the risk-benefit
ratio between an acceptable level of risk versus what in fact may turn
into a benefit over time.

Another participant, commenting on the Edmonton protocol and the
importance of non-immune factors in progressive β-cell mass loss and
loss of secretion, asked Dr. Hering what is being done with human islet
transplantation in terms of biopsies or such to learn what is really
happening to β-cell mass from non-immune processes. He also asked how
the acute and long-term or chronic effects might be dealt with in the
future if only about 25 percent of the β-cell mass that has been
transplanted is functional.

Dr. Hering agreed this is currently a problem of increasing importance.
Most centers see their patients with initially successful islet
transplants later experience failure. The reason or reasons are not
really known. Biopsies will help in the short-term. A major focus of the
new islet transplant consortium that is being established in 2004 will
be mechanistic studies with respect to pre-transplant evaluation of
islet mass potency and also post-transplant immune monitoring using the
most sophisticated and developed technology that is available to monitor
allo-immunity, autoimmunity, and innate immunity after transplantation.
This will be very sophisticated metabolic monitoring involving studies
looking at insulin sensitivity, insulin action, and so forth. Dr. Hering
also expected to see progress in the field of islet bioimaging to
monitor islets post-transplant using non-invasive technology. There is
not just one approach to the problem of why some transplants fail. Maybe
it is because a marginal mass was present initially. Maybe it is a
failure of replication. Maybe it is autoimmune recurrence. There are
many possibilities for studying this question.

Dr. Sherwin agreed that the basic problem is starting out with a
marginal β-cell mass and then a number of factors contribute to the loss
of function, be it failure to replicate, apoptosis, or core perfusion.
It is not really known if the islet normally is perfused inside-out or
how it is perfused. More information also is needed on amyloid
production. The fact that mild hyperglycemia develops with time,
probably doesn't help the β-cell function; therefore, if even a
successful transplant has not more than 30 and maybe only 20 percent of
β-cell mass, it is not difficult to see how, over time, small effects
quickly add up to produce insulin requirement.

Referring to the suggestion from Dr. Sherwin about using islets from
obese individuals whose pancreases are otherwise not used, the comment
was made that one thing that happens with obesity is that there is an
adaptation that clearly includes an increase in β-cell mass. Using the
obese persons' islets that have more β-cells actually may be a better
answer than taking people who have been sick, who are on drugs, and who
are insulin resistant, and transplanting them with an islet equivalent
mass of what are thought to be healthy islets, but in which the β-cell
is not able to replicate quickly enough.

Dr. Hering said he thought most programs do isolate islets from obese
donor pancreases because they are available. In his opinion, the reason
for late failure in transplantation is more immune-related than islet
mass-related. The experience in islet autotransplantation indicates that
patients who received a very low β-cell mass (2,000 or 3,000 islet
equivalents per kilogram, or one-third of what an islet autograft
recipient would receive) showed stable function long-term. In the
Minnesota islet autograft data, late failure was seen in no more than
one or two patients out of 110 transplanted so far; thus it was a rare
occurrence.

In answer to Dr. Sherwin's question about allocating human donor islets
to islet allograft recipients based on matched tissue antigens, Dr.
Hering replied that it is probably helpful, but not very practical. If
possible, Dr. Hering would do it, but it is difficult to accomplish.
Most programs have a very small list of islet recipients and finding a
patient with a 6-antigen match pancreas is very unlikely, so that is the
limiting factor.

Dr. Jose Caro, Eli Lilly and Company, asked if there was a plan to
develop collaborative arrangements among the transplant centers, employ
a common protocol, and jointly accrue enough patients to obtain a
reasonable amount of outcome data and then modify the protocol based on
that outcome data. The question was based on the seeming lack of
adequate outcome data possibly being related to the number of different
centers that are using different protocols and the relatively small
number of patients that each one of those centers had.

Dr. Hering responded that progress in any field in medicine is only
possible if well organized and carefully designed multi-center clinical
trials are organized to address clinically important questions. The very
first multi-center trial has just been more or less completed, testing
whether the Edmonton data can be confirmed at a number of additional
sites. Results will be presented at the ADA meeting and at the American
Transplant Congress later this year. One question is how to standardize
and address roadblocks. With NIH's establishment of the islet transplant
consortium, there will be many opportunities to promote collaboration
between centers and address important questions. Dr. Hering added that
designing an islet transplantation mega-study, involving a few hundred
patients, as has been done in hypertension or in diabetes intervention,
requires substantial resources not readily available. Dr. Hering
recommended using a multi-disciplinary approach and focusing on a small
subset of people with difficult-to-manage diabetes such as those with
severe hypoglycemia-related problems. Well-defined, controlled, and
consistent islet manufacturing processes would have to be in place. Once
a process is licensed for this very defined subgroup of patients,
additional resources through third-party reimbursement may become
available so other clinical trials can be performed. Dr. Hering pointed
out that the per patient cost for the type of trial under discussion is
\$100,000 to \$150,000, which is difficult for even NIH or JDRF to
sponsor.

Dr. Caro asked what FDA's position was about using a multi-center,
collaborative arrangement with a defined patient population and
agreed-on protocols to establish a defined starting point and then
modify the protocols based on outcomes. Dr. McFarland answered that he
thought FDA would support such an attempt, in general, if it provided
them with more clinical information. He reminded the group that an
important point is the quality of the islets that would be used by the
collaborative. FDA is currently involved in the INDs (Investigational
New Drug Applications) process with the ITN multi-center trials.

In response to a question about the possible benefit of expanding the
mass of the islets that are transplanted or supporting them after
transplant with, for example, GLP or exendin-4 or DP- IV inhibitors, Dr.
Hering said that any strategy that would accomplish this would be very
helpful. Dr. Gordon Weir and his group at the Joslin Diabetes Center
studied this in an animal model using GLP-1 and did not find evidence of
a beneficial effect in the first study. Dr. Hering was not aware of any
other studies.

Dr. Marcel Salive, Centers for Medicare & Medicaid Services (CMS),
stated that CMS was very pleased to be directed by Congress to
participate in the islet cell transplant trials under the Medicare
Modernization Act. CMS has begun the process in coordination with NIH,
FDA, and other agencies. Currently, CMS is providing coverage for
Medicare-eligible patients who are participating in the clinical trials.
In order to provide future coverage to Medicare patients, CMS needs to
see clinical evidence of effectiveness rather than surrogate markers as
endpoints. Dr. Salive asked Dr. Sherwin if the types of clinical trials
he proposed would be designed to provide such data.

Dr. Sherwin said they would. A problem in clinical trials is the amount
of duration required to show benefit. For people with severe
hypoglycemia who are nearly incapacitated by that complication,
Dr. Sherwin thought the answer would be easy and straightforward. These
patients do not do well long-term and consequently would benefit. The
patients who have kidney transplants can be followed for kidney outcomes
and to see whether the islet graft prolonged kidney graft survival,
which presumably would have an impact from the standpoint of Medicare.
That is why Dr. Sherwin proposed trials with those two groups of
patients. For the general patient with type 1 diabetes, longer trials
would be required to validate that islet transplantation was an
improvement over insulin therapy. Longer trials are more expensive. Dr.
Sherwin expressed the idea that the short-term trials with the
specialized subgroups would provide a valuable learning process and to
help design a longer, more expensive trial. At this point in time, Dr.
Sherwin said he doubted that one could prove that islet transplantation
can provide a better survival benefit and any major complication
differences for the majority of type 1 patients.

Dr. Hering agreed. The islet transplant community at this time is not
expecting coverage of islet transplantation for just any patient with
type 1 diabetes. Granted, coverage would be very helpful, for the
patients and for the field, for patients that present with diabetes that
cannot be managed satisfactorily by any other available treatment. This
is the place to start. Then, as treatments improve with respect to islet
manufacturing, or in particular, immunosuppression, and data from
randomized clinical trials becomes available, additional patient groups
could be considered.

The comment was made that diabetes and its treatment is more complex
than dealing with a malignancy. To begin with, defining the patient
at-risk is very subjective. The speaker liked Dr. Sherwin's suggestion
of having a patient cared for by a committed diabetes care team for 6 to
12 months before deciding that this person had uncontrollable diabetes.
Treatment advances in diabetes are happening all the time. There is
uncertainty as to which patients to study; there is uncertainty as to
what a good islet quality is; there is uncertainty about how to monitor
outcome; and there is uncertainty in the immunosuppressive protocol
selected. Designing a multi-center study that might be the very best
design one can come up with today would very likely be quite different
if designed 6 months later. This presents a very difficult conundrum.

Dr. William Tamborlane, Yale School of Medicine, said that the problem
with long-term clinical trials is that by the time one arrives at an
answer, the therapy is outdated. Dr. Tamborlane thought that a network
of transplant centers collaborating on targeted trials was a good idea.
A single study cannot respond to all the transplantation issues. A
multi-site effort would be more effective, in his opinion.

Dr. Caro added that the idea is not to get a protocol that is going to
answer all the questions, but rather an evolving protocol that changes
over time. Given the amount of information that is not known, it would
be good to at least have a starting point and then, as more is learned,
modify accordingly.

**Session V: Devices**

*Moderator: Patricia Bernhardt, Office of In Vitro Diagnostics, Center
for Devices and Radiological Health, FDA*

**Device Issues: Glucose \]Monitoring**

***William V. Tamborlane, MD**, Professor and Chief of Pediatric
Endocrinology and Diabetes, and Deputy Program Director, General
Clinical Research Center, Yale University School of Medicine, New Haven,
CT; Steering Committee Chair, DirecNet*

Dr. Tamborlane, whose background includes 25 to 30 years of working to
achieve good control of type 1 diabetes in children and adolescents as
well as being the current Steering Committee Chair of DirecNet (Diabetes
Research in Children Network), noted that DirecNet is an NIH-funded
collaborative study group of five centers, similar to what Dr. Caro
suggested for islet cell transplants. DirecNet's objective is to
critically evaluate the clinical usefulness of current and future
glucose sensors in youth with type 1 diabetes. Dr. Tamborlane stated
that one of the great strengths of the network is its outstanding
coordinating center in Tampa, Florida, the Jaeb Center for Health
Research.

Dr. Tamborlane explained that his presentation would try to answer the
following two questions:

-   What criteria should be used for approval of new glucose monitoring
    sensors?

-   Can data from continuous glucose monitoring sensors be used as
    outcome measures for evaluation of the safety and efficacy of new
    diabetes treatments?

Dr. Tamborlane said the answer to both of these separate, but related,
topics depends on sensor accuracy. This was the conclusion derived by
the DirecNet study group when they designed their first study that
focused on the accuracy of the two FDA-approved continuous sensing
systems---the Cygnus Glucowatch Biographer II and the Medtronic MiniMed
CGMS. For the DirecNet study, the investigators planned to recruit 90
youngsters ranging in age from 1 to 17 years, and were successful in
recruiting 89 (ages 3 17 years) in the record time of only a few months.
Dr. Tamborlane explained that each patient was admitted to one of the
inpatient clinical research centers (CRCs) participating in the study
for a 24-hour admission process that included serum samples for
reference glucose measurements collected every hour during the day and
every 30 minutes during the night. The samples were processed and mailed
to Dr. Mike Steffes' lab, which was also the central laboratory for
DCCT. The study participants wore at least one Medtronic MiniMed CGMS
and one Glucowatch simultaneously, and some wore two Glucowatches and
two Medtronic MiniMed CGMSs simultaneously. In addition to noting
spontaneous fluctuations in glucose, there was the intent to stress the
sensor systems by looking at their performance during acute
hyperglycemia and acute hypoglycemia. The hyperglycemia subprotocol to
cause a rapid increase in glucose involved a high carbohydrate liquid
meal without a pre-meal bolus of rapid-acting insulin. In the older
children, the equivalent of an insulin tolerance test also was done.

Dr. Tamborlane remarked that one of the wonderful advantages of working
in pediatrics is how the children respond to these kinds of studies. The
principle outcome of the DirecNet study was fairly standard
point-to-point differences between the sensor and reference glucose
values. Dr. Tamborlane pointed out that the differences can be looked at
in multiple ways: simple, absolute, relative, and relative absolute
difference. Looking at the simple difference, if there is random error
on either side of the reference value, then the difference should be
close to zero. If there is a systematic bias, then there will be a
consistent mean difference between the sensor and the reference values.
Looking at the relative difference, which is the difference divided by
the reference value expressed by a percent, one obtains a relative
absolute difference, or RAD, which was the primary accuracy metric used
in the DirecNet studies.

Dr. Tamborlane continued that another way to look at the performance of
sensors as well as meters is by International Standards Organization
(ISO) criteria, which says, "If the reference glucose is greater than 75
mg/dL, then the sensor reading should be within ±20 percent. If the
reference glucose is less than 75 mg/dL, rather than a percentile, the
sensor glucose value should be within ±15 mg/dL." DirecNet data were
expressed as a percent of paired values meeting these ISO criteria.

Main results of the DirecNet trials as presented by Dr. Tamborlane were
fairly consistent with published results for these sensors; however, the
data do support the argument that these are first-generation devices.
Their accuracy could be said to be analogous to the accuracy of the
original glucose meters that were introduced 20 years ago. The
Glucowatch reports glucoses every 10 minutes and the Medtronic MiniMed
CGMS every 5 minutes. The mean relative absolute difference in the
percent error for the Glucowatch was about 22 percent, and for the
original Medtronic MiniMed CGMS, it was about 26 percent. Dr. Tamborlane
said that, in looking at the overall dataset, the study investigators
decided that mean was not the best metric to use, that median was a
fairer test of the accuracy of these meters, because a few sensors were
outliers that pulled up the average value. The median value RAD data was
better: 16 percent for the Glucowatch and 19 percent for the original
Medtronic MiniMed CGMS, with neither meter meeting ISO criteria
consistently. Dr. Tamborlane explained that about 80 percent of the way
through the study, Medtronic MiniMed modified the sensor matrix that
they used, giving DirecNet the opportunity (albeit with a smaller number
of subjects) to look at the accuracy of the modified sensor, which was
much better (16% for mean RAD, 11% for median RAD, and within 72% of ISO
criteria). Correlations between sensor and reference values also were
better. Since the data for the later model was from only 1,120 paired
reference and sensor values and only from one or two lots, Dr.
Tamborlane recommended further confirmation of these encouraging
results. While the children were on the research unit, Dr. Tamborlane
explained that to make decisions regarding their therapy, the One-Touch
Ultrameter, a more mature technology, was used. In 1,200 pairs, r-values
between reference glucose and the Ultrameter values were 0.97, and the
accuracy was between 6 and 7 percent.

In looking at the data, Dr. Tamborlane cautioned the audience to keep in
mind that there is error involved with obtaining a reference value and
sending it to a central lab, where there is the possibility of error as
well. During the IV insulin test, the study measured and compared the
Ultrameter measurements with measurements from YSI and Beckman
instruments, which they had bedside for safety. Both sets of
measurements were sent to a central lab during acute hypoglycemia, and
there was no difference in the relative error between the instruments.
Dr. Tamborlane stated that this was an impressive performance and
indicated what the meter industry is currently able to produce for
patients.

Looking at error as a function of plasma glucose level, both the
Glucowatch and the Medtronic MiniMed CGMS had problems in the
hypoglycemic range (25 to 40 percent error in glucoses under 60), which
is an important issue related to FDA using continuous glucose monitoring
as a safety index. The Ultrameter did fairly well even in the
hypoglycemic range.

Dr. Tamborlane stated that, instead of just looking at point-to-point
comparisons, the sensors were compared for ability to pick up a real
hypoglycemic event and for incorrectly reporting a hypoglycemic event
that was not real. The data collected during the IV insulin infusion
test, where reference glucose dropped to values lower than 60 and
hypoglycemia was usually achieved, the modified Medtronic MiniMed CGMS
appeared to do best, although there were too few events to ensure the
results; the original CGMS did the next best; but only 12 of the 48
Glucowatches detected the episode.

The DirecNet study group was particularly interested in detection of
hypoglycemia at night. With the Glucowatch, there were 18 events where
the sensor said the patient had a night where the glucose levels fell
below 60, but only 10 of those were confirmed by the actual reference
glucose. The Medtronic MiniMed CGMS reported 26 events and only 8 were
confirmed, and the modified Medtronic MiniMed CGMS was accurate with 3.

False alarms, either for hyper- or hypoglycemia, were considered a very
important function for the sensors in relation to their use with
children. A selling point of the Glucowatch is that it has both hypo-
and hyperglycemic alarms. With the alarm set for a glucose under 60, the
Glucowatch only picked 23 percent of actual hypoglycemic episodes, and
had a 51 percent false alarm rate. Sensitivity was better at a setting
of 120 (92 percent of real events) but the false alarm rate rose to 85
percent. Dr. Tamborlane reported that, in practice, patients tend to
quit using the sensor at night after they, and their families, are
repeatedly awakened with so many false alarms. The Medtronic MiniMed
CGMS does not have an alarm system built into it; its sensitivity for
real events was better at 49 percent, but it also had a high "false
alarm" rate (58%).

In discussing metrics to use for analyzing the sensors, the DirecNet
study group chose not to use the Clark error grid analysis or
correlation analysis with R values for a number of reasons. In the Clark
error grid analysis, there are zones, good and bad, and a reference
glucose plotted against the meter or sensor glucose. The different zones
are intended to distinguish clinically meaningful versus less important
errors in glucose measurements. For example, when the grids were set up,
if the blood glucose was between 50 and 250, treatment was not required,
an easy decision. The correlate was that the grid divided glucose
measurements into zones that distinguished increasing clinical
significance of error, to ensure not mistaking hyperglycemia for
hypoglycemia, and treating the patient with insulin. Sensor accuracy
with the Clark error grid is usually measured by percentage of values
within the A and B zones. The problem with this, Dr. Tamborlane
explained, is that zones A and B are large enough that even inaccurate
sensors will hit them the majority of times. Secondly, current insulin
dosage adjustments are based on much smaller variations in glucose than
when the grids were initially set up (e.g., there is now a difference
between a 50 and a 250 and a correction dose is administered at 250).
Third, one can get a misleading notion of sensor accuracy through chance
agreement as in Dr. Tamborlane's example of randomly shuffling sensor
and reference glucose pairings, which a statistician at the Jaeb Center
did as a test, with 10,000 simulations. Even with these random pairings,
the result was the average A and B zone accuracy was still 76 percent.

Dr. Tamborlane next discussed the problems with correlation analyses of
r-values, beginning with the fact that r-values are so sensitive to the
amount of variation in glucose levels that their reliance is limited. In
correlation, variability is required. The DirecNet study group used the
example of four hypothetical simulated sensors, each with identical
accuracy, and 10,000 data pairs per sensor. Sensor value was equal to
the "true" value or the reference value plus a normally distributed
error with a standard deviation of 25 mg/dL. The actual mean of all the
glucoses was 200. For the analyses, the range of true glucose values for
each sensor was varied. The results were that if the reference values
ranged between 175 and 225, the Pearson correlation R value was 0.5.
With the same accuracy, if the range wais 50 to 350, the R value was
0.96.

Other limitations of point-to-point assessments of accuracy listed by
Dr. Tamborlane included that methods developed for meters are
single-point tests, which cannot capture the dynamic nature of
continuous glucose sensors. Also, it is difficult to assess trends and
there are issues about how to do accurate trend analyses to determine
how well sensors characterize acute changes in glucose. Dr. Tamborlane
stressed that these are very important questions that, hopefully, smart
mathematicians can address.

Dr. Tamborlane next discussed potential physiologic contributions to
so-called error between reference values of plasma glucose obtained by a
meter and sent to a central lab and sensor glucose values measuring
interstitial glucose concentrations. It has been demonstrated that there
is undoubtedly variability in the plasma and interstitial glucose
gradients during the day. In a Yale study, euglycemic-hyperinsulinemic
clamps were used at baseline and a sensor calibrated against baseline
plasma glucose levels where nothing was infused. In this process,
basically, the sensor is "told" what the plasma glucose level is, it
measures a current coming off the interstitial glucose, and comes up
with a ratio to account for the gradient between plasma and interstitial
glucose. Next a euglycemic clamp was done with an infusion of high doses
of insulin while maintaining plasma glucose unchanged, which lowered
interstitial fluid glucose concentrations dramatically, measured by
microdialysis, and the sensor followed the interstitial. This
demonstrated that there are possible physiologic reasons why there is
going to be some discrepancy between the reference blood glucose, or
serum or plasma glucose, and the sensor glucose, which may actually be
very important. Dr. Tamborlane said currently how to interpret these
differences is unknown. In addition, in comparing a reference plasma
glucose and an interstitial glucose, the interstitial is going to lag 10
to 20 minutes behind the plasma. If doing point-to-point assessments,
one must find a way to account for that lag time.

For future studies of sensor accuracy, Dr. Tamborlane stressed the
importance of studying children from diverse populations, especially
type 1 diabetics post-transplant, those with hypoglycemic disorders, as
well as type 2 diabetics and non-diabetics. When the Glucowatch and
Medtronic MiniMed CGMS originally came out, there was a lot of interest
in pediatrics to use these sensors to diagnose and manage
hypoglycemia-related disorders. Unfortunately, the accuracy was
insufficient, but there was still interest in seeing how well they
performed with non-diabetic as well diabetic individuals. When these
sensors, particularly the Medtronic MiniMed CGMS, were used with
non-diabetic individuals, it was discovered that the algorithms
developed to convert electrical current coming off the sensor into a
plasma glucose level were based on type 1 patients with wide
fluctuations, and those algorithms did not work in non-diabetic
individuals where the fluctuations were much more modest, so algorithms
had to be redone for non-diabetic studies.

Other areas for future studies recommended by Dr. Tamborlane would be
frequent sampling in an inpatient study with Clinical Laboratory
Improvement Amendments (CLIA)-certified laboratory methods and also an
outpatient study to investigate the accuracy of outpatient data using
well-characterized meter methods as reference values. Beyond accuracy,
Dr. Tamborlane called for testing the efficacy of using glucose sensors
in clinical management to lower HbA1c levels, including whether this
would lower or increase the risk of hypoglycemia. Dr. Tamborlane
referred to a plan to do this in an outpatient study with one sensor as
the therapy and the Medtronic MiniMed CGMS as an outcome measure,
because one could mask the patients to the CGMS data. However, the CGMS
is not a good outcome measure to determine the frequency of hypoglycemia
in clinical trials due to insufficient accuracy in measuring glucose in
the low glucose ranges. He added that the continued obstacle in looking
at safety related to hypoglycemia that goes beyond clinically important
events is that there is no simple test. There is no HbA1c for
hypoglycemia, just as there was no HbA1c for hyperglycemia until 1980.
Dr. Tamborlane noted that this inability to have a simple outcome
measure for hypoglycemic exposure in patients obviously has important
implications for islet cell transplantation as well as other therapies.

Another issue raised by Dr. Tamborlane was that not only do sensors need
to be accurate and effective, they also need to be user friendly or
patients will not use them. Also, how will patients and clinicians deal
with the reams of data from 24x7 sensors? Who will provide the support
to assess this data? Will the cost be reimbursed?

In responding to the question of whether current sensors are accurate
enough to be used for outcome measures for diabetic therapy, Dr.
Tamborlane said the answer depends on what is being measured.

-   For mean glucose values, the average difference between the
    Medtronic MiniMed CGMS profile and the actual reference was 2 mg/dL,
    so the answer would be "Yes." However, the HbAlc values are still
    easier and better.

-   For hyperglycemia, the answer would also be "Yes" since current
    sensors are reasonably accurate in the hyperglycemic range. With the
    CGMS, one can mask the patients to the sensor data, and a number of
    different metrics to do analyses can be used, such as meal-related
    excursions, AUC (area under the curve), or amount of time during the
    day above cut-offs.

-   For glycemic variability, again "Yes," using day-by-day profiles,
    MAGE values, M-values, standard deviation scores, and so forth. The
    therapeutic question of particular importance to FDA is "Is
    postprandial hyperglycemia an independent risk factor beyond HbA1c
    for diabetic complications?" The answer is not known.

-   For hypoglycemia, the answer is "No. They are not accurate enough."

According to Dr. Tamborlane, the real excitement about continuous
monitoring is not only the present, but the promise for the future,
especially the potential to combine sensors and pumps and develop a
closed-loop artificial pancreas. Studies completed at the University of
California at Los Angeles tested the Medtronic Guardian system, which is
a wireless, continuous glucose monitoring system that sends real-time
glucose readings from a sensor via wireless transmission to a computer
that then drives a pump to respond to high and low glucose alarms.
Ultimately, the sensor connected to the pump will have a computer in the
unit itself.

In using such a closed loop system to regulate overnight insulin
delivery to a patient with type 1 diabetes, the concern would be the
sensor's reading higher than the true plasma glucose level, and
therefore extra insulin would be infused when the plasma glucose was
normal. Dr. Tamborlane said the solution is to set the target at 120 at
night so that, even if the sensor is mis-reading plasma glucose by 50
percent, the pump will go back to basal insulin infusion when the
glucose hits 80. If the error is 100 percent, there will be a
back-to-basal insulin infusion when the glucose gets to 60. He stressed
that such an overnight insulin delivery to control glucose in the type 1
patient would be a tremendous therapeutic advancement.

**Pumps: Hopes and Expectations**

***Christopher D. Saudek, MD**, Hugh P. McCormick Family Professor of
Medicine; Director, Johns Hopkins Diabetes Center; and Program Director,
General Clinical Research Center, The Johns Hopkins University,
Baltimore*

Dr. Saudek suggested that, broadly speaking, a cure for diabetes could
be considered achieved if the person were able to forget that he or she
has diabetes, and were able to live life normally, free of the
complications of diabetes. Dr. Saudek said he thought it reasonable to
consider approaches to "cure" as either biological approaches or
mechanical. Today those present had heard about organ transplants and
islet cell transplants as therapies and, although not mentioned,
embryonic and adult stem cells also were possibilities. As a mechanical
approach, "open loop" pumps have been around for a long time. There is
an external open-loop pump and an implantable open-loop pump. With
continuous sensing, the ultimate answer will be a closed loop external
or implantable pump. All the approaches have to be assessed for efficacy
and effectiveness within particular circumstances and timeframes.

The current conventional treatment of diabetes is multiple daily
injections of a long-acting glargine and short-acting insulin
preparations, which are adjusted according to meals and bedtime. Dr.
Saudek said that subcutaneously delivered insulin response is affected
by a whole series of variables such as the depth, the location, the
surrounding tissue, heat of the tissue, and so forth., all of which
contribute to making injectable insulin imperfect.

The theory behind external pumps and, in fact, implantable pumps is to
establish a known basal rate that can be varied, but is relatively
constant, as an infusion and to supplement that by specific boluses that
are given by the patient choosing the dose and given precisely in the
same spot as a relatively exact amount of insulin. The currently
available external pumps have developed from the "Continuous
Subcutaneous Insulin Infusion" (CSII) first accomplished with the Mill
Hill Infuser. The new models of CSII are small, relatively convenient,
but still injecting from a syringe housed in the external device,
through a catheter into subcutaneous space. In the last year or so, Dr.
Saudek said that telemetry from a glucose monitor has been one newly
available approach, the pump then doing some of the arithmetic that
patients ordinarily do when they calculate a bolus dose. This telemetry
system, available as the Medtronic MiniMed Guardian device, can suggest
an insulin dose based on the blood sugar. As mentioned by
Dr. Tamborlane, Medtronic MiniMed has also developed--- and had approved
recently---the Guardian System, a telemetry system that takes a sensor
reading and telemeters it to an alarm system. There are, then, continual
improvements being made on the available external delivery and sensing
systems.

External pumps are now a viable business and have been an available
option since the 1980s for treatment of type 1 and unstable type 2
diabetes. Regarding indications for using a pump, Dr .Saudek commented
that the distinction between type 1 and type 2 diabetes is, in some
clinical respects, artificial since beta cell secretory capacity in type
2 deteriorates, and patients can end up so insulin-deficient as to be
metabolically similar to type 1 diabetes. Insulin pumps may be indicated
for unstable, labile diabetes, regardless of whether type 1 or type 2
diabetes is the underlying diagnosis. Well over 100,000 have been sold,
produced now by at least four manufacturers (Medtronic MiniMed,
Roche/Disetronic, Deltech, and Animus).

Dr. Saudek listed advantages and disadvantages of the external pumps.
The external pump offers flexibility of meal and activity timing. The
patient can choose a meal time, even skip a meal, and theoretically,
with the right basal rate going, not have to worry about eating on time.
Other advantages are freedom from multiple daily injections, more
precise insulin delivery patterns, and true basal/bolus insulin
delivery. Most of the evidence suggests improved glycemic control. A
major limitation of external insulin delivery is that the patient must
wear the device at all times, and some people do not like that, are
truly phobic about it. Other disadvantages include occasional skin
irritation, infection, need to change the site regularly, poor skin
insert sites, and peripheral insulin delivery. Dr. Saudek stressed that
therapies such as injectable insulin, external pumps, and even whole
pancreas transplants deliver insulin peripherally, not hepatic portally.

When implantable insulin pumps (IIPs) were invented, the potential
advantages included that there was none of this externality that many
patients find very inconvenient. The maintenance or refill procedure is
done only every 3 months, rather than every 3 days or so as required by
external pumps. The implantable provides the more physiologic, hepatic
portal insulin delivery, with the potential advantages of that for
hepatic glucose handling, lipids, and so forth. Dr. Saudek referred to
the latter as potential advantages because while the exact effects of
portal delivery of insulin is an area of science he thinks is
under-tapped, it does appear to have beneficial clinical effects.

Dr. Saudek noted that the history of the implantable pump is almost as
long as that of islet cell transplantation. Dr. Buchwald started in the
1970s with the continuous rate pump. NASA in the late 1970s developed a
little pump that landed on the Mars surface and became the basis of a
so-called Programmable Implantable Medication System (PIMS) developed at
the Johns Hopkins Applied Physics Laboratory, which then became the
basis of today's implantable pump. There have been a couple of other
manufacturers of implanted pumps, but the present day Medtronic MiniMed
pump is the one that has linearly descended from the PIMS.

Preclinical dog trials conducted by Dr. Saudek in the mid-1980s led to a
proof-of-concept set of human implantations done in the late 1980s, with
about 21 implanted pumps. These studies showed that a variable rate pump
could work and could manage type 1 diabetes. The trials were greatly
expanded in the 1990s and the incidence of pump implantations during the
mid-1990s increased dramatically.

Between 1990-2000, Dr. Saudek said it was shown that IIP therapy was
safe and effective on a large scale, that the refills were practical and
safe, and that metabolic control and lipid metabolism could be improved
with the IIP and hypoglycemia could be lessened. It also was found that
the catheters and the insulin are vulnerable points that have to be
taken very seriously in the evaluation process. Autoimmunity, pocket
complications, refills, and flushes were manageable, but they also were
issues, and battery programming needed to be improved. Dr. Saudek
presented information on each of these positive points and areas of
concern.

***IIPs are feasible on a large scale***. The number of IIP implants per
year grew worldwide in the early 1990s. In the mid-1990s, there was a
brief period of decline due to an insulin problem, which has been
resolved, and now the field is back to more and more implants. Most
active centers are in France because the French government chose to
support and pay for pump implantations and the pumps; therefore, MiniMed
spent a lot of its time working in France to develop the technology. In
2000, there were 340 active patients and in 2003, there were 365 in
France and 59 in the United States for a total of 424.

***Refills are practical and safe***. The refill procedure involves a
little scrubbing of the abdomen, some xylocaine in the skin, an
introducer needle, and then a thinner needle going into the refill port
of the pump, pulling the old insulin out, and then, with another
syringe, putting new insulin in. Dr. Saudek explained that one of the
key safety features of these Medtronic MiniMed pumps is that the
pressure of the reservoir is negative relative to atmosphere, so that
when the insulin is replaced, the "old" insulin must be pulled out but
when the needle with new insulin is inserted, because of the negative
pressure, the insulin is drawn into the pump, not pushed. This is a
major safety feature when introducing about 6,000 units of insulin in
the refill procedure; if the needle is not actually in the pump
reservoir the insulin will not be injected; it will be drawn in only if
the needle is properly in place. The refilling procedure is now routine,
and takes about 10-15 minutes, done every 3 months.

***Metabolic control can be improved with IIP***. Dr. Saudek expressed
some skepticism about the ability to prove superiority of any one method
of insulin delivery over another, perhaps excepting fully closed loop
delivery, noting that metabolic control can be improved with any variety
of insulin delivery approaches. It can be improved by a diabetes team,
an attentive endocrinologist, an external pump, an implanted pump, a
transplant, and so on. It is not so much that measures of metabolic
control are not important---they are. But in considering relative
approaches to the management of diabetes, regulators should not consider
improved blood glucose control the only parameter, since it is such a
"manipulateable" feature, subject to all levels of bias in study design
and investigator or patient involvement. This said, Dr. Saudek's Johns
Hopkins data suggest that HbA1c is reduced and mean plasma glucose is
reduced significantly (Udelsman R., H. Chen, K. Loman, H.A. Pitt, C.D.
Saudek. 1997. Implanted programmable insulin pumps: 153 patient years of
surgical experience. Surgery 122:1005-11).

A number of other studies of implanted insulin pumps also showed a
decrease in mean blood glucose with IIPs and a drop in HbA1c and
introduced the fact that the standard deviation of blood glucose came
down very significantly in this study. The French consortium, Evaluation
dans le Diabete du Traitement par Implants Actifs (EVADIAC), has
collected very good data on implanted pumps, comparing subcutaneous and
multiple dose insulin with external pump insulin and with implanted pump
insulin. Their experience also showed reduced HbA1c and a marked
reduction in severe hypoglycemia.

***Hypoglycemia can be lessened***. A large, randomized,
company-independent trial in the VA system was, in Dr. Saudek's opinion,
the best and largest randomized trial done. The initial goal was to
achieve equal glucose control with multiple dose therapy and implanted
pump therapy. The goal was stated prospectively, to get equal measures
and to look at other parameters. Dr. Saudek stressed to those who are
involved in regulation of devices and evaluation, that if mean blood
glucose is lowered without lowering the standard deviation, the result
is what happened in the DCCT, there is an increase in hypoglycemia. If
the mean glucose and the standard deviation are both lowered, then it
can be proven medically or statistically that people are not driven into
hypoglycemia. This can be seen in downloads of glucose meters and so on.
He emphasized that in managing diabetes, it is very important to look at
how variable the blood glucose is, whether you call it MAGE or whether
you call it measure of standard deviation. Results in the VA trial
demonstrated significantly decreased definite and suspected mild
hypoglycemia. Results also showed decreased severe hypoglycemic
reactions, although the number of events was not large enough to be
significant.

***Lipid metabolism can be improved***. Dr. David Kelley measured free
fatty acid data showing a more finely tuned regulation of fatty acid
metabolism for patients on the implanted pumps than on subcutaneous
insulin. Dr. Barbara Howard also published favorable changes in lipid
status with IIP therapy.

***Portal absorption of peritoneal insulin delivery**.* Dr. Saudek
presented older data from Schade to show that there is a portal
peripheral gradient of tagged insulin, when you infuse insulin into the
peritoneal space. This indicates, at least to some extent, that this
insulin is absorbed into the hepatic portal system and there is a
hepatic portal gradient established by peritoneally delivered insulin.
Another study of Micossi et al. showed that the different routes of
delivery---upper peritoneal, lower peritoneal, intramuscular and
subcutaneous---all had different pharmacokinetic characteristics. Dr.
Saudek commented that the millimeter differences between intramuscular
and subcutaneous insulin can be a significant factor in the variability
seen with glucose in response to conventional insulin injections. With
IIP therapy, the free-floating intraperitoneal catheter tip may vary in
its lower-versus-upper peritoneal cavity insulin delivery, although this
has not been studied.

***Catheters and insulin are a vulnerable point**.* Dr. Saudek explained
that in the first dog implantation, there was a vicious attack on the
catheter by the peritoneum. The Johns Hopkins study group worked on
catheter materials and came up with a much better result. Today catheter
blockage is occurring at about 10 to 15 percent per year. A side-port
catheter is used now that can be pushed through blocks.

The early dog trials showed that insulin precipitation in the catheter
meant that the insulin was not going to go very far with a clot right in
the middle of the catheter. A stabilizing factor worked; polyethylene
polypropylene glycol stabilized the insulin very well. It was first used
*in vitro* and then *in vivo* for upwards of 8 years without any
indication of an insulin problem. Then, all of a sudden in the
mid-1990s, the EVADIAC group noted that there was a systematic increase
in the pump slow-down rates and problems such as catheter survivals that
did not relate to how long the pump was going, but related to the
stability of the insulin being used. Dr. Saudek explained that what
happened was that, in the mid-1990s, Hoechst changed its insulin
manufacturing technique, causing serious problems. The insulin was
aggregating in the catheter and precipitating on the pump valves,
causing some backflow and under-delivery of the insulin. Catheter flush
and pump procedures were developed to handle the problem temporarily.
Then Van Entwerp at MiniMed developed a technique for the rapid
assessment of insulin stability, so it was not necessary to wait months
to assess the stability of insulin preparations. In the meantime, work
was done to improve the insulin, so that the newer Aventis HOE 21 PH
seems to be stable at this point. Today, the insulin being used is much
better than in the mid-1990s.

***Autoimmunity, pocket complications, and refills/flushes are
manageable***. Reported data indicate that the incidence of pump pocket
infections varies from 0 to 28 percent per patient year, which is a very
wide range. The mean was 7 percent. Dr. Saudek said the importance here
is that it is difficult to clear if it happens. Usually, the device has
to be explanted or changed entirely.

Autoimmunity has also been a long-time concern, sometimes bordering on
obsession regarding anti-insulin antibodies in IIPs. One study showed an
increase in insulin antibody titer. The amount of total antibody
increase was divided up into so-called responders and non-responders,
and obviously, the responders responded and had much higher insulin
antibody titer. Dr. Saudek said he did not favor this type of study
design. Over the years, the responders' levels tended to come back down,
possibly indicating regression to the mean; however, in looking at the
data, a wide range of insulin antibody levels were found. Then a
syndrome appeared that seemed to suggest what were called "fasting
lows." Even cutting the infusion rate way down overnight, people were
still low in the morning. On looking at the antibody titer of people who
were suspected of the syndrome clinically, it was, in fact, the people
who were at the very high end of the antibody syndrome who had the
fasting lows, indicating that antibodies can be induced in persons with
a high affinity. There were no metabolic consequences overall, but Dr.
Saudek said he thought that IIPs do occasionally cause high antibody
titer and a prolonged insulin action that is rarely clinically
significant.

Dr. Saudek remarked that when MiniMed became Medtronic MiniMed, the
implants slowed down while the company went through its consolidation
period, before resuming implantations in 1993. Now Johns Hopkins is
implanting the new IIP model 2007, which Dr. Saudek showed in a slide.
The new model has a much smaller and more efficient communicator, and
the battery life is now up to 8 years.

In discussing the future of insulin pumps, Dr. Saudek stressed that he
certainly hoped patients did not have to wait too long for a closed-loop
system, but cautioned that it will take time to develop because it
requires very high levels of safety and reliability of both the sensor
and delivery systems. Nevertheless, it is too limited to think of the
closed loop system only as entirely implanted. It could be developed as
an external-to-external system, with an external pump and a subcutaneous
sensor; or it could be a combination of an external sensor and an
implanted pump; or implanted sensor with external pump; or both
implanted. Dr. Saudek stated that developing the software to link the
glucose monitoring with the insulin delivery will not be easy, but is
do-able. Initial forays and initial trials into developing such a closed
loop system are beginning, but Dr. Saudek sees the successful
development of a safe and successful system as being some years away.

Dr. Saudek acknowledged the contributions of his collaborators at Johns
Hopkins, the founding fathers and young contemporaries in the field,
and, in particular, the research subjects who have been such an
important part of the study projects to develop and test insulin pumps.

**Discussion**

Ms. Bernhardt opened the discussion period by asking if Dr. Tamborlane
and Dr. Saudek thought that before a closed-loop system could actually
be used clinically that management of diabetes would have to change to
be based on interstitial values rather than blood glucose values. Her
question was based on taking into account the physiological differences
between the interstitial glucose and the blood glucose, and the fact
that current diabetic management is based on blood glucose measurements.

Dr. Tamborlane responded that he had raised the issue of interstitial
versus blood glucose values because of small differences in accuracy.
Another physiologic observation that may or may not have real clinical
importance is that 10 minutes off may not make a big difference in how a
patient is treated, but it may make a big difference in the error of the
method used. For example, his group did a more complicated clamp study
where there was a measurement at baseline and then at an acute
euglycemic phase, a hypoglycemic phase, and an acute hyperglycemic
phase, and there was a discrepancy. If all calculations were done at
basal, aligning the gradient between the plasma and interstitial
resulted in an abnormal sensor value. On the other hand, if measurements
were calibrated throughout the four different phases of study, and the
small changes in gradients were averaged out, the numbers came out quite
well. Dr. Tamborlane added that this is something to consider, but it
should not have a major impact on use of the closed loop system.

Dr. Saudek commented that his group had done some studies of time-lag
between subcutaneously measured glucose and blood glucose, finding also
that there is a gap of between 9 and 12 minutes. They did not find a
consistent difference dependent on whether the blood glucose is
increasing or decreasing under insulin's effects, contrary to the
findings of some others. In driving a closed-loop system, what may be
more significant than the GLP issue is whether reproducing a "cephalic
phase" of insulin secretion (i.e., the anticipation of an up-coming
meal) is needed to normalize postprandial glucose. The patient would
have to somehow signal the pump that he/she was going to eat, because
the pump would have no way of knowing that (i.e., no way of reproducing
a cephalic phase of insulin secretion). Dr. Saudek said that he doubts,
however, that this is clinically significant, and emphasized that
absolute normality of glycemic response is not necessary to control
blood glucose between 90 and 110. Diabetic complications should be
preventable with something a lot less fine-tuned than that.

Dr. Tamborlane added that the point is particularly relevant to the
external-external model, where insulin is infused subcutaneously.
Between the time the glucose is rising on the sensor and insulin is
being augmented and delivered subcutaneously, there is that lag time.
Two separate issues with the external-external are "How well can
postprandial excursions be controlled and then what about overnight?"
The overnight does not have to be extremely accurate. Gains on the
algorithms can be adjusted fairly quickly to tell the pump how fast to
infuse the insulin, so that even if there is not a perfect glycemic
excursion---the peak values may go up into the low 200s---but 2 or 3
hours later they will be back to basal. Looking at postprandial
hyperglycemia data in 56 youngsters with HbA1c of about 7.5, which is
outstanding for children, 50 percent of postprandial glucoses were over
300.

Asked to expand on his concern about control of variability,
particularly as it relates to postprandial glucose, and why this
happens, given the tools available, Dr. Tamborlane answered that he
supposed the normal pancreas does respond to cephalic phases. He related
an anecdote about when he was a student in medical school. The students
were required to fast for 24 hours, taken into a room and shown a big
meal, and then had blood drawn to measure the increase in their insulin
levels based on seeing the meal. That is probably the cephalic phase
where the pancreas is primed to secrete insulin even before meal
ingestion. Portal delivery may affect the post-meal excursion, but Dr.
Tamborlane said he doubted this was clinically significant.

Dr. Fradkin asked Dr. Saudek for more detail about the differences in
lipids that he saw when delivering the insulin portally versus
peripherally and also, did he look at any inflammatory markers such as
CRP or plasminogen activator inhibitor-1 (PAI-1). Dr. Saudek said they
have not looked at inflammatory markers. In the VA study, Dr. Kelly did
look at fatty acid metabolism and found free fatty acids to be more
finely tuned with the implanted pump. Dr. Barbara Howard also has shown
there is less atherogenic LDL with the implanted pump. A thorough
fractionation of lipids has not been done, but he thought it would be
interesting to see whether portal delivery makes any difference.

In reply to a question about whether anyone had put GLP-1 in a pump to
treat type 2 diabetes, Dr. Saudek had not heard of this being done. He
had received a call at one time about putting growth hormone in a pump
for cattle, but to do this was too expensive. The regulatory process
takes a long time, which is reasonable.

Asked if he thought the current sensor devices were accurate enough to
be used to manage hypoglycemia unawareness, Dr. Tamborlane said he
thought this would certainly be worth a study, especially in patients
who suffer 5 or 10 treatable episodes a week that lead to serious
defects in their regulatory responses.

Related to the issue of quality of life, as came up earlier in the islet
transplant discussion, Dr. Tamborlane asked if the FDA ever put on the
label, information about quality of life. For instance, given two
hypothetical therapies, a standard therapy and a new therapy that had a
non-inferior efficacy but superior quality of life, would this
information be reported on the label? The reason for the question was
the reimbursement problem that concerns most everyone. Fortunately,
pumps in children are not a big problem, but there are artificial
barriers put up by insurance companies unless one can show that the
patient has failed every other therapy.

Dr. Orloff answered that a group at FDA is working intensely on quality
of life issues and instruments to measure it. Within CDER, institutional
procedures and policies are being developed to give guidance,
essentially, to industry for developing products with quality of life
measurements and thereby labeling them. If two products had non-inferior
efficacy, or had equivalent efficacy, but there was a difference in some
other aspect, then in that instance, to some extent, the quality of life
would fall under the rubric of safety. The reason for this would be
because, as an example, refractory problems with repeated hypoglycemia
are ultimately a safety issue. Clearly, there is a quality of life
aspect in terms of the psychological misery, but FDA is primarily
interested in comparative safety of products that have essentially
equivalent efficacy and would use that as a way of judging the overall
merits of the therapy.

Dr. Tamborlane commented that this was very helpful, because there are
aspects of quality of life that have to do with symptoms or adverse
effects of the therapy, but there also are aspects that are simply
quality of life that usually fall under the rubric of patient
convenience, which is not looked on favorably by insurance companies.
One could say that an aspect of what is being called convenience is that
life is more livable with the disease when there is a better way of
delivering a drug to a patient or monitoring control of the drug's
action.

Dr. Orloff remarked that it was his impression that currently there is a
change from the time when FDA would have said that greater convenience
would have had to translate to greater efficacy by showing that, for
example, people tended to adhere to the therapy better, compliance
improved, and thus some meaningful clinical outcome was improved. Now
FDA is saying it is comfortable with validated, tested quality of life
instruments that are customized for the disease and the treatment being
studied.

Dr. Tamborlane replied that diabetes care is really all about making
life easier for persons with diabetes, but calling a therapy tool or
measure a "convenience" is not usually understood in this light. He was
very glad that FDA was interested in this. He also suggested that tools
for measuring the quality of life of approaches and concepts were
needed.

Dr. Orloff offered some observations he thought might be valuable in FDA
and NIH interactions. Quality of life is an interesting rubric that has
come to take on a lot of meanings, but what they were talking about here
was quality of life specific to treatment. In other words, quality of
life is a big area. Quality of a person's treatment for diabetes is
specific. In clinical trials for drugs, quality of life is specific to
that trial. In asking about the impact of one form of therapy versus
another form of therapy, on how the patient perceives life as a person
with or without, in this case, diabetes, Dr. Orloff said he would be
cautious in trying to get standardized instruments that would fit all
possible scenarios, because that would be difficult to do, given the
different kinds of profiles that drugs present in terms of how people
react to them, how they incorporate them, and the symptoms that go along
with them.

For Dr. Marrero, an important point was that quality of life is a moving
target in relation to therapy. While initially a patient may not like
something; later, with experience, the person may like it a lot. He
cited his own experience with the insulin pump as an example. In the
beginning, he did not like the pump at all. As mentioned by Dr. Saudek,
it was an external device constantly attached to him. With time and
experience, it became more agreeable. His assessment of his quality of
life thus varied, based on his initial and then later experience.
Questioned in the initial phase, his response would have been very
negative. Six months later, his assessment would have been very
different. This is an important issue, because a patient's decisions
about treatment are based on the quality of treatment life---what it
does to one's life and well-being in the long-term, what it does in
terms of convenience of management of the disease, what the tradeoff is
in terms of efficacy versus tolerability, and so forth. Dr. Marrero
strongly recommended that this quality of life issue be amplified in the
interface between FDA and NIH.

The first day's meeting was adjourned at 5:37 p.m.

**[Day 2: perspectives on the Future of Prevention and
Therapy]{.smallcaps}**

**Session VI: Prevention of Type 2 Diabetes**

*Moderator: Sanford Garfield, PhD, Senior Advisor for Biometry and
Behavioral Research Program, DDEM, NIDDK*

**The Metabolic Syndrome**

***Robert H. Eckel, MD**, Professor of Medicine and Professor of
Physiology and Biophysics, University of Colorado Health Sciences Center
(UCHSC); Denver; Program Director, NIH-sponsored Adult General Clinical
Research Center, UCHSC, Denver*

In the absence of Dr. Barbara Howard, who could not attend the meeting,
Dr. Eckel's task for the day was to cover both her and his portions of
the agenda. First, he discussed definitions, demographics, and disease
risks related to the metabolic syndrome, particularly risks for
cardiovascular disease and diabetes. Secondly, he spoke of the metabolic
syndrome as a therapeutic target for the prevention of type 2 diabetes.

**Overview of Metabolic Syndrome**

**Definitions**. Dr. Eckel presented the following major definitions of
the metabolic syndrome as offered by (1) the National Cholesterol
Education Program (NCEP) and the Adult Treatment Panel III (ATP IIII)
guidelines; (2) the World Health Organization (WHO); and (3) for the
American Association for Clinical Endocrinologists (AACE) and the
Association of Clinical Endocrinologists, the insulin resistance (IR)
syndrome:

**NCEP/ATP** **WHO**

3 or more Hyperinsulinemia or fasting plasma glucose [\>]{.underline}
110mg/dl

Abdominal circumference AND at least 2 of the following

men \> 40 in women \>35 in Abdominal circumference:

Triglycerides \> 150 mg/dl Def. 1: W/H \> 0.90 or BMI \> 30 kg/m^2^

HDL cholesterol Def. 2: Waist [\>]{.underline} 94 cm (37 in)

men \<40 mg/dl women \< 50 mg/dl Dyslipidemia

Blood pressure \>130 diastolic or \> 85 systolic Triglycerides
[\>]{.underline} 150 mg/dl OR

Glycemia as fasting plasma glucose \> 110 mg/dl HDL cholesterol \< 35
mg/dl

Blood pressure. 160/90 OR on medication

Microalbuminuria, AER \> 20 μg/min

**AACE/ACE**

Cluster of abnormalities

> Blood pressure and lipid criteria of NCEP/ATP III
>
> Abnormal glucose tolerance (i.e., if type 2 diabetes not present)

Fasting glucose of 110-125 mg/dl OR

> 2-hour post-glucose (75g) \> 140 mg/dl

BMI and waist circumference increased risk but

> Not a criterion

Needs to be adjusted for ethnicity

> Other factors increasing risk
>
> E.g., family history of type 2 diabetes

Dr. Eckel noted that the criteria for glycemia has been reduced to \>
100 mg/dl, which will change the prevalence of the metabolic syndrome
but only by a couple of percents, not 5 to 10 percent. He added that the
NCEP/ATP definition is more CVD-driven whereas the WHO definition is
more diabetes-driven. This difference is important when speaking of
preventing diabetes. Hyperinsulinemia in the WHO definition is defined
as the upper quartile of the non-diabetic population. AACE urged glucose
tolerance testing if diabetes itself were not already present. AACE
allowed for ethnic differences in waist circumference. For example,
African Americans tend to have a larger waist but the type of fat
distribution varies (decreased visceral, increased subcutaneous).

In Dr. Eckel's opinion, the metabolic syndrome is more than these
criteria. If one thinks of the metabolic syndrome as the insulin
resistance syndrome, which is open to controversy, the following
components that affect insulin resistance would apply:

-   Cigarette smoking.

-   Presence of small dense LDL and HDL particles.

-   Increases in the following:

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-   apoB, which reflects atherogenic dyslipidemia

-   uric acid.

-   fibrinogen, PAI-1, viscosity.

-   inflammatory markers as reflected by increased hsCRP, IL-6.

-   asymmetric dimethyllarginine (decreased nitric acid).

-   homocysteine.

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```
-   Decreases in adiponectin, reflecting insulin sensitivity.

**Demographics.** Dr. Eckel stated that the current emphasis on the
metabolic syndrome is the result of the prevalence of obesity. According
to the 2001 Behavioral Risk Factor Surveillance System (BRFSS), every
State now has a greater than 15 percent prevalence of obesity, in spite
of the inaccuracies of self-reporting body weight and BMI in a telephone
survey. Data from National Health and Nutrition Examination Surveys
(NHANESs) show that since 1999, there has been a 2½ to 3-fold increase
in the prevalence of obesity as defined by a BMI \> 30 kg/m^2^.^.^In
fact, data for obesity in the United States projected by Dr. Peter
Kopelman in 2000 (Kopelman, P.G. Nature Insight 404:637, 2000) were
superseded by the later NHANES data. However, if Dr. Kopelman's slopes
continue as projected, 42 percent of Americans will have a BMI \> 30
kg/m^2^ by 2025. NHANES data also show a dramatic increase in obesity in
children and adolescents over the last four decades. Dr. Eckel noted
this ensures we will have the metabolic syndrome with us for some time.

**Etiology of Obesity**. Dr. Eckel explained that the issue of obesity
relates to the balances between energy intake and energy expenditure.
The gene pool has not changed, although today there is awareness of
monogenic syndromes and susceptibility genes. The environment is where
most of the problem has arisen through increased food availability,
especially energy-dense foods and larger portion sizes, and reductions
in physical activity.

Dr. Eckel described an experiment asking what the effects of being
sedentary for 24 hours had on substrate utilization and the energy
intake/expenditure balance in people randomized to either a
high-carbohydrate (60 percent of calories) or a high-fat diet (40
percent of calories), followed by a wash-out period, and then put on the
opposite diet. The important part of this longitudinal study, supported
by NIDDK, was the impact of this type of energy balance assessment on
changes in fat mass and body weight over 4 years. Subjects included
normal weight, overweight, and obese men and women and remained on the
diets for several weeks and then had energy balance measured in the hold
room calorimeter chamber where they lived and were inactive for 24
hours. These people were weight-maintaining before they entered the
chamber. The calorimeter assessed oxygen consumption and CO~2~
production, and because urinary nitrogen was known and protein balance
can be determined, fat balance and carbohydrate balance could be
calculated. On the high-carbohydrate and high-fat diets, subjects
respectively had 800 and approximately 925 calories of positive energy
balance. Those on the high-fat diet had 400 calories of fat balance,
whereas those on the high-carbohydrate diet were nearly zero for fat
balance. Dr. Eckel said that this last data indicates that those on the
high-carbohydrate diet, although overfed, did not convert the calories
to fat within the 24 hours of inactivity. The CHO balance was
understandably higher on the high-carbohydrate diet than on the high-fat
diet, but protein balance was the same regardless of diet.

Over the 4 years of the study, fat mass measured by kg/year changed by
0.31 ± 0.15, a p value of 0.0477, and weight measured by kg/year changed
by 0.29 ± 0.15, a p value of 0.0592. Dr. Eckel pointed out that this
represents the importance of power analyses in predicting outcomes
because they had powered a p value of 0.05 for weight gain over the 4
years. Dr. Eckel stated that the overall results of this study, after 4
years of subsequent analysis, showed that it was *how* people responded
to carbohydrates that determined their weight and fat mass. In a 24-hour
inactive state, if a person is in positive carbohydrate balance, then
the person is protected from weight gain or fat mass gain.

Dr. Eckel said the overall prevalence of the metabolic syndrome is about
23-24 percent; however, NHANES reports differences in populations.
African-American men probably have a lower prevalence because their
triglycerides are lower and their HDL is higher. Hispanic women have a
greater prevalence, probably due to a combination of waist circumference
and fasting glucose. Of the components that lead to the prevalence of
the metabolic syndrome, waist circumference is more prominent in women
than in men; triglycerides are higher in white men, which probably
drives the higher prevalence of the syndrome in white men. Men and women
are about equal in HDL cholesterol (\< 40 men, \<50 women). Hypertension
and fasting glycemia are higher in men than in women.

**Causes of Metabolic Syndrome**. Dr. Eckel pointed to obesity as
possibly the foundation of the metabolic syndrome, but in discussing
causes, there remains the issue of whether the metabolic syndrome
represents an insulin-resistant state. He noted that Dr. Gerald Reaven
had established the principles of the metabolic syndrome a decade before
its definition by listing a number of covariants that are highly
associated with each other and reflect inadequacies in insulin
sensitivity. Free fatty acids (FFAs) are central to the development of
the metabolic syndrome or to insulin resistance. One of the most
sensitive impacts of insulin action is anti-lipolysis. Once there is an
increase of FFAs, then lipolysis tends to be enhanced, which results in
a vicious cycle of increased production of FFA and insulin resistance.
The FFA burden then drives the prothrombotic state and the production of
atherogenic lipoproteins, which are modified in density. The increase in
FFA flux also drives the defect in insulin--mediated glucose disposal
and the increased production of glucose by the liver and kidney, and in
susceptible individuals, this leads to impaired glucose tolerance and
hyperinsulemia. Dr. Eckel stated that the link between hypertension and
insulin resistance is much more questionable and has generated
considerable controversy. He cited an article by Dr. Gerald Reaven, Dr.
Earl Ford, and others in the May 2004 issue of *Diabetes* (Diabetes.
2004 May;53(5):1195-1200),\] that reported the results of steady state
plasma glucose (SSPG) tests in more than 400 persons that identified the
metabolic syndrome in about 20 percent. The study investigators did not
find any relationship between SSPG and blood pressure. Dr. Eckel thinks
that, therefore, the metabolic syndrome in part reflects insulin
resistance, however if hypertension is to be included other factors must
be involved.

**Metabolic Syndrome and Risk of Atherosclerotic CVD**. Dr. Eckel
presented data from the Kuopio study that investigated the impact of the
metabolic syndrome, using WHO criteria, for mortality, in 55-year-old
men, from coronary heart disease, CVD, including stroke, and all other
causes of mortality. The study showed that when the data was adjusted
for cholesterol, smoking, and other known cardiovascular risk factors,
there was an impressive relative risk of the metabolic syndrome
impacting all three causes of mortality in the study subjects. Dr. Earl
Ford in NHANES III presented a comparison of ATP III and WHO criteria
and the prevalence of self-reported myocardial infarction and stroke in
persons over the age of 20 who had or did not have the metabolic
syndrome. Dr. Eckel pointed out that Dr. Ford's data indicate that WHO
and ATP III criteria are basically equivalent in predicting CVD.

Dr. Charles Alexander and Dr. Steven Haffner analyzed the impact on CVD
of the metabolic syndrome, with or without diabetes, from NHANES III
data for persons 50-years-old and older. They reported (Diabetes
2003;52:1213) that without the metabolic syndrome or diabetes, the
prevalence of CVD in this group is 8.7 percent. When persons have
diabetes without the metabolic syndrome, the prevalence of CVD is
approximately the same (7.5%) as for those without either diabetes or
the metabolic syndrome. Dr. Eckel stressed that having diabetes
certainly implies the presence of the metabolic syndrome; however, if
someone has diabetes and is not overweight and does not have high blood
pressure or lipidemia, then the risk of CVD is nearly the same as that
of someone without diabetes. When the metabolic syndrome is present
without diabetes, the prevalence of CVD doubles (13.9%); however, when
the person has both the metabolic syndrome and diabetes, the prevalence
jumps to 19.2 percent, almost 3 times the risk for diabetes alone.

**Metabolic Syndrome and Risk of Diabetes**. Dr. Eckel emphasized that
the literature is weak in this area and, although it shows that the
metabolic syndrome is a predictor of new-onset diabetes, better evidence
is needed regarding *how* the metabolic syndrome predicts diabetes.
Based on literature published in the last 4 to 5 years, the risk of
diabetes in someone with the metabolic syndrome is about 2- to 4-fold.
To estimate the risk, one would have to apply the metabolic syndrome
criteria to the study data on the cohorts from various clinical trials.

**Metabolic Syndrome as a Potential Target for Prevention of Type 2
Diabetes**

In considering the particular components of the metabolic syndrome that
would make the best therapeutic targets for prevention of type 2
diabetes, Dr. Eckel selected waist circumference, blood pressure, and
glycemia. Physical activity for weight reduction seems to reduce waist
circumference more than diet alone, although this has not been
thoroughly substantiated. Based on this relationship to physical
activity, he recommended keeping waist circumference on the target
list.  The rationale for blood pressure lowering relates to the
increasing number of clinical trials in which ACE inhibitors or ARBs
have proven to reduce the incidence of type 2 diabetes. Ways to reduce
triglycerides relate to most of the elements of the metabolic syndrome,
but aside from weight reduction, he set triglycerides aside as a target.
Nicotinic acid is the only reasonable pharmacological target to raise
HDL cholesterol, and this is not a promising intervention to reduce the
incidence of diabetes in individuals with impaired glucose tolerance; in
fact, it does the opposite. Dr. Eckel felt that there basically was not
enough evidence for intervening with dyslipidemia as a target. The
effects of statins and fibrates on type 2 diabetes incidence are modest
at best and mostly absent. In fact, niacin can increase glycemia. Blood
pressure and insulin resistance as reflected in abdominal obesity and
impaired glucose tolerance were better targets.

**Treatment of Hypertension**. Dr. Eckel listed four classes of drugs
commonly used to treat hypertension: diuretics, beta blockers, ACE
inhibitors, and ARBs. Diuretics and beta blockers tend to increase the
incidence of diabetes. There are only modest effects on insulin
secretion. On the other hand, clinical trials have shown that ACE
inhibitors (captopril, lisinopril, ramipril) and ARBs (losartan,
candesartan) *do* reduce the incidence of diabetes, as *secondary*
outcomes of using these blood pressure-lowering drugs. The overall
effects in lowering type 2 diabetes incidence have been relatively
modest but significant, with the exception of the SCOPE trial with
candesartan (relative risk = 0.81, p\<0.09). Dr. Eckel felt the effects
were insufficient in impact to recommend these drugs as a primary
strategy, but there was a rationale for using an ACE inhibitor or ARB as
adjunctive therapy in the setting of the metabolic syndrome. Dr. Eckel
said to keep in mind that the trials supporting this rationale were not
conducted on the basis of the metabolic syndrome and prevention of type
2 diabetes.

**Treatment of Insulin Resistance**. A more fruitful area of
intervention within the metabolic syndrome is "insulin resistance,"
particularly obesity/abdominal obesity and impaired glycemia. Dr. Eckel
recommended converting abdominal android fat distribution to lower body
gynoid fat distribution. He remains unconvinced that obesity in women
that puts most of their fat below their waist leads to CVD and diabetes,
but feels more evidence is needed to show whether or not this is true.

Weight reduction is the target to reduce waist circumference. Dr. Eckel
briefly reviewed some clinical trials on weight reduction and its
effects on diabetes. In the Finnish Diabetes Prevention study, 522 men
and women, ages 55±7 years, with BMI of 31.2±4.6 kg/m^2^ were randomized
as a control group and a lifestyle intervention (diet and exercise)
group and had a mean follow-up of 3.2 years with an oral glucose test to
indicate diabetes. The lifestyle intervention diet included restricted
fat, especially saturated fat, and increased fiber. The lifestyle
intervention group had a 55-60 percent reduction in new-onset type 2
diabetes. The DPP (27 centers in the United States, 3, 234 men and
women, ages 25-85, with an average BMI of 34 kg/m^2^) was a 3.2-year
ramdomized trial with three arms---placebo, lifestyle modification (goal
7 percent weight loss), and metformin (850 mg bid). A fourth arm was
discontinued earlier due to concern over potential adverse events from
the use of troglitazone. Lifestyle had the greatest effect on preventing
type 2 diabetes, followed by metformin. Both of these strategies
favorably modified insulin sensitivity and thus are strategies to use to
target insulin resistance in the metabolic syndrome.

Dr. Eckel asked "How long will the weight loss last?" Even in the highly
constructed and controlled DPP, weight was regained. He also asked, "How
long will the prevention of type 2 diabetes last?" Both are crucial
questions. He added that before considering pharmacological
interventions to lose weight, it is important to remember that lifestyle
changes do work. Dr. Eckel said it was also interesting that the diets
used in the Finnish study and DPP were both diets that restricted fats,
not carbohydrates.

Moving on to weight-loss drugs, Dr. Eckel noted that there are basically
two choices in anorectics. Sibutramine is FDA-approved for weight loss;
phentermine is not listed but is commonly prescribed because it is much
less expensive. Dr. Eckel thought that in spite of the phen-phen issue,
phentermine remains a major anorectic being used by physicians. The
other choice as a weight-loss drug is orlistat, a lipase inhibitor.
There are no clinical trials using these in the prevention of diabetes,
but there is the XENDOS study in which orlistat plus lifestyle change
resulted in more weight reduction than lifestyle change plus placebo.
Again, there was the regaining of weight that always occurs. Orlistat
plus lifestyle reduced the incidence of diabetes in subjects with IGT by
45 percent and in all patients by 37.3 percent compared to the placebo
plus lifestyle.

Dr. Eckel listed other hypoglycemic therapies that might favorably
modify insulin sensitivity: sulfonylureas, meglitinides, α-glucosidase
inhibitors, metformin, and thiazolidinediones. There are no such trials
with sulfonylureas or meglitinides. As mentioned, metformin was used
fairly successfully in DPP. In the STOP-NIDDM (Studies to Treat or
Prevent Type 2 Diabetes) trial, there was a dramatic impact of acarbose
(an α-glucosidase inhibitor) on patients with IGT in reducing all CVD
events, and especially myocardial infarction (from 12 events in the
placebo group to 1 event in the acarbose group). Dr. Eckel added that
there is some concern about the validity of the results of STOPP-NIDDM
involving selection bias, inadequate blinding, bias in data analysis,
and potential sponsoring bias.

Dr. Eckel cited Dr. Ronald Evans' review of work on PPAR compounds in
*Nature Medicine* (Nat Med 2004 Apr;10(4):355-61) Thiazolidinediones do
not cause weight reduction, but they change where body fat is deposited.
For example, in a study by Dr. Miyazaki and colleagues (Miyazaki Y et
al. JCEM 2992;87:2787) after 16 weeks of pioglitazone, there was
dramatic redistribution of abdominal fat from the visceral depot to the
subcutaneous depot. Data from that study also showed that changes in
visceral fat contribute to improvements in insulin sensitivity, since
the visceral fat area predicts the metabolic clearance rate of insulin
and thus reflects insulin sensitivity. Likewise, Dr. Tom Buchanan's
study of troglitazone (Buchanan, TA et al. Diabetes 2002;51:2798) showed
a long-lasting benefit in the prevention of type 2 diabetes in high-risk
Hispanic women with gestational diabetes, even subsequent to
discontinuation of the drug in the study. Dr. Eckel concluded that the
PPAR class of compounds looks promising in the prevention of type 2
diabetes in patients with the metabolic syndrome.

The PPARs that are available, at least those targeted for reduction of
insulin sensitivity, are largely the PPARγ class. Many pharmaceutical
companies have bi-agonist drugs that combine PPARα/γ properties. The α
properties reflect mostly changes in fatty acid metabolism and the γ
relate to both carbohydrate and lipid metabolism. Dr. Eckel added that
recently the PPARδ compounds or, theoretically, ligands that impact the
PPARδ system, seem promising, as described by Dr. Ronald Evans' group
(Yong-Xu et al., Cell 2003; 113:159-170). This study showed that by
modification of the PPARδ system, fat metabolism could be altered in a
way that enhanced fatty acid oxidation and prevented obesity and,
ultimately downstream, in Dr. Eckel's opinion, type 2 diabetes and the
metabolic syndrome that precedes it. This is an area in human biology,
physiology, and pharmacology that there is not much information on yet,
but a promising area of this PPAR class of drugs.

Dr. Eckel also listed other non-FDA-approved drugs that affect the
metabolic syndrome by modifying weight first and then incidentally type
2 diabetes. These include anti-epileptics (topiramate, zonisamide),
MCH-1 inhibitors, cannabinoid antagonists, GLP-1 and DPP-IV inhibitors,
and other new players in the field. At this time, there are limited data
on these drugs in terms of their application to patients with the
metabolic syndrome and much less data on their application to the
prevention of type 2 diabetes. Zonisamide has shown an impressive weight
reduction in obese persons compared to placebo (Gadde, KM et al. JAMA
2003;289:1823) as has topiramate in a randomized trial (Bray, GA et al.
Obes Res 2003;11:727). Dr. Eckel recommended that these compounds and
their side effects be intensely studied.

In summary, Dr. Eckel said "The metabolic syndrome is upon us" and is
going to increase its prevalence, and likely predict a much higher
incidence of type 2 diabetes, as well as coronary heart disease and
stroke. Lifestyle interventions should be the initial and sustained
therapeutic approach. Some drug therapies already seem to work such as
metformin, TZDs, ACE inhibitors, and ARBs. A variety of other
therapeutic options appear to be forthcoming. As illustration of what
can be done, Dr. Eckel showed a "before slide" of a patient who had all
the components of metabolic syndrome plus type 2 diabetes and an "after
slide" of this attractive patient after successful weight reduction.

**Discussion.** Dr. Garfield asked Dr. Eckel if he would be more
optimistic regarding intervening to reduce triglycerides if future
therapies such as use of adiponectin to promote fatty acid oxidation
existed today. Dr. Eckel responded that he understood that adiponectin
is being considered as part of the pharmacological "toolbox" to treat
type 2 diabetes and IGT. The idea of modifying triglycerides as a target
reflects opportunities to modify triglyceride production rates and/or
lowering triglycerides by increasing removal of triglycerides from the
system. The evidence is that increasing lipoprotein lipase (modifying
clearance) is probably not the way to reduce triglycerides, but
modifying production rates reflects that fatty acids are being
partitioned into different pools. So if triglycerides are not going into
triglyceride biosynthesis, because of this effect on AMP kinase they are
going to oxidative metabolism, then here the PPARδs become particularly
attractive. There is not much evidence that metformin, also an activator
of AMP kinase, does much to serum triglycerides. Dr. Eckel said he thus
thinks that targeting triglycerides will be an indirect method of
altering fatty acids. He also suspected that insulin sensitivity would
improve with triglycerides just being an innocent passenger.

The comment was made that metformin has not been studied enough yet to
know how far up the dose response curve would go in terms of activating
AMP kinase, and also what the effect of these and other tissues would
be. Metformin per se may not do what is needed; we do not know for sure
what the possibilities are of that mechanism, depending on how much and
where it can be activated.

**The Diabetes Prevention Program and New Perspectives on the Metabolic
Syndrome**

***Harry Shamoon, MD,** Professor of Medicine and Associate Dean for
Clinical Research, Albert Einstein College of Medicine, Bronx, New York*

Dr. Shamoon stated that he would present a brief overview of the DPP
data and some new analyses from the study that might shed light on the
metabolic syndrome and the issue of should it be treated, and if so, how
should it be treated. Dr. Shamoon acknowledged the contributions of the
many DPP investigators, many of whom are now involved in the DPPOS. He
noted that DPP was sponsored by several NIH institutes and offices in
addition to NIDDK (i.e., National Center on Minority Health and Health
Disparities; National Center for Research Resources, GCRC Program;
National Institute of Child Health and Human Development, National
Institute on Aging, and Office of Research on Women's Health), other
Federal agencies (i.e., Indian Health Service, Centers for Disease
Control and Prevention), the American Diabetes Association, and private
industry (i.e., Bristol-Myers Squibb, Warner-Lambert, LifeScan, Inc,
Merck &Co., Health O'Meter, Nike Sports Marketing, Hoechst Marion
Roussel, Inc., Slim Fast Foods Co., Merck-Medico Managed Care, Inc., and
Quaker Oats Co.).

**Primary Goal and Results**. Dr. Shamoon said the primary goal of DPP
was to prevent or delay the development of type 2 diabetes in persons
with impaired glucose tolerance. The study design included a randomized
three-group clinical trial at 27 sites with a common protocol across all
sites, staff training, and a data quality control program. The criteria
to define a high-risk IGT population was a 2-hour post OGTT plasma
glucose of 140-199 mg/dl and a fasting glucose in the non-American
Indian population of 95-125 mg/dl, thus persons from the upper end of
the glucose range. Other eligibility criteria were being 25 years of age
or older and having a BMI [\>]{.underline} 24 kg/m^2^. Persons from all
ethnic groups were recruited with a goal of up to 50 percent from
high-risk ethnic populations. The study interventions, following
randomization and the giving of standard lifestyle recommendations to
all the subjects, were intensive lifestyle, metformin, and placebo (NEJM
346:393-403, 2002).

The DPP was very successful in recruiting ethnic minorities plagued with
the problems of diabetes. The DPP population was 20 percent African
American, 16 percent Hispanic, 5 percent American Indian, 4 percent
Asian or Pacific Islander, and 55 percent Caucasian. There was a
two-thirds (women) to one-third (men) gender distribution. Besides the
45-59 age group (49%), there were young people ages 25-44 (31%) and
older people over 60 years of age (20%).

Dr. Shamoon said the primary outcome of the DPP was glucose: (1) annual
fasting plasma glucose (FPG) and a 75 gm OGTT with the following
criteria for a diagnosis of diabetes: FPG [\>]{.underline} 126 mg/dl or
2-hour [\>]{.underline} 200 mg/dl with either of these confirmed by a
repeat test and (2) a semi-annual FPG of [\>]{.underline} 126 mg/dl,
confirmed.

The lifestyle intervention was a multi-component effort involving
behavioral and medical components to achieve a minimum weight loss of
[\>]{.underline} 7 percent of body weight and maintenance of weight loss
with a dietary fat goal of \< 25 percent of calories from fat and a
calorie intake goal of 1200-1800 kcal/day. In addition, sustained
physical activity of a minimum of 150 minutes per week was encouraged
and documented. Medication interventions were 850 mg per day of
metformin escalating after 4 weeks to 850 mg twice a day compared to
placebo.

Dr. Shamoon confirmed that the DPP subjects were an obese group. The
average BMI was 34.0 ± 6.7 kg/m^2^. Weight loss was a predominant effect
of both lifestyle and metformin and was dramatically different initially
in the lifestyle group, although some weight was regained after almost 4
years. At study end, there still was about a 4 kilo reduction in weight
from baseline in the lifestyle group. Leisure physical activity was by
self-report; it increased and was maintained by the lifestyle group in
comparison to the placebo and metformin groups. In terms of adherence to
medication regimen, Dr. Shamoon reported that approximately 80 percent
of participants took at least 80 percent of their prescribed placebo or
metformin dose over the course of the study, with just slightly better
adherence in the placebo group.

As has been reported often, Dr. Shamoon repeated that for the DPP
participants as a group, the risk of diabetes was reduced 31 percent by
metformin and 58 percent by the lifestyle intervention versus placebo.
Secondary analyses show that lifestyle, followed by metformin, was
similar for both men and women in lowering the risk for diabetes. By
age, there were some differences. In the 25-44 age group, metformin and
lifestyle were almost equally effective in reducing the incidence of
diabetes. In the 45-59 years of age, metformin was intermediate. In the
60 years and older group, lifestyle was the most effective, with
metformin and placebo being about equally effective.

Dr. Shamoon continued with the analyses by showing that in the least
obese group (BMI 24-29), metformin was much less effective than
lifestyle. In the most obese group (BMI [\>]{.underline} 35), metformin
was basically equivalent to lifestyle in reducing the incidence of
diabetes. Dr. Shamoon said fasting glucose obviously plays a big role in
the conversion to diabetes. His data showed that in subjects with the
lowest range of fasting plasma glucose concentrations (95-109), the
diabetes incidence rates were much lower than in the group with the
higher glucose concentrations (110-125). Again, there was a stepwise
effect, with metformin having an intermediate effect on the prevention
of diabetes compared to lifestyle. Across all ethnic groups, the effects
of lifestyle in reducing risk of diabetes was the most effective
intervention, with metformin again being the second most effective.

Regarding adverse events, based on 100 person years, Dr. Shamoon
reported that metformin was well tolerated. There were no differences in
major adverse events. Gastrointestinal symptoms, not unexpectedly, were
greater in the metformin group compared to the placebo or lifestyle
intervention, and musculoskeletal symptoms were slightly higher in the
intensive lifestyle intervention.

Following the reduction of incidence of diabetes, there was still a
trend in the DPP cohort toward a rising fasting plasma glucose even with
the two successful therapies. Dr. Shamoon said whether there is an
inexorable change to developing diabetes, a possible question is "Is the
effect of the drug, for example, transient?' The DPP tried to address
this question with a 1-week withdrawal of metformin, followed by a
re-challenge with an OGTT (Diabetes Care 26:977-980, 2003). The test
showed that the rate of prevalent diabetes declined a little, but the
summary conclusion of the analysis was that approximately one-quarter of
the effect of metformin to prevent development of new diabetes can be
attributed to an acute pharmacologic effect; after washout, metformin
*still* reduced the incidence of diabetes by 25 percent compared to the
placebo. Dr. Shamoon interpreted this data to indicate that lowering
plasma glucose with metformin has its own effect beyond prevention of
diabetes by mechanisms unknown.

Dr. Shamoon explained that the DPP was originally designed as a
four-group study. Between 1996 and 1998, subjects were randomized to
troglitazone (585 of the total of 2,345 subjects), as well as the other
three arms. Due to emerging data on the hepatoxicity of troglitazone,
and the death of one subject, the drug was discontinued in 1998 and
ultimately withdrawn from the U.S. market 2 years later. Analysis of the
data on diabetes incidence rates per 100 person years for the four
groups up to discontinuance of troglitazone was not different than the
final results. The lowest projected incidence was with the troglitazone;
however, the safety of the drug precludes its use. Although troglitazone
was highly effective, there was not a significant difference between it
and intensive lifestyle as an intervention. Unlike Dr. Buchanan's Tripod
Study, Dr. Shamoon said that DPP did not find a persistent effect of
troglitazone on prevention of diabetes. Data on incidence of diabetes
after troglitazone was discontinued in 1998 showed that, while there was
no "catch-up" increase in incidence, the cumulative incidence basically
followed the same trend as placebo, suggesting there was no persistent
effect of that brief 9-month exposure to troglitazone.

***Conclusions and implications*** drawn by Dr. Shamoon regarding the
two drugs used in DPP to prevent diabetes included the following:

-   Metformin was safe and effective, particularly in younger and more
    obese persons; its effect did not wash out after 1 week, suggesting
    it did not simply "mask" hyperglycemia.

-   Troglitazone markedly reduced diabetes incidence during its brief
    use, but the action did not persist after it was discontinued.

-   The effect of troglitazone was due in part to improved insulin
    sensitivity with maintenance of insulin secretion. This same
    mechanistic effect was true for intensive lifestyle on the
    prevention of diabetes.

**DPP Secondary Goals and Results**. The secondary goals of the DPP as
listed by Dr. Shamoon were to reduce CVD events, reduce CVD risk
factors, and reduce atherosclerosis. The DPPOS will look at the data for
these outcomes; Dr. Shamoon therefore said he would not directly address
this data in the current meeting in discussing the metabolic syndrome.
He posed the interesting question of whether the metabolic syndrome is
related to CVD directly, not just to CVD as a complication of the
diabetes developed following IGT.

**Metabolic Syndrome and DPP**. Many of the subjects in DPP had at
baseline a family history of type 2 diabetes, a history of high
cholesterol and hypertension, in addition to obesity and IGT, and, in
women, a history of gestational diabetes. Dr. Shamoon pointed out that
thus some members of this cohort were likely to have metabolic syndrome.
Objectives of the new analysis were to determine the prevalence of the
metabolic syndrome in this multiethnic DPP population with IGT and to
evaluate the effect of the two interventions---intensive lifestyle
changes and metformin---on the incidence of the metabolic syndrome in
those subjects without the syndrome at baseline. Data were also analyzed
on those who did have the syndrome at baseline. The definition selected
to make the diagnosis of metabolic syndrome was that of the NCEP ATP
III, 2001.

Only fifty-three percent (1,711 of the 3,234) persons had the metabolic
syndrome at time of randomization. Prevalence did not vary by gender or
age group, but did vary by ethnicity, being highest in Caucasians (57%)
and lowest in Asians (41%). Dr. Shamoon explained that one of the
reasons for this difference might be that the NCEP criteria were
developed for Caucasians, or there may be other reasons for this.
Prevalence of the components of the metabolic syndrome did vary by age
group. The most frequent combination of components was high waist
circumference + elevated triglycerides + low HDL. The least frequent
combination of components was elevated fasting plasma glucose + elevated
blood pressure + low HDL. In those with the metabolic syndrome, a waist
circumference \> 102 cm (40 in) in men or 88 cm (35 in) in women was
true for all age groups. Low HDL cholesterol was clearly less important
in the older age group and more important in the younger persons.
Conversely, hypertension was more prevalent in the older age group and
less so in the younger group. Triglycerides were about the same across
all the age groups.

Looking at those *without* the metabolic syndrome at baseline, the DPP
study group asked "What did the interventions achieve?" There were 1,523
subjects without the metabolic syndrome (490 in the placebo group, 503
in the metformin group, and 530 in the lifestyle group). In the 3+ years
of the study, there was a risk reduction of about 17 percent in the
metformin group versus the placebo group, 41 percent in the lifestyle
group versus placebo, and 29 percent in the lifestyle intervention group
versus the metformin group. The lifestyle reduction rate was therefore
similar to that for prevention of diabetes, but not quite as potent.

Data presented by Dr. Shamoon for the 3-year incidence of the components
of the metabolic syndrome for those *without* the syndrome at baseline
showed that those in the placebo group had a 33-percent incidence of
reaching the criteria for waist circumference, compared to a
significantly reduced 15 percent and 8 percent, respectively, in the
metformin and intensive lifestyle groups. Low HDL cholesterol was not
affected by these interventions compared to placebo, and triglycerides
were reduced in the intensive lifestyle group. As expected, occurrence
of high fasting plasma glucose was prevented by intensive lifestyle and
metformin. Hypertension was reduced only in the intensive lifestyle
group.

In the subjects *with* the metabolic syndrome at baseline, the 3-year
incidence data for the various components was very high in the placebo
group as shown in Dr. Shamoon's slide of this data. Waist circumference
was modestly but significantly reduced by both the metformin and
lifestyle intervention. HDL cholesterol, interestingly, was about
equally increased in both the metformin and lifestyle groups, and
lifestyle also had an effect on triglycerides and blood pressure.
Lifestyle also reduced fasting plasma glucose about 5 percent more than
metformin, but both were significantly better than placebo, of course.

***Conclusions and Implications*** from Dr. Shamoon for this DPP
volunteer cohort selected for the high end of IGT and treated for 3.2
years included the following:

-   Over 50 percent of the cohort had metabolic syndrome at baseline in
    contrast to NHANES III data for persons over 20-years-old (22
    percent) in the United States . (Ford E.S., Giles WH, Dietz WH.
    Prevalence of the Metabolic Syndrome Among U.S. Adults: Findings
    From the Third National Health and Nutrition Examination Survey.
    JAMA 2002; 287(3):356-359). Among people age 50 years and older with
    IGT, a recent analysis of the NHANES III data set suggests 33
    percent have the syndrome (Alexander CM, Landsman PB, Teutsch SM,
    Haffner SM. NCEP-Defined Metabolic Syndrome, Diabetes, and
    Prevalence of Coronary Heart Diseases Among NHANES III Participants
    Age 50 Years and Older. Diabetes 2003; 52(5):1210-1214).

-   Components of the metabolic syndrome varied by age, gender, and
    race.

    -   Waist circumference and low HDL criteria were more prevalent in
        the younger group; blood pressure was more prevalent in the
        older group; triglycerides were equivalent across all groups.

    -   Waist circumference and low HDL criteria were more prevalent in
        women; fasting plasma glucose and blood pressure criteria were
        more prevalent in men.

    -   In order of prevalence, the metabolic syndrome was more
        prevalent in Caucasians, then in African Americans, Hispanics,
        American Indians, and Asians.

-   Metformin was not effective in preventing the metabolic syndrome in
    women and was less effective in persons with the higher fasting
    glucose; it was most effective in obese and younger men.

-   Intensive lifestyle intervention prevented the metabolic syndrome by
    decreasing waist circumference and blood pressure, not by correcting
    dyslipidemia, surprisingly.

In summary, Dr. Shamoon emphasized that the DPP has provided a valuable
reservoir of stored samples and biomarkers and information to help
design new studies and chart the course in this complicated area of
obesity and its effect on the metabolic syndrome and the risk for
diabetes and/or CVD.

**Discussion**

In response to a question from Dr. Garfield regarding the possibility of
there being a single target for drug action within the metabolic
syndrome, Dr. Eckel said that, with the exception of hypertension, he
thought the other components could be targeted by a single intervention,
particularly if insulin resistance is considered the working paradigm.
For example, C-reactive protein can be influenced by fibrins. Other
inflammatory markers can be favorably modified. Prothrombotic components
as risk factors for CVD can be improved by agents that improve insulin
sensitivity.

Dr. Shamoon added that, independent of the data about preventing
diabetes with metformin in DPP, enough data exists showing the effect of
metformin on preventing and treating the metabolic syndrome components.
The challenge to the community, including ADA, is to define a treatable
subgroup of individuals who are most likely to respond to metformin. Dr.
Shamoon answered Dr. Garfield's question about what research support
would be needed from NIH and FDA to determine if the metabolic syndrome
is an actual syndrome or a coincidental aggregate of several syndromes,
by suggesting that NIDDK apply resources and mine new information from
trials with children. One of the problems in studying the metabolic
syndrome in adults is that aging and obesity complicate the analysis.
For larger kinds of analyses of the pathophysiology of the syndrome, he
believed that children or adolescents would be the best starting point.

Dr. Amy Rosenberg, FDA, noted that everybody recognizes there is a
growing epidemic of obesity and type 2 diabetes in children. She pointed
out that children are a captive audience. Most are in school until
nearly 18 where there is a real opportunity to focus on lifestyle
issues, such as exercise. Currently, the amount of time for recess and
for physical education has been cut back. Dr. Rosenberg recommended that
there be a major public health effort to evaluate the benefits of
physical education programs in schools and perhaps to expand them so
that children will be inculcated with the importance of diet and
physical activity. She stressed the enormous benefit to be gained by
preventing obesity in children, and therefore type 2 diabetes.

Dr. Shamoon agreed. His researchers had published some papers in
collaboration with a Columbia University group analyzing 2- and
3-year-old Hispanic children, from upper Manhattan, in whom the
biomarkers of insulin and C-reactive protein were already present and
related to BMI.

Dr. Tamborlane referred to a paper being published in June 2004 by Dr.
Caprio from Yale reporting that the incidence of metabolic syndrome is
more than 40 percent for obese teenagers and obese pre-adolescent
children, a real problem that supports the need for studies in children,
not only for prevention, but also to look at management and
interventions. Dr. Tamborlane suggested a MetNet, a network approach to
not only do a very large study that would take years but also smaller
studies focused on interventions such as proof-of-concept studies of
therapies for children. DPP showed that in 20- to 49-year-olds,
metformin *is* as effective as lifestyle. Similar studies are needed for
children. Dr. Tamborlane stressed that researchers and physicians are
focusing in pediatrics on the rising incidence of type 2 diabetes, but
they believe it is only the tip of the iceberg---a warning signal for
the future. What they will be seeing as these young people approach
their 20s is an 18-year-old with a heart attack.

Dr. Garfield commented that shortly after publication of the DPP
results, ADA presented a position paper in *Diabetes Care* on
recommendations based on the DPP as well as other studies within a
similar timeframe. The paper encouraged the lifestyle changes, but urged
caution in prescribing drugs for those at risk. Dr. Garfield asked if
the speakers thought we were now at a point when drugs could be
recommended as part of NDEP's outreach efforts.

Dr. Shamoon noted DHHS Secretary Tommy Thompson's prescription to
Americans has had at least a limited impact in encouraging the lifestyle
intervention. As a national mandate or public health task, this is
important, but difficult to carry out. Dr. Shamoon questioned, though,
why 2 years after the publication of the DPP results, there is not an
indication for the use of metformin. In New York at least, physicians
are eager to treat patients at an earlier level of their glycemic
history, and metformin's safety record is remarkable.

Dr. Eckel stressed that the public health issue before the American
public and most of the civilized world is that the metabolic syndrome is
set by obesity with CVD as the primary outcome, either directly or by
way of diabetes. Educating the public about lifestyle changes is
important for modifying obesity and for good health in general, but this
cannot be accomplished readily. Therefore, Dr. Eckel thought the
pharmaceutical industry would actually be the one to accomplish this
task better than healthcare professionals, researchers, or government
agencies. Nevertheless, the message about eating better and being more
active needs to continue to be promoted. A related issue to some extent
is that even if a patient fails weight reduction, the person still can
become more active and eat well. The quality of the diet also can
potentially impact hard outcomes that relate to the consequences of
obesity and the metabolic syndrome or diabetes. Dr. Eckel emphasized
that these are messages that need to be forthcoming, but there also is a
need to take a more aggressive approach through a pharmacological
intervention in those patients who cannot modify the components of
metabolic syndrome by lifestyle alone.

Dr. Bob Silverman, Merck and Co., Inc., asked if it would be useful to
the therapeutic community if there were drugs available and indicated
for the treatment or the prevention of metabolic syndrome. Dr. Shamoon
answered that if there were agreement on the criteria for the metabolic
syndrome and the definition of the syndrome as a treatable entity, there
already is an effective drug to prevent metabolic syndrome in some
groups such as younger more obese men. The results suggest that if one
targets the glucose component roughly described by the DPP cohort,
metformin might be effective in reducing other components of the
metabolic syndrome.

Dr. Eckel stated the pharmaceutical industry should think about
targeting the metabolic syndrome as an intervention that could have long
lasting and favorable consequences, not only for diabetes but
particularly for CVD.

Dr. Richard Bradley inquired, "What does it mean to prevent diabetes
with a drug that lowers glucose levels? Why not just treat patients who
develop diabetes? What benefit is actually being accrued?" He also asked
what would be the endpoint to prove that a drug impacted the metabolic
syndrome.

Dr. Shamoon explained that in treating diabetes, one actually treated
hyperglycemia, the salient feature of the disease. There are different
components of hyperglycemia along the continuum of increased hepatic
glucose production, postprandial hyperglycemia, plasma glucose per se,
and other defects. A drug that prevents the rise in hepatic glucose
production, which is metformin's major effect, prevents the occurrence
of fasting hyperglycemia, which is the definition of diabetes. So it is
somewhat circular in that sense.

Two outcomes suggested by Dr. Eckel would be either reduction in
incidence of diabetes or, since the definition for the metabolic
syndrome in the United States is based on atherosclerotic cardiovascular
disease not diabetes, reduction in CVD events. He added that determining
the appropriate outcome for a drug to be approved was an important
question for discussion.

Dr. Harold Lebovitz, State University of New York, stated that the
practicing physician requires more specific guidance. They are being
told all about the metabolic syndrome and about CVD. They are being told
about the severe consequences of diabetes. However, when it comes to an
intervention, they are uncertain about what they can really do. They
have known since 1960 that losing weight and exercising helps their
patients prevent diabetes, but in the real world this has not been
effective. Now two drugs are known to be effective---metformin and
acarbose. They have been used for years and have excellent safety
records. Dr. Lebovitz strongly recommended that these drugs be approved
for use in treating patients with the metabolic syndrome.

Dr. Orloff said that the group would probably spend some time at the
panel discussion on the issue of indication. In a discussion about
indications, it will be important to look at who in fact is the target
population, for a broad prevention kind of indication. First, insulin
resistance seems to be a unifying mechanistic starting point for the CVD
risk-related abnormalities that comprise the syndrome. For diabetes, not
everybody with metabolic syndrome develops diabetes and not everybody
with diabetes has metabolic syndrome. Dr. Orloff asked how to reconcile
what appear to be somewhat disparate results from the DPP with regard to
prevention of diabetes with metformin and prevention of metabolic
syndrome with metformin, given that the two are not 100-percent
correlated in the current observational database.

Dr. Eckel said that over half of the DPP subjects already had the
metabolic syndrome at baseline. It is therefore difficult to look at the
database and the impact on diabetes versus the metabolic syndrome, when
the majority already had the outcome.

Dr. Shamoon added that such secondary analyses are difficult. The
question seemed to be based on the metformin and lifestyle interventions
being less effective in preventing transition to the metabolic syndrome
than they were in preventing diabetes, thus raising the issue of choice
of a target. Dr. Shamoon said that is why he recommended targeting
subgroups, since the DPP subjects were specifically selected on the
basis of having high glucose resistance and therefore there may have
been a group with the metabolic syndrome with no degree of fasting
hyperglycemia.

Dr. Eckel commented that interventions that modify glycemia may in fact
work through different mechanisms, so the metformin effect on insulin
resistance, although it does improve insulin sensitivity, is mostly a
hepatic effect, whereas the TZD class of drugs has a plethora of effects
that involve potentially multiple tissues such as adipose tissue,
muscle, and liver. The idea of modifying insulin resistance with drugs
that have multiple mechanisms of action is very different than thinking
about an intervention that is more glycemia targeted. It is necessary to
understand drug action related to the indications for insulin resistance
and glycemia, both separately and together.

Asked what would be appropriate endpoints for FDA to approve a drug for
an indication of insulin resistance or metabolic syndrome, Dr. Eckel
replied that perhaps the criteria would be that the drug favorably
modifies at least two of the three out of five components of the
metabolic syndrome. He added that this was a matter for discussion. Dr.
Shamoon said that from a gluco-centric point of view, in a high-risk
population like the DPP subjects, the lowering of triglycerides has to
be done independently from treatment of hyperglycemia. Dr. Eckel added
that only 15 percent of the subjects with the metabolic syndrome also
had hyperglycemia, using the 110 cutpoint.

**Session VII: Industry and Advocacy Perspectives**

*Moderator, Robert Meyer, Director, Division of Metabolic and Endocrine
Drugs, FDA*

**Drugs**

***Simeon Taylor, MD, PhD**, Vice President, Discovery Biology,
Pharmaceutical Research Institute, Bristol-Myers Squibb, Hopewell, New
Jersey*

Dr. Taylor listed the following objectives for pharmaceutical research
and development (R&D): production of safe and effective drugs,
addressing unmet medical needs, and, ultimately, extending and enhancing
human life. Dr. Taylor stressed these objectives are not trivial
undertakings faced with the challenges the industry faces such as the
need for cost-effective drug development and for increased success
rates, especially in the very expensive late stages of the R&D process.
Learning which drugs "fail fast" in earlier stages is critical as well
as being able to predict "go-no go" business decisions early on.

To illustrate the R&D process, Dr. Taylor presented a schematic
depicting the two major phases: drug discovery and clinical development.
Together, these phases tend to span nearly a decade. The drug discovery
phase includes the following steps:

-   Target identification.

-   Target validation.

-   Lead generation.

-   Lead optimization.

-   Pre-clinical safety.

Dr. Taylor stated that, during the basic research phase of drug
discovery, novel target identification and validation depend on efficacy
and the potential for mechanism-based toxicity, as with the PPARγ
compounds and their tendency to cause edema. With the mapping of the
human genome, the industry now has more potential targets for disease.
Biomarkers provide evidence for inhibiting targets and are useful to
predict dose-response in these. In addition, through DNA and blood
tests, biomarkers identify the exceptional patients who may be at risk
for toxic reactions to a drug. The practicing physician does not want to
titrate the dose for each patient, as is necessary for the patient with
diabetes. Of course, this principle of "one dose fits all" has to be
different in prevention trials.

The second R&D clinical development phase is comprised of the following
trials and elements familiar to those present:

-   Phase 1: Safety

-   Phase II: Efficacy

-   Phase III: Registration

-   Phase IV: Post-marketing

Dr. Taylor pointed out that during the translational research period of
R&D, surrogate markers not only predict clinically relevant outcomes but
are key to acceptance of the drug for regulatory approval. He stressed
that the Phase I and II trials conducted by the Government and by
academia are of great importance to the pharmaceutical industry in
identifying surrogates and in establishing safety and efficacy of drugs.
He particularly noted the large, longitudinal trials such as the DCCT,
UKPDS, and the epidemiology of diabetes studies with the Pima Indians.
Dr. Taylor suggested that such trials offer excellent opportunities for
public-private partnerships in basic scientific research, translational
research, and developing regulatory policy.

As an example of the benefit to the pharmaceutical industry of such
studies, Dr. Taylor referred to the landmark DCCT study that
demonstrated that HbA1c could serve FDA as a surrogate marker in
predicting the efficacy of intensive glycemic control interventions to
prevent the development and progression of complications in type 1
diabetes. Likewise, the DPP showed that metformin was very effective in
preventing type 2 diabetes in high-risk persons with impaired glucose
tolerance, especially in young obese men. Dr. Taylor asked how much
benefit would need to be shown for FDA to approve the use of metformin
in this subgroup.

To meet the objective of targeting unmet medical needs through
development of new drugs, Dr. Taylor said he would select prevention of
diabetes, the metabolic syndrome, and prevention of the chronic
complications of diabetes, which are not being prevented as well as
could be done with the knowledge we have gained. He emphasized that the
pharmaceutical industry would be facilitated by the establishment of
clear criteria for approval of drugs to address these unmet needs. Such
criteria exist in other areas, but not for obesity and prevention of
type 2 diabetes.

In summary, Dr. Taylor stressed that success could be achieved by the
partnering of Government, academia, and the private sector in sharing
the objectives to identify and develop safe and effective drugs that
address unmet medical needs and enhance and extend human life.

**Biologics**

***Alain Baron, MD**, Senior Vice President, Clinical Research, Amylin
Pharmaceuticals, San Diego*

Dr. Baron defined biologics as those products that are often
first-in-class drugs and/or novel therapies for which R&D (research and
development) largely takes place in settings other than those of the
large pharmaceuticals. Biologics include peptides, proteins, cytokines,
monoclonal antibodies, and cell- or gene-based therapies. They tend to
employ non-oral routes and target important unmet medical needs. The
scientific community and technology are often advanced in the area of
biologics far ahead of the regulatory guidelines for their use in the
practicing healthcare community. Dr. Baron stressed that, therefore,
regulatory risk and other uncertainties impede companies from investing
in R&D programs in novel therapies.

Dr. Baron emphasized that industry takes decided financial, scientific,
clinical, and developmental risks in translating basic research advances
and bringing novel therapies to the marketplace. There is a clear value
chain. Following the R&D stage, with its inherent risks, there is also
the risk involved in the regulatory review stage. Finally, industry
assumes a high degree of responsibility for the long-term safety and for
the acceptability of such therapies following their introduction into
the marketplace. Industry recognizes that innovation does not come
without risk, but it must carefully define and implement risk controls
at various levels of the process.

[]{.mark}

The previous day, Dr. Baron had asked where in the list of serious
diseases one should place type 1 diabetes on a scale of 1 to 10, if
cancer is an 8. He explained that the importance of the answer to this
question is that the seriousness of a disease is a paramount factor in
determining the amount of risk one is willing to take to develop a
therapy and to use the therapy. His answer would be that type 1 diabetes
and insulin-requiring diabetes are incredibly serious and require very
serious therapies. Given the choice between type 1 diabetes at the age
of 16 and stage 1 lymphoma with a 95-percent cure rate, Dr. Baron would
opt for the lymphoma. He urged that diabetes be taken as seriously and
with the same sense of urgency as cancer and AIDS, diseases for which
patients undergo an incredible degree of therapy risk, as do patients
who undergo pancreatic transplantation, islet transplantation,
immunomodulation, and immunosuppression. Today, in spite of important
advances in insulin therapy, glycemic control for the type 1 and
insulin-requiring patients is not optimal. They do not achieve their
glycemic goals. Dr. Baron said he would therefore place the emphasis in
his presentation on the issue of risk and the need for a better
glucose-lowering therapy.

Dr. Baron offered the hope that in time there will be a cure for type 1
diabetes through immodulation, stem cell, islet transplantation, islet
growth, and gene transplantation therapies. Meanwhile, over the past 20
years, intensive insulin therapy with glucose monitoring has enabled
patients to lower their glucose, but with increasing insulin dose the
risk of hypoglycemia also increases. Dr. Baron noted that every new
insulin coming on the market is associated with an increase in
hypoglycemia or loss of control or both. The "sweet spot" for each
person is highly individualized, which is why an insulin vial does not
have a label specifying how to use it. The patient learns how to use it
over time. With hypoglycemia, the patient backs off the insulin. With
hyperglycemia, the patient adjusts the insulin dose. This can take place
on a moment-by-moment basis. Clinics are staffed with nurses and
diabetes educators to help patients with this. Adjusting the dosage
takes time. Dr. Baron pointed out that, thus, patients have accepted
this incredibly high risk of insulin therapy, which is actually a
dangerous therapy.

In his opinion, while waiting for an actual cure, the greatest unmet
need in type 1 diabetes and insulin-requiring type 2 diabetes is the
need for a novel therapy to provide another control variable beyond the
single-control variable we have today, insulin. While insulin is clearly
necessary for life, it is not necessarily sufficient to achieve optimal
glycemic control. Risk and regulatory guidelines continue to be daunting
problems to development of such a system, not just technical- and
patient-related barriers.

[]{.mark}

Dr. Baron stated that the critical question then is "What is an
acceptable risk-benefit ratio for novel therapies?" Also, if a second
control variable is added to intensive insulin therapy, how can it be
studied? This is a real challenge. If there is a partial cure, for
instance with a cell-based therapy in which a little bit of insulin is
coming out of the cell but not enough to make the patient insulin
independent, how can the therapy be studied and the risk-benefit ratio
be evaluated? Are blinded studies with a novel therapy appropriate---and
safe---when the sweet spot is individualized for each patient and takes
so much time to determine? Dr. Baron concluded that the insulin
experience in a blinded study---all that had been learned about diet,
exercise, insulin dose, monitoring, and insulin adjustment for each
subject---would actually be lost in a blinded study testing a second
control variable, making such studies impossible to do.

Another question raised by Dr. Baron was "Is superiority of HbA1c always
necessary for approval?" Dr. Taylor had made the same point with regard
to implantable insulin therapies (IITs). Variables other than HbA1c
matter in patients with IIT, such as postprandial glycemic excursions.
Although HbA1cs of 7 and 7.5 are achieved in patients treated with
insulin, they have incredible excursions and anxiety over those
excursions. So the HbA1c level really does not help in that regard.
Patients want glycemic control that is more predictable, with fewer
fluctuations and less hypoglycemia. Weight control matters to patients.
Quality of life matters to them. Complications are a major concern. Dr.
Baron recommended that the scientific community and industry listen to
patients rather than being concerned only with validated instruments
that might be had 20 years from now.

In discussing risk and a cure or partial cure, Dr. Baron raised
questions about the value of insulin independence or partial
independence at any cost. He asked who would determine the level of
acceptable risk---patients, industry, FDA? Dr. Baron noted these are
very difficult questions but ones that must be answered if innovation is
to take place.

On the path to novel drugs and consideration of the value chain, Dr.
Baron stressed that each partner has a large area of responsibility. FDA
has to be basically dispassionate yet passionate. They have to be
careful and also innovative. This is a very tight, tight balance. Dr.
Baron said the solution requires risk management. Clearly, all the
answers cannot be in place before going to the marketplace. The
marketplace teaches us about a lot of things, as has been seen with
insulin. Years of experience have made insulin acceptable in the
marketplace. He continued that all innovation has risk, and there is a
learning curve. Reducing regulatory uncertainties are essential to spur
innovation. Ultimately, however, if these therapies are not brought to
the marketplace, there will not be an incentive for any more research
translation, and all will suffer; most of all the patients will suffer.

**Devices**

***David Horwitz, MD, PhD,** Vice President, Medical and Clinical
Affairs, LifeScan, Inc., Milpitas, California*

Dr. Horwitz explained that he was representing the device industry and,
in particular, the Advance Medical Technology Association and the Blood
Glucose Working Group. He planned to speak primarily about *in vitro*
diagnostics and innovations in blood glucose monitoring, including home
glucose monitoring and, with a liberal definition of *in vitro*,
continuous glucose monitoring.

Dr. Horwitz pointed out that innovations in glucose monitoring systems
have improved accuracy, speed of testing, sample size, the ability to
sample from alternative anatomic sites, and the ability to gain more
information from meters (data summaries, trend analysis, and so forth).
Monitors are easier to use, are more convenient, have safety features
such as 24-hour patient hotlines, and have special features, including
data analysis through interfaces with computers.

For the future, Dr. Horwitz foresees continuous monitoring, open-loop
control of insulin pumps, the "artificial pancreas," (i.e., mechanical
pancreas), and the ability to optimize and individualize diabetes
management with actionable health information. Achieving these goals
will require exploring and facilitating a number of research,
regulatory, and reimbursement areas. Relevant questions include:

-   How can we advance and enhance the regulation of *in vitro*
    diagnostics?

-   How can we address the reimbursement challenge?

-   How can we fund the research to move the field forward?"

**Regulation**. Dr. Horwitz commended the FDA's progressive efforts to
aid the device industry. The availability of published guidance
documents make the regulatory path clear and facilitate the ability to
get products to market more quickly and cost-effectively. The new 510(k)
paradigms enable industry to take a shorter loop for a less risky
product or for measures that are not likely to affect product
performance. For example, the regulatory path has been simplified by the
ability to classify open-loop infusion pump controllers as Class II
devices, even though they do not have a true predicate device. Another
important regulatory advance cited by Dr. Horwitz has been the ability
for *de novo* classification of a device as Class II when there is not a
predicate device, instead of going the Pre-Market Approval (PMA) route,
which has facilitated getting devices on the market.

The FDA Modernization Act (FDAMA) has enhanced communication with FDA
through the ability to meet with FDA and solve problems ahead of time,
instead of conducting a study, submitting the data, and then finding out
that the wrong study was conducted from the FDA's regulatory
point-of-view. This has also helped to get products to the marketplace
more quickly. Dr. Horwitz remarked that the FDA Office of Combination
Products is becoming more and more important as products become a
combination of devices and biologics, devices and drugs, biologics and
drugs, and so forth. In the area of *in vitro* diagnostics, the Office
of *In Vitro* Diagnostics, which looks at products throughout their
lifecycle, has eased the process of working with FDA.

In considering how FDA can prepare for new technologies, Dr. Horwitz
said that one obvious area that FDA is currently engaged in is global
harmonization of premarket reviews. He noted that industry must deal
with differing requirements, types of studies, and device standards in
different parts of the world, which increases costs and time for
developing products and bringing them to market. Achieving global
harmonization is a particularly important area for the industry. Another
helpful area would be to develop criteria for device
down-classification, such as reclassifying Class III devices without a
predicate device down to Class II where the regulatory path is clearer
and products can be on the market sooner. This is critical in the device
area, particularly for *in vitro* diagnostics, where product lifecycles
are often only 2 or 3 years long before the next generation comes out,
unlike pharmaceuticals that often have a 10-year or longer lifecycle.

Dr. Horwitz noted that screening for diabetes has been getting a lot of
attention. While there is some controversy over who should be screened,
when screening is indicated, glucose test strips are not an approved
indication for screening. Nevertheless, the device firms are constantly
being asked for glucose test strips for screening. Dr. Horwitz said that
resolving this issue depends on establishment of a public health policy
for diabetes screening that considers and balances the tradeoffs between
diagnostic accuracy standards and the accuracy of the test strips and
establishes appropriate criteria. The clinical studies needed to
establish this indication involve large populations that are beyond the
scope of the industry to study and may benefit from NIH-sponsored
studies.

The review of genetic diabetes testing was another area in which Dr.
Horwitz felt FDA needed to develop criteria to regulate *in vitro*
diagnostics test systems, test reagents, test kits, and related
pharmacogenetic products that look at various genetic aspects related to
diabetes. As more and more drugs and different mechanisms for the
treatment of diabetes are considered, there is a need to choose what
drug might be the most important and which genetic factors are most
important. Dr. Horwitz suggested that some of the regulations today,
such as those related to analyte-specific reagents, are perhaps no
longer completely relevant given the new directions being taken in
genetic research. He added this is an area that needs some advanced
thinking to speed the regulatory processes as these diagnostics begin to
reach the market.

**Reimbursement**. Dr. Horwitz pointed out that blood glucose monitoring
equipment seems to be continually targeted for Medicare payment
reductions, creating a major reimbursement challenge for the industry.
As the incidence of diabetes grows, the cost of monitoring will
obviously grow. The problem is being specifically called out now in
Medicare legislation. Reimbursement limitations directly impact patient
access to what, for many, is the most appropriate technology in managing
their diabetes. Dr. Horwitz added that lack of reimbursement for this
equipment has the potential to affect blood glucose monitoring
compliance by patients, and the impact of non-compliance on blood
glucose control has clearly been shown. Reimbursement issues also limit
the availability of new technologies, because they are not reimbursable
and thus not immediately billable. Obviously, from a business
standpoint, reimbursement affects the willingness of companies to invest
in additional R&D to provide new products and new services for the
market and can inhibit development of new molecular tests and
pharmacogenomic solutions, as well as new devices. As an example of the
reality of the issue, Dr. Horwitz cited data showing that Medicare costs
from 1982 to 2001 grew by 382 percent, while spending for *in vitro*
diagnostics was essentially flat, which, as a proportion of overall
Medicare expenses, indicates a significant decrease in spending for *in
vitro* diagnostics.

Dr. Horwitz noted that there has been an increasing public health policy
emphasis on the importance of diabetes as a public health measure and,
as a result, an increase in awareness of diabetes. He stressed that
today's meeting is evidence of the concern as are DHHS Secretary Tommy
Thompson's frequent statements about preventing diabetes and its
complications. At the same time, the Centers for Medicare & Medicaid
Services (CMS) have had to enact policies that discourage diabetes
testing and monitoring. More cuts are planned for the future. In noting
this discrepancy in public policy, Dr. Horwitz said this is currently a
major issue for the industry, and one that needs to be addressed through
proper research on what really is cost-effective therapy.

In closing his remarks, Dr. Horwitz listed the following areas of needed
research according to the device industry:

-   Effectiveness of screening using blood glucose monitors, which is
    going to have more and more impact as the potentially diabetic
    population grows.

-   Medical and economic benefits of tight glycemic control in type 2
    diabetes. In type 1, this is clearly established. In type 2
    diabetes, there is an important need to translate research findings
    into clinical practice, especially in the primary care community,
    where therapy targets are not being reached and where educational
    efforts are needed to provide the data that glycemic control *is*
    important.

-   Optimization of ways to achieve the desired glycemic control, an
    area where research is significantly lacking.

Dr. Horwitz suggested the following research questions regarding
optimizing ways to use self monitoring of blood glucose to achieve
glycemic control: When should it be done? How should it be done? By whom
should it be done? How should it be used to guide therapy? Is
postprandial testing important? Is control of postprandial glucose
important? Advances being made include advances in biomarkers and
surrogate endpoints, which can certainly help in studies. Questions
remain about non-glycemic or non-HbA1c endpoints. There are also the
quality of life issues that have been discussed at this meeting and
frequency of hypoglycemia issues as indications for therapy,

***Recommendations for fostering innovation*** in diabetes care,
presented by Dr. Horwitz for the industry, included regulations that
facilitate the introduction of innovative products; payment systems that
place emphasis on early detection and optimization of treatment to
prevent complications; and increased research dollars to find ways to
make living with diabetes easier by discovering solutions for better
screening, better management, and better cellular, genetic, and
pharmacogenomic therapies.

**American Diabetes Association**

***Nathaniel Clark, MD, RD,** National Vice President of Clinical
Affairs, American Diabetes Association, Alexandria, Virginia*

Dr. Clark acknowledged the collaborative relationship ADA has had with
NIH, particularly NIDDK, and with FDA over a number of years. He noted
that an important role of ADA, as the representative of the 18 million
persons with diabetes and the increasing numbers of those who are at
risk, is to be the translator of the research being funded. The ADA call
center receives 20 thousand calls per month from persons asking
questions about diabetes, questions about this drug or that, about
treatment options, and so forth. ADA also receives 300 thousand visits
per month through its website and requests for the books, magazines, and
journals the association publishes. Dr. Clark stressed that this
connection with the diabetic and pre-diabetic populations and their
families and friends provides ADA with a tremendous opportunity to "get
the word out." The overall question for him as he sits in meetings like
this one is, "What is the word? What is the word that we should be
getting out?"

The mission of the American Diabetes Association is to prevent and cure
diabetes and to improve the lives of all of those affected by it.
Prevention has obviously been in the press of late, and ADA has been
very active in this critically important and highly challenging area.
Dr. Clark cited CDC data that predicts that a child born this day has a
one-in-three chance of developing diabetes in his/her lifetime. New
numbers based on the redefinition of pre-diabetes are that perhaps 40
million Americans have pre-diabetes. When researchers and clinicians
came together and discussed defining a normal blood glucose level in the
fasting state as less than100 mg/dl, not the previous 110, Dr. Clark
wondered if the full significance of that decision was clear to
everyone. This simple change doubled the number of people with
pre-diabetes. The public health impact of doubling the group was not a
major topic in the scientific discussions about whether the data
warranted this redefinition. How to treat 40 million persons with
pre-diabetes is now a primary issue for research translation and thus an
issue of major concern for ADA.

As mentioned earlier, ADA saw the impressive DPP as a proof-of-concept
study and put out a position paper addressing the DPP results. Dr. Clark
said the main message from the DPP was that lifestyle change is very
effective in preventing or delaying progression to diabetes in those at
high-risk, roughly twice as effective as using a medication such as
metformin. The main issue for ADA was how to translate that result, what
should be done to operationalize it. The National Diabetes Education
Program's Small Steps, Big Rewards and other programs that Secretary
Thompson has supported have helped advance the cause of diabetes
prevention. ADA has supported these.

As a Registered Dietitian, in addition to being a physician, Dr. Clark
wondered if the prevention of diabetes through lifestyle change concept
was still being undersold. It is very difficult to receive reimbursement
for dietitian services or for increasing a patient's physical activity
level. On the other hand, there is a drug that works, and so the
question is raised, "Why not approve this drug for prevention and use
it?" As a physician, Dr. Clark admitted it is much easier to write a
prescription than it is to get patients to undergo lifestyle changes. On
the other hand, the benefits of losing moderate amounts of weight and
increasing physical activity are so enormous globally---across a
person's complete health spectrum---compared to the relatively small
gains of simply improving blood glucose levels with a medication. He
added that these obviously are controversial areas.

Dr. Clark explained that the reason ADA interpreted the DPP the way they
did (emphasizing lifestyle change over medication) was because of their
deep concern that once that study was published and people saw that
metformin worked, practitioners would immediately move to the drug
option and ignore the lifestyle option. This concern continues and a
recent example of their reason for it was an interesting article in the
*Washington Post* about pre-disease. The article spoke of an
endocrinologist in Washington, D.C., who prescribed metformin for a
15-year-old girl, even though her laboratory results of blood glucose
levels did not qualify for pre-diabetes by any criteria, new or old. He
put her on the drug because he felt that her insulin level was somewhat
elevated. Dr. Clark stressed that responses such as this to research
results clearly raise questions about indications for use of a drug,
about endpoints, and about the goals of treatment.

Referring to Dr. Nathan's earlier concern about not appropriately using
the drugs we have now for treating diagnosed diabetes, Dr. Clark raised
the issue of diverting attention from this valid concern by talking
about drugs for pre-diabetes. In the field of diabetes, there also are
already many drugs to treat hyperglycemia, hypertension, and
dyslipidemia to prevent complications in diabetes, yet these are not
being used optimally to treat these problems. While it is important to
support approval of new therapies by FDA, there is also a need to
promote better use of existing, proven therapies.

Dr. Clark introduced the problem that ADA and the public face in trying
to interpret research studies that are done in very different ways. The
DPP was an excellent, randomized, long-term, controlled trial that
produced excellent data. Dr. Clark though is repeatedly asked by the
media to comment on other studies being published by colleagues. He is
presented with such questions as "Is it true that Oolong tea prevents
diabetes? That drinking five to six cups of coffee a day prevents
diabetes? That eating peanut butter prevents diabetes? That having your
blood tested for an increased iron level predicts diabetes?" The public
is being challenged to compare a study done by correlating numerous
variables using a computer to show that five to six cups of coffee
prevents diabetes with the DPP that showed that lifestyle change and
metformin prevent diabetes. The public's attempt to compare and
interpret results from such disparate study designs is a challenge for
the ADA, the FDA, and NIH in terms of their prevention translation
efforts.

The second part of ADA's mission is seeking a cure for diabetes. Dr.
Clark said this begins with supporting good research. Along with NIH's
expansive efforts, ADA provides seed grants to encourage young
researchers and to enable them to collect the data to apply for an NIH
grant. Islet cell research is an area about which ADA receives many
questions.

The largest area that Dr. Clark is personally involved in has to do with
improving the lives of those with diabetes, including the development of
ADA's evidence-based clinical practice guidelines. Dr. Clark emphasized
that defining the cutpoint for HbA1c or LDL or any of the
diabetes-related factors has to be based on good research. ADA largely
relies on NIH for this basic and clinical research.

In the area of medication, ADA obviously relies on the FDA in terms of
what gets approved. ADA and FDA have collaborated well to date and plan
to continue doing so in the future in looking at how drugs are used and
what problems might occur. For example, a working group assessed the
effect of glitazones in terms of edema and congestive heart failure. As
the manufacturers came through and presented their data, a member of the
FDA staff was present to comment on the validity of the data and assist
the working group in preparing their paper. At a recent meeting on
antipsychotic use and the development of diabetes, an FDA representative
was invited to present the agency's experience in this area. Lastly, Dr.
Clark said that, at the request of FDA, a future working group would be
looking at hypoglycemia, including to what extent hypoglycemia should be
used as an endpoint in new drug approvals and equipment approvals and if
there is there is special relevance of night-time hypoglycemia.

Dr. Clark noted that there has been an explosion over the last 10 years
in the number of drugs to treat diabetes, specifically new insulins, new
oral medications, a number of drugs for dyslipidemia, and also a number
of ACE-inhibitors and ARBs for treating blood pressure. This plethora of
new drugs, along with what we know about diabetes and risk factors, has
led to the issue of whether simply having diabetes is a sufficient
indication to be on all these pills. Also, is there a need to develop
what has been called the polypill---a single pill that contains, for
example, aspirin, an ACE inhibitor, and a statin and is prescribed upon
diagnosis of diabetes? Dr. Clark added that then the question would
become if for those with pre-diabetes or the metabolic syndrome, who are
also at risk, should these drugs be introduced earlier and earlier into
people's lives, even though all these drugs have potential side effects?

According to Dr. Clark, there also are current questions applicable to
laboratory tests. ADA is very proud of the HbA1c standardization program
using a reference range, which was largely based on data from the DCCT.
The Association is interested in trying to standardize the insulin
assay, so that this assay can be used more effectively. They are also
looking at the same issues with regard to C-peptide. Dr. Clark explained
that a very important question that comes up now is in regard to home
testing of HbA1c and of lipids. Once a laboratory test is moved out of
the clinical arena where there is a physician or other experienced
healthcare provider to determine when to get the test and to interpret
the test, costs may increase while benefits may not change or decrease.
For example, to what extent is it a good idea for patients to check
their HbA1c once a day, once a week, or once a month as current
guidelines suggest checking 2-4 times per year? Will such home testing
provide the patient with any truly useful information?

In summary, from the American Diabetes Association's perspective, Dr.
Clark said they take very seriously the responsibility to dispense
reliable information, to help those with diabetes whom ADA serves, and
to work closely with NIH and FDA. Certainly, together the three
organizations can accomplish more than any one group can separately.

**Juvenile Diabetes Foundation International**

***Robert Goldstein, MD, PhD,** Chief Scientific Officer, Research
Department, Juvenile Diabetes Research Foundation International, New
York*

Dr. Goldstein said he was really a pinch-hitter for either an articulate
child with diabetes or a mother. JDRF is run by dedicated volunteers who
would be very interested in everything that was discussed at this
meeting. He stressed that, in addition to NIH, FDA, academia, and the
pharmaceutical industry, the future also depends on foundations and
advocacy groups.

The mission of JDRF is to find a cure for type 1 diabetes and its
complications through supporting research. Cure is defined as restoring
blood sugar to normal, preventing complications, and preventing
diabetes. Dr. Goldstein explained that over the past 6 or 7 years, JDRF
has been becoming increasingly focused, as opposed to becoming
increasingly broadened, in its research agenda for a cure. He listed the
following significant outcomes on a 5-year path toward a cure:

-   Generate permanent euglycemia by islet transplantation without
    chronic immunosuppression.

-   Generate a replenishable, stable, universal source of
    glucose-responsive beta cells and insulin-secreting cells that
    resist immune attack for human transplantation and begin Phase 1
    trials.

-   Restore euglycemia and insulin independence by activating endogenous
    beta cell regeneration and inducing immune tolerance to beta cells
    in animal models of autoimmune diabetes. (Dr. Goldstein remarked
    that regeneration with a capital R is becoming a topic for a variety
    of disorders.)

-   Create permanent euglycemia and prevent complications with a closed
    mechanical loop artificial pancreas.

-   Encourage novel approaches to predict and novel therapeutics to
    prevent and treat complications.

-   Accurately predict the risk of type 1 diabetes and develop novel
    therapeutics to prevent diabetes, including a vaccine to prevent
    this disease. JDRF is working with a variety of NIH institutes, as
    well as governments outside the United States, to accomplish this.

Dr. Goldstein explained that although it is not a typical cure item, the
closed loop artificial pancreas is a goal that responds to children and
parents wanting their lives to be better in terms of their ability to
manage and control their disease and, thus, they would settle for a
device to help them do that while waiting for the promised cure. JDRF
has stopped funding this area of research and secured funding of
approximately \$4 million from the Department of Defense specifically to
promote innovative work to accomplish this goal.

After 9/11, JDRF's funding leveled off somewhat. In FY 2003, the
association's \$81 million research budget was divided up approximately
into 57 percent for achieving euglycemia, 27 percent for prevention of
complications, and 16 percent on prevention of type 1 diabetes.
Dr. Goldstein said that this year, JDRF will spend approximately \$93
million on research.

Presenting a pie chart depicting where JDRF research funds are spent,
Dr. Goldstein noted that 38 percent of the 2003 money was allocated
outside the United States. JDRF has partnerships with medical research
councils in 10 to 15 countries that advocate for type 1 patients and
promoted enhanced activity on their research and public health agendas
in their respective countries. He pointed out that both Finland and
Sweden, where there is a tremendous amount of type 1 diabetes, have
wonderful healthcare systems that permit JDRF to do clinical trials that
probably would be more difficult to do in the United States. They
collect enormous amounts of phenotypically well-characterized patient
specimens that JDRF is trying to bring together so that other
researchers will have access to them. When clinical trials are conducted
outside the United States, the study groups look to FDA for ultimate
guidance. This is also true for the EU regulatory system, and so forth.
Dr. Goldstein assured those present that JDRF's funding of research
outside the United States has not been in order to work where the rules
were less difficult, but to go where there are excellent patient
resources and dedicated physicians.

Dr. Goldstein stated that JDRF is sponsoring clinical trials in islet
transplantation---a cooperative clinical trial with NIDDK and another
one with CMS and NIH in Medicare recipients, which will provide a
post-kidney transplant opportunity. JDRF also is organizing its five
largest European groups to complement this U.S. activity. Dr. Goldstein
said that over the past couple of years since the Edmonton protocol
publication, the focus of attention has been on freeing patients from
having to take insulin shots. He stressed that, unfortunately, many of
the publications have emphasized insulin-independence and have
under-emphasized the ultimate therapeutic benefit of islet
transplantation itself. Over time, insulin-independence drops off;
however, the therapeutic benefit remains. Dr. Goldstein recommended that
more attention be paid to documenting and observing this ultimate
benefit. Taking some insulin would not be a terrible imposition on the
patient population currently receiving transplants.

New onset type 1 diabetes immune intervention represents a frustrating
paradigm for JDRF, according to Dr. Goldstein. JDRF has a study group
working with CD3. The group is based in Brussels, but the Principal
Investigator overseeing the trial is in France. The research reagent was
not permitted to cross the border from England to France, but was
allowed to go from England to Brussels. The government of Belgium
supports a diabetes registry and tracks the patients. This is an example
of the kind of opportunities that exist overseas. In the United States,
JDRF is sponsoring anti-CD3 trials in new onset type 1 diabetes.
Anti-CD3 has shown a potentially reasonable effect, but given over a
period of time, it also has some toxicity issues. To date, Dr. Goldstein
feels the issue of issue of trials in children, particularly prevention
trials in at-risk children who are quite healthy, has not been
adequately addressed. This partially explains why most type 1 prevention
studies are being done with insulin, because a lot is known about
insulin and about its safety. Dr. Goldstein emphasized that working with
the next generation of therapeutic agents is a huge challenge in efforts
to move forward. Many, if not most, of the current approaches to immune
modulation involve toxicities that the scientific community is not used
to and thus do not know whether these toxicities are theoretical or
real. Dr. Goldstein stressed that a way must be found to deal with this
issue if the field is to advance.

Other clinical trials supported by JDRF include advanced glycation
endproduct (AGE) inhibition for which the group has seeded a grant that
is blocking RAGE receptors and trying to work on complications. An issue
in this clinical trial is the difficulty of obtaining high quality
material. Dr. Goldstein explained that there is not a lot of venture
capital available for these very early novel therapies. The FDA in
particular does not like the use of research grant-level material; the
agency wants higher quality material. Dr. Goldstein commented that this
was another area for future discussion.

Dr. Goldstein also raised the issue of collecting ell-characterized
patient populations in order to begin to stratify and find subgroups,
particularly for genetic studies or therapeutic trials in molecular
medicine, genomics, and proteomics. He stressed that this is a resource
that all groups currently need. NIDDK has made a commitment to accept
the challenge of assembling these critical patient populations in a
manner suitable for researchers to gain access. This often requires
re-consenting people from international studies to have modern and
up-to-date consent to do new studies. Once this resource is freed up,
Dr. Goldstein is optimistic that the work will go forward more quickly
in type 1 than in some other disease areas where such resources do not
exist.

Regarding stem cell research, Dr. Goldstein stated that JDRF took the
position, politically and scientifically, after August 2001, that more
work was needed than could be done in the United States at NIH.
Therefore, JDRF has partnered with half a dozen countries in an effort
to derive new stem cell lines, characterize existing lines to study beta
cell development, promote information exchange and research according to
the highest ethical standards, and make the stem cells freely available
to researchers by removing the constraints that currently exist with the
NIH lines. The effort is being carried out by the International Stem
Cell Forum, which was organized in the United Kingdom by the Medical
Research Council and is made up of groups from numerous countries,
including NIH from the United States. Additional information about the
Forum and its objectives is available at
[http://www.mrc.ac.uk](http://www.mrc.ac.uk/). Dr. Goldstein announced
that within the next 6 to 9 months, the Forum will be characterizing
about 50 new cell lines, including ones with human fetuses. He
acknowledged that for FDA and for anyone wanting to do therapeutics
based on embryonic stem cells, the challenge will be how to bring
potential therapeutics from outside the United States into the United
States; however, it is JDRF's hope that this will occur, ultimately, but
not next week, of course.

Dr. Goldstein concluded by saying JDRF also has a program for supporting
small companies, usually headed by academics who have come up with a
novel idea. It is sort of a pre-SBIR (Small Business Innovation
Research) type program.

**Discussion**

To lead off the discussion, Dr. Meyer noted that the industry speakers
had presented a litany of challenges and areas of therapy requiring
research. He asked Drs. Clark and Goldstein if they saw the gaps or
failures to achieve optimal therapy in clinical practice being driven by
lack of adequate therapies and/or devices or by inadequate use of the
therapies currently available.

Dr. Clark responded that, in general, his feeling and that of ADA was
that there are an enormous number of tools that are not being used
effectively at this time. There clearly are gaps, and ADA supports and
looks forward eagerly to new drug and device development. Meanwhile, his
and ADA's wish would be for better utilization of what already exists
rather than waiting for the creation of something new.

Dr. Goldstein declined to give an answer for JDRF, but personally, he
agreed with Dr. Clark that the United States is not doing all that it
could do. In Scotland, for example, all persons with diabetes are
registered in a database, along with every laboratory test, x-ray,
prescription, and so forth. Of course, Scotland's population is around 5
million people. Anyway, 4 or 5 years ago, the database showed that
insulin-dependent diabetics were not getting eye exams, so they
instituted a mandatory eye check and achieved a 95-percent compliance.
This did not increase their costs because they had a basic
infrastructure in place. Dr. Goldstein said one had to be amazed at a
functioning healthcare delivery system that could accomplish this type
of thing. In other countries, particularly ones interested in islet
transplants, their quality control and their ability to achieve tight
control is exceptional. In Finland, for instance, it does not matter who
the patient is, access to all the specialty information is available for
anyone with type 1 diabetes. That is not true in the United States.

Dr. Taylor agreed that delivery of the healthcare technology that exists
is imperfect, but was unsure if that presented an either/or choice
regarding development of new therapies versus application of current
ones. Type 1 patients who receive the absolutely very best care
available in the world with the best utilization of the technology still
do not achieve normal HbA1c. They still have diabetic complications,
which is why JDRF is looking for a cure. Similarly, with metabolic
syndrome, cardiovascular risk, and type 2 diabetes, people who receive
the very best available medical care still have problems controlling
their weight. Dr. Taylor suggested that the issue may be that therapies
need to be more user-friendly in order to do a better job of getting
people to use the available therapeutic modalities. An implantable
closed-loop pump, for example, or an artificial beta cell, would make
patient compliance much easier. Dr. Taylor said there would still be
economic issues to address, but outcomes would be better.

Dr. Clark commented that there might be more success in diabetes clinics
if there were fewer meters or monitors available, which were selected
based on patient and provider characteristics. Today, for example, some
children have three or four different types of meters, and there is
therefore no easy ability to download results effectively because every
instrument requires its own software program. When the different
manufacturers are asked about standardization, the answer is that there
is no possibility at this time of standardizing the technology.

Dr. Tamborlane brought up the reimbursement challenge in attempting to
run a large-scale treatment program for youth with Type 1 diabetes. He
said the fee-for-service model to pay for intensive diabetes care for
1,000 children is just not a doable operation. As a result, his group
must subsidize the care with money from whatever source they can. Dr.
Tamborlane stressed that other reimbursement models were needed, such as
global fee models or disease management models. He suggested that this
was a target for the advocacy groups to pursue. He mentioned that JDRF
has a committee and a grant to look at how to pay for the personnel
required to implement advanced technologies.

Dr. Goldstein responded that JDRF had not solved the problem yet but
were continuing to work toward a solution. The association's focus has
been on research so it has been difficult to shift to paying attention
to fixing the healthcare system.

Dr. Clark added that even though we have good meters and good insulins,
there is not a willingness to reimburse the time of healthcare
professionals that is needed to help patients make maximum use of these
existing technologies. For example, physicians and their staff members
spend a lot of time going over glucose levels with patients,
particularly over the telephone, and there is no reimbursement for this.
The reimbursement issue is an important point in physicians' better
applying what is known about diabetes care.

A member of the audience asked what processes were available to help
investigators and evaluators make conscious, deliberate use of the
unique expertise of patients. More to the point, in order to provide
patients with access to therapies that have ambiguous results in terms
of being safe and effective for average patients in a static protocol,
what can be done to enable patients to conduct their own personal
clinical trials to determine what is safe and effective for them. As
background to the question, the inquirer said that when her daughter was
diagnosed with type 1 diabetes 15 years ago, the Chief of Pediatrics at
Joslin Diabetes Center told her that once she learned to care for her
daughter under his tutelage, she would know more about her care than he
would know. This statement was confirmed by many other professionals
over the years until now, at 19, the patient knows better how to care
for herself than any physician does. In looking at the development of
new therapies and in designing clinical trials, how are procedures
decided for evaluating whether the new therapy is right for an average
patient and whether the therapy will have the proper effect on average
levels of blood glucose, granting that there is no such person as an
average patient? New trials and evaluations are based on fixed
protocols. Her daughter's protocol changes every day, sometimes every
hour. Use of HbA1c was a huge advance for research, but it is wrong to
call it a gold standard because there is never an average blood glucose.

Dr. Baron responded that on the device side, glucose meters, in
particular, are largely a consumer-driven market. Market research begins
at the user level. Different users clearly have different desires,
different wants, and different preferences. That is one reason why there
are so many multiple products. Dr. Baron suggested that large databases
are obviously needed to obtain the statistics for the "average" patient.
A challenge that must be dealt with is how to deal with small numbers of
persons in special situations. Should this be part of the practice of
medicine or part of the regulatory process?

Dr. Horwitz commented that patients make choices all the time. For some
investigators, pumps are the ultimate form of delivery of insulin.
Currently there are approximately 120,000 to 150,000 patients on pumps.
Clearly, most patients with diabetes have opted not to use pumps. Others
have opted to discontinue the pump and to go on to Lantus therapy.
Others have discontinued regular insulin and gone to newer insulin
analogs. Dr. Horwitz agreed that all patients are different and all of
them have their own paradigm of what is best for them. Mean values do
not respect the individual. With respect to type 1 diabetes, Dr. Horwitz
believes it is such a devastating disease, that patients do need to be
listened to more carefully.

Dr. Taylor remarked that industry and regulatory agencies do work
together to ensure that compounds meet minimal standards of safety and
efficacy before they are made available for patients in clinical trials.
Once a drug is approved, there is in effect a post-marketing clinical
trial to further monitor the drug's safety. In exceptional cases, where
early data are especially encouraging, the FDA and the industry partner
work to make a product available on a compassionate use basis if it is
believed that there is value in making it available to people who would
otherwise be harmed by preventing early access to the product, even if
the product has not met the normal regulatory standards for approval.
There are many controls involved in this early availability, but the
practice does recognize the issue that for some patients, this is an
appropriate course of action.

Dr. Taylor went on to say that it is sadly true that, for the most part,
patients with either type 1 or type 2 diabetes must be viewed as a more
or less homogenous group, Physicians are taught to treat the average
patient. However, Dr. Taylor said that over the next 10 or 20 years,
genetic ways, for example, will be found to identify patients who vary
from the average and who have special characteristics. These patients
will then be treated, not necessarily as absolutely individualized
patients, but as members of a definable group of patients for whom
particular treatment regimens have been identified as being safe and
especially effective. He added that this is one of the important areas
for contributions from Government and private-sponsored research.

Dr. Horwitz added that gene identification of subtypes of type 1 and
type 2 diabetes is needed. There are patients with type 1 diabetes who
can achieve reasonable glycemic control and not gain a massive amount of
weight. Others cannot. This needs to be recognized, rather than simply
telling the weight-gaining patients they are not doing the treatment
correctly. Residual C-peptide secretion in a patient enables that
patient to get better control. Not everybody has the same degree of
residual C-peptide secretions. Dr. Horwitz recommended identifying
patients who have particular needs. He said it is wrong to ignore the
fact that there are highly motivated people who cannot achieve the
results from a therapy for which other people are successful.

Dr. Alex Szidon, DARA BioSciences, asked the panel to identify elements
or hallmarks to keep in mind that would foster preclinical and early
clinical development of new diabetes and obesity drugs further down the
road. This would be a valuable benefit to take away from the symposium,
along with the discussions about clinical outcomes and endpoints.

Dr. Horwitz responded that it is difficult to ask that investments be
made in targets that are uncertain with regard to the risks and the
regulatory process. In the drug development industry currently, it is
better to be number two in coming up with a novel class of medications
because you can piggyback on number one's risks and experience. This
happened with statins. Dr. Horwitz thinks this will also be true with
ACE inhibitors. The ability to take a novel chemical entity or a
biological therapy all the way to the marketplace is so daunting today
because of the uncertainties that, in order for choices to be made early
on, there needs to be a better sense of the risk-benefit ratios in terms
of what patients want and what the FDA thinks is in the best interest of
patients, rather than what is the easiest regulatory door to get
through. Dr. Horwitz recommended that the FDA continue to aggressively
initiate conversations with industry about better risk management
methods. Otherwise, he believes it will be very difficult for people to
invest in true innovation early on.

Dr. Taylor disagreed slightly. It is partially true that to get a drug
approved that is the nth in its class is appealing because of the lower
risk. On the other hand, to get a drug that is say 5^th^ in its class
but that truly adds value, that really distinguishes itself, that is
going to make a real difference for patients, is extremely challenging.
For the most part, people in the industry try to balance the risks. If
there is a class of drugs that are seen as having benefit but there is a
problem with the drug, people will try to improve it. There needs to be
room for improvement with any drug to make a difference with patients
and have a commercial success. It does make life easier if some of the
risks are known, if a company knows what kind of data will be needed to
have a new class of drug approved. This allows the company to make a
fair and reasonable assessment of its risks. It is the unknown and
unmeasurable risks that are particularly discouraging.

Dr. Horwitz said that Dr. Taylor's statements were correct. In a big
company with a portfolio of risk, there can be four or five versions of
a drug that is known to work and that people have accepted. The
difficulty is when people look for go-no-go decisions and the regulatory
path is unclear. This makes for a very risky situation in the minds of
the business people. Dr. Horwitz stressed that for true innovation to
occur, and it is happening, industry does have to be bold. They are very
capable when the science is there to be harnessed. Industry has to be
convinced that the need is serious, for instance for better type1
treatments. They are aware of this seriousness for AIDS and for cancer,
where in a sense the risk is minimal because death is the other outcome.
To deal with the epidemic of diabetes in children, where the level of
incidence of children with type 2 diabetes is replacing the level of
those with type 1 diabetes, is going to require bold thinking on the
part of research and industry. It is a daunting task. There are many
tough decisions that all parties must make---the Government, industry,
academia, advocacy groups, patients, healthcare professionals,
third-party payers, policymakers and decisionmakers, and the general
public who ultimately pay the bills.

**Session VIII: Targeting Safe and Effective Prevention and Treatment:
Steps Forward by FDA and NIH**

*(Moderators: David Orloff, MD, FDA, and Judith Fradkin, MD, NIDDK)*

**Panel Members:** *Drs. Robert Eckel, Christopher Saudek, Harry
Shamoon, Robert Sherwin, William Tamborlane, and Simeon Taylor*

Dr. Orloff convened the panel and expressed his appreciation to Dr.
Garfield and to Dr. Fradkin for their assistance in organizing this
meeting. He particularly wanted those present to be aware of Dr.
Fradkin's clarity of insight about this area and her knowledge of the
people at the forefront of the issues.

Dr. Fradkin responded that the partnership with Dr. Orloff had been
excellent and expressed her appreciation for those who had come together
to share their knowledge, perspectives, recommendations, and commitment
to the goals of the meeting. She noted that the speakers had presented
eloquent descriptions of both the public and the private burden of
diabetes. As stakeholders, they had offered a wide range of
perspectives. Dr. Fradkin acknowledged that selecting targets and moving
forward was a challenging task for all and, in particular, for NIH and
FDA.

Dr. Fradkin asked the panel to comment on two issues:

-   What might NIH and FDA do to further enhance the research climate
    and to enable industry to translate the discoveries coming from
    academia into new therapies?

-   What is a meaningful outcome for prevention and treatment studies in
    diabetes?

With regard to the second question, Dr. Fradkin listed insulin
independence or increased beta cell function or C-peptide preservation
as choices for outcomes for islet transplantation. She added that a
meaningful outcome for treatment or prevention of the metabolic syndrome
is also important, since the syndrome is becoming a large, emerging
problem as a collection of risk factors for CVD and diabetes.

Dr. Shamoon responded that the workforce issue is one that NIH could be
addressing. Referring to NIH's Roadmap Initiative, he remarked on the
enormous number of targets, possibilities, and opportunities that
fundamental science has created in the last 20 years. The gap now is the
lack of trained clinical investigators to carry the science forward. He
emphasized that an important task of the next generation of clinical
investigators is to take the up these problems in a way that addresses
public health. Dr. Fradkin commented that NIH recognizes this need and
continues to be active in encouraging medical students to pursue
research careers.

Dr. Tamborlane stated that for youth with type 1 diabetes, he would
encourage industry to move forward in the technological development of
artificial pancreases as a key area. New sensors are overcoming
obstacles that stood in the way for the past 20, 30, or 40 years. Dr.
Tamborlane thought it likely that the artificial pancreas will be a
successful mode of treatment well before the problems and risks from
islet transplants and immuno-suppression are resolved in children.

[]{.mark}

Regarding meaningful outcomes for type 1 diabetes, Dr. Tamborlane listed
HbA1c, reduced risk of hypoglycemia, improved quality of life, and
reduced treatment burden. He said that the 900 type 1 diabetes patients
at the Yale clinic are doing so well with an HbA1c of 7.5 that he tells
them that, for the most part, they have beaten diabetes. This control of
their hyperglycemia will have a tremendous impact on late complications.
The problem is that they must beat diabetes every day. That is the
burden, and that is what exposes them to risk. Dr. Tamborlane stressed
that this daily struggle is the top problem that needs to be solved.

Dr. Sherwin said that an important area for NIH support would be
development of drugs, particularly a vaccine for type 1 diabetes. This
is not area that is on the radar screen of the large pharmaceutical
companies because of the size of the market. In clinical trials, NIH
could help determine the risk-benefit ratio for islet transplantation
once the procedures move ahead sufficiently for it to be potentially
more readily available; identifying the risk-benefit ratio would help
with reimbursement and product development issues. In reducing the risk
of CVD, trials are needed to answer what extent lowering glucose in
people with the metabolic syndrome contributes to the equation of
treating dyslipidemia and lowering blood pressure to optimal levels,
along with aspirin treatment. Dr. Sherwin's bias is that hyperglycemia
does have an impact, but FDA would need evidence of this as an endpoint
for the metabolic syndrome. Meaningful endpoints for type 2 diabetes are
first, prevention of CVD; second, prevention of complications of
diabetes; and third, achieving a sense of well-being, which is hard to
define but is relevant.

Dr. Sherwin continued that the daunting task is identifying surrogate
endpoints. There are valid endpoints for cholesterol, blood pressure,
and glucose. He asked if there was a valid endpoint yet for treating
insulin resistance, as this would be a major problem for FDA in
relationship to the metabolic syndrome. Dr. Sherwin stressed this was an
area that needed further discussion and debate in a larger forum to
resolve. Other issues to be discussed further include endpoints for
treatment of persons with pre-diabetes and pre-CVD. Something other than
CVD itself is needed. Dr. Sherwin recommended that preparing a position
paper for FDA on these subjects was in order.

Dr. Taylor stated that preventive medicine is a huge challenge. If
someone has pneumonia, the person is given penicillin and gets
better---a very short-term endpoint. Whereas preventive medicine has
much longer time spans. DCCT required about a decade. He explained that
it is difficult for a pharmaceutical company that has a patent clock
ticking to consider trials in which the patient may well expire by the
time the outcome study is done. Dr. Taylor said it would therefore by
very helpful if there were validated surrogate markers, like HbA1c,
viewed as an outcome rather than as a kind of risk factor. He suggested
that Phase II studies could identify biomarkers that could help industry
assess risk and make decisions early on, even if they were not
FDA-approved biomarkers. For example, once HbA1c and LDL were validated
as mechanisms for insulin and statins, respectively, then industry knew
that any mechanism that changed these biomarkers was going to predict a
good outcome. This is not known for HDL. If it was known that HDL is
truly the good cholesterol and that raising it would be beneficial, then
HDL as a surrogate marker would stimulate industry to seek ways to raise
it.

Dr. Eckel pointed out that raising HDL per se could not be the endpoint
because of other factors equally important to an outcome. For example,
one of the ways to raise HDL cholesterol the most is eating the Atkins
diet. On the other hand, a diet of high intake of saturated fats and
cholesterol will likely not provide a satisfactory outcome for CVD.

A panel member commented that NIH needs to continue to investigate the
genetic, molecular, cellular, and pathophysiologic causes of disease. It
is not NIH's job to develop drugs but the institutes can assist the
process through clinical trials like those suggested by Dr. Sherwin. It
was noted that NIH sponsors workshops for medical students to teach them
clinical research skills and introduce them to clinical research as a
potential opportunity for their future. Also, through its K-series
awards, NIH has several mechanisms to develop clinical support for the
transitional scientist. What was needed was support for R01
investigators who must compete with cellular and molecular biologists.
The speaker suggested that in investing in clinical research, which is
the pathophysiological basis of drug development to some extent through
helping to understand the mechanisms by which drugs work, NIH is
assisting the industry. Another role NIH plays is in training those who
have the tools and capability of understanding the mechanisms of disease
operation.

A panel member spoke about the major issue of long-term weight
maintenance after weight loss. He said he was not actually convinced
that there was a health benefit to weight reduction if the weight loss
is not maintained, although all the biomarkers say there is. Current
clinical trials have demonstrated the transient nature of weight loss.
Once a person is obese, that person tends to maintain that body weight
against most odds. The speaker stressed that the public message of
prevention of weight gain is what should be heeded. NIH's LookAHEAD is
an important clinical trial to show whether or not people at high risk
of CVD can, under the best of circumstances, not only lose weight, but
maintain the weight loss over years and gain a long-term benefit with
respect to cardiovascular outcomes.

In reference to raising HDL by different mechanisms, a panel member
referred to a recent article in the *New England Journal of Medicine*
about cholesteryl ester transfer protein (CETP) inhibitors that showed
that CETP inhibitors raise HDL and lower LDL and triglycerides
(Broussau, ME et al. NEJM 350:1505-1515; April 2004). He raised the
concern that the mechanisms by which HDL changes and how the changes
relate to the atherosclerotic process are unknown. For instance, if HDL
is raised by modifying its clearance, then the HDL is being raised in a
mechanism that does not relate to its ability to reverse cholesterol
transport. It is the lipid-poor HDL that binds membranes in reverse
cholesterol transport. It is not modified clearance.

Dr. Taylor stressed that his earlier comments about the need for support
for research in biomarkers for atherosclerotic disease or the metabolic
syndrome was not specifically about HDL but about how critically
important these problems facing the Nation are with respect to the
growing numbers of obese youngsters. If the country must wait for a
decade-long clinical trial, the epidemic of heart disease in 20- and
30-year-olds will already be taking place.

Dr. Saudek commented that as FDA moves forward in the management of
diabetes, the agency will have to increasingly think of the burden of
the disease. Established biomarkers can show that something is effective
in managing HbA1c or managing biomarkers for CVD and so forth. He
stressed that the burden of treatment is a major factor today. While
there are patients who are excellent at managing their treatment
regimens, there are many more who are not and are not capable of doing
so. Type 1 diabetes involves dozens of interventions every day. Anything
that eases that burden of treatment is going to pick up another small
percentage of people who will be successful in managing their disease.

[]{.mark}

Dr. Saudek continued by saying that for type 2 diabetes, losing weight
is critical. Losing weight and getting active is a major need for a
large portion of the population of the United States; however, this fact
has not penetrated very far. Given this situation, Dr. Saudek asked what
criteria are being set up for approval of, for example, obesity drugs.
He said that he sat in on a discussion for a company a few years ago and
learned that FDA had a criterion for effectiveness in managing diabetes
that was independent of blood glucose lowering. In his practice, the
first thing he did for overweight diabetics was institute a weight
management program. Thus, would not an effective weight reduction
medication be valid as a treatment for diabetes regardless of whether it
had been shown in animals or in people that it had an independent effect
on blood glucose? Other items that have been on the back burner, such as
insulin antibodies, also should be continuously addressed.

Dr. Taylor suggested that major opportunities existed to help in
understanding new targets and to identify what would be good targets,
including genetic markers or other kinds of biomarkers to define
subpopulations that are particularly likely to benefit in terms of
efficacy or safety from a particular mechanism. In the areas of drug
development and a regulatory path for drug approval, he said that
important questions for prevention of type 2 diabetes have followed the
excellent work of the DPP. The DPP showed that there is a statistically
significant impact of lifestyle and/or metformin. This statistic is
important from the viewpoint of science-based evidence, but it does not
clarify the question of whether or not a person should be treated prior
to developing diabetes to delay the onset for a year or a little longer.
Is that year delay really important? Does something irreversible happen
during that year? Other questions are "Should glucose be lowered even
earlier? Are beta cells irreversibly destroyed during that time period?"
Dr. Taylor stressed that if FDA had data showing there was a particular
window of opportunity for lowering the glucose before there was
irreversible damage, then people would take notice. In other words,
there are policy implications for therapy beyond showing a statistically
significant difference in an endpoint.

Dr. Shamoon reminded those present that the design of clinical trials
frequently creates an artificial situation. The assumption often is that
what happens in the clinical trial can be extrapolated to the broader
population, such as translating the interventions from DPP to other
persons with IGT, without conducting further trials. Dr. Shamoon said
that some of the frustration about having scientific-based evidence that
is not being put into practice is caused by setting the bar too high. It
is very difficult to cost-effectively transition into everyday clinical
practice the results of a carefully designed clinical trial. The
subjects in the DPP cohort who had all the CVD risk markers and
transitioned to diabetes were already close to becoming diabetic.
However, in this high-risk IGT cohort, 40 percent of those in the
intensive lifestyle group and 30 percent of those on metformin had
normalized their 2-hour and fasting glucoses after 1 year. After 4
years, 30 percent of the intensive lifestyle group had normal glucose
tolerance. In those who went back to normal, all surrogate markers
improved in a favorable direction.

Dr. Taylor said that he was not questioning the validity or importance
of the DPP results in suggesting learning more about the window for
irreversible harm to the beta cell. His question was based on the burden
the regulatory and public health agencies face before spending the money
needed to try to prevent type 2 diabetes in all those considered at risk
or subjecting them to even the small risk of taking a medication. His
intention was to suggest that further information would be helpful to
them in making their decisions.

Dr. Orloff agreed that additional information would be helpful. He said
that the discussion so far clearly indicated that, regardless of what
part of the process a group is involved in, the concept of prevention is
very complicated. FDA's responsibility in this area is as complex or
more complex, perhaps, than in any other area of the agency's work. He
presented some of the principles under which FDA works and described how
they come into play in some of the practical aspects of FDA's job. FDA
is charged through the Food, Drug, and Cosmetic Act with labeling of
drugs for safe and effective use. The mandate involves generating and
translating into labeling an enumeration of the expected benefits and
risks for an intervention. He reiterated that this is extremely
complicated in the context of prevention. Some of the issues in the
prevention of type 2 diabetes involve determining which endpoints truly
assess benefit. Another key issue is identifying the target population
for the drug---who will definitely benefit, who may possibly benefit,
and who will not benefit.

Dr. Orloff stressed that in prevention versus treatment, the bar
actually has to be raised with regard to requirements for safety. Even
though a drug may have been shown to be exceedingly safe for other
indications, there are always risks associated with drug treatment and
their relative importance obviously increases with decreasing risk of
development of the target condition, as exists in disease prevention.

Dr. Tamborlane commented that when he has participated as a consultant
on Phase III trials with children and questioned why the pharmaceutical
company was doing things a particular way when he thought it should be
done a very different way, the feedback was "This is what FDA wants."
When asked if the study group had had an opportunity to discuss this
issue with FDA, the response was usually "No." Dr. Tamborlane asked Dr.
Orloff what was the best way to deal with such a situation, where a
company calls in a consultant with particular expertise in design and
conduct of these types of trials and runs into this kind of obstacle.

Dr. Orloff answered that one of the things that has come out of the new
legislation has been an easier and more enforceable process for formal
interactions between FDA and industry. In addition, there are also many
informal interactions. FDA gives guidance on the agency's *current* best
thinking on an issue. Dr. Orloff explained that his position and
attitude is that "current" is a keyword meaning that everything is
always open to change as more information is brought to bear on an
issue. He assured those present that he would certainly listen if a drug
company came to him and said they thought there was a better way to do
something based on expertise gained from other similar trials by using a
different method than the FDA-specified one that would not only answer
the questions FDA considered important but answer other questions that
may be even more important. Dr. Orloff added that bringing effective,
safe products to market is an enterprise where reasonable people have to
come to agreement. Sometimes reasonable people will disagree, and that
is life, but there is always a way to come back and say, "Tell me where
you think I am wrong and tell me why, and then we will continue the
conversation."

Regarding FDA's policy of calling together a panel of experts---very
reliable experts--- to review the final product of studies and advise
FDA, Dr. Tamborlane suggested that perhaps there could be a mechanism
for meeting earlier on with an impartial panel, perhaps from NIH or
academia, to provide advice to both sides on evaluation of products and
study designs and so forth..

Dr. Orloff responded that part of the process of guidance development
involves, or can involve, open public hearings. That is what has been
done in the past and what is intended for future guidance development in
obesity, osteoporosis, and diabetes. In addition, there is a Notice and
Comment process, whereby notice of the existence or issuance of a draft
guidance document is made in the *Federal Register* and comments are
requested. To the greatest extent possible, the FDA guidance system is
an open process.

Dr. Orloff next addressed the advisory process that Dr. Tamborlane had
referred to that reviews individual products. This process is to some
extent constrained due to the availability of limited information and
limited expertise not only on the subject matter, but in making the
bridge to regulatory decisions, which is complicated. Advisors are not
expected to have regulatory experience. Referring back to the
separateness of the guidance process for establishing the required
criteria, Dr. Orloff stressed that no one wants to get to the point of
an advisory committee to discuss a particular product unless some ground
rules have been laid previously so those present understand the basic
rules for approval of this type of product.

Dr. Saudek raised the issue that in these 2-day advisory meetings, a
great deal of information is shared. Could not that process become
integrated, not as a formal regulatory-related process, but as a way to
get ongoing conferencing with staff at FDA by objective, outside people
who are not linked to the company submitting the product? This could
make the guidance development process less passive. People have to
initiate contact when something is put in the *Federal Register*. Dr.
Saudek suggested that a special panel be brought together to discuss
important study design issues related to prominent subjects in public
health, as for instance, the studies to evaluate drugs for type 2
diabetes in adolescents. Input from the academic community might have
improved those study designs.

Dr. Richard McFarland, Center for Biologics, FDA, agreed with Dr.
Orloff's remarks about FDA having an open door. In the Center for
Biologics that deals with many novel products that stretch the
regulatory paradigm, there is an advisory committee that meets to
discuss issues in the realm of translation between science or clinical
trials and regulation. This committee, which does not review products
for licensure, meets two, three, or four times a year. Public forums on
held on various topics that have generated substantial disagreement. The
committee is composed of standing members and supplemented with members
of other FDA advisory committees and other people in the particular
field under discussion. FDA members also participate. Transcripts of the
meetings are on the FDA website. These meetings contribute to the
development of FDA's current way of thinking that Dr. Orloff mentioned.

Dr. Taylor added that industry frequently discusses their relations with
FDA and he had never heard anybody say that FDA people were not willing
to meet with them. There may be times when industry thinks it knows what
FDA has said and does not think another meeting would be productive, or
there may be delays in scheduling a meeting that interfere with a
timeline and make the meeting unnecessary later. However, Dr. Taylor
said he would agree that the door has always been open.

A symposium participant commented that a lot is known about the risks
for heart disease, and preventing a myocardial infarction (MI) is common
practice. When talking about pre-diabetes, people are really referring
to pre-myocardial infarction. When someone is in the pre-myocardial
infarction state or has had a prior myocardial infarction, the person is
treated with a statin to lower high cholesterol. The Scandinavian
Simvastatin Survival Study (Lancet 344:1383, 1994) studies and data from
other studies on cholesterol lowering clearly show that when cholesterol
was lowered in patients with IGT, the risk of MI was lowered and
mortality was lowered. In spite of all the data that has been
accumulated, the current recommendation for treating IGT is basically to
watch it, unless the person has elevated blood pressure or elevated
glucose, then the patient is treated for each of those problems. Much of
the discussions about preventing diabetes are largely about preventing
microvascular disease, while these patients are currently at risk for
macrovascular disease. The speaker thus recommended that if cholesterol
were treated in the IGT patient, even if the patient had a "normal" LDL
of 130, then the patient would be treated the same as a patient with a
prior myocardial infarction or a patient with diabetes. In response to a
comment from Dr. Tamborlane that there is no current evidence-based data
showing that lowering glucose is going to prevent cardiovascular disease
in the IGT group at high-risk for diabetes, the speaker said he was
referring to giving the IGT patient a statin not a glucose-lowering
medication.

The symposium participant continued that not everybody with IGT develops
diabetes. Although patients with diabetes tend to have macrovascular
disease and most will die of macrovascular disease, diabetes is a
microvascular disease. He noted that many patients are so elderly that
they never will suffer from microvascular disease, even when they
develop diabetes. Meanwhile, there is a large body of data showing a
huge impact is possible on CVD in these patients, and it is not being
done. The participant's point also was that a clinical trial is not
needed to answer every question that comes up, when there already exists
good data from other trials that can be analyzed and applied. He urged
the group to mine the data that they had, stressing that the approaching
epidemic is serious enough to call for such measures.

Dr. Sherwin said that in the consensus data, he believed there was a
recommendation to treat this high-risk population for cholesterol.

Dr. Fradkin stated that studying the metabolic syndrome from the
viewpoint of treating glycemia in persons with pre-diabetes or the
metabolic syndrome did not seem to be the practical direction to take.
Therapies studied in relationship to the metabolic syndrome would likely
affect multiple components of the syndrome, rather than a specific
component such as glycemia. On the other hand, the DPP interventions
clearly did not exert their effects solely on glycemia.

Another member of the audience followed up on the issue of the amount of
accumulated data that exists. Researchers in CVD are conducting large
outcome trials and pooling the data in very large registries to find out
more about the natural history of cardiovascular disease. The speaker
recommended that academia, NIH, and FDA do the same in diabetes. This
could enable the sub-phenotyping of patients and increase understanding
of how these sub-groups respond to different drugs. There are not a lot
of incentives for individual pharmaceutical companies to partner with
one other to do this, and this is not likely to happen; however these
companies do have quantities of data that are left behind as they move
on to other therapies. Dr. Fradkin noted that this was a good
suggestion.

Dr. Tamborlane said that if IGT is defined as a disease, the outcome for
prevention would be a normal fasting glucose. In DPP, the lifestyle
intervention was the most effective, but metformin was also highly
effective in restoring glucose to normalcy. In the metabolic syndrome,
lowering blood pressure to normal would apply.

[]{.mark}

A participant stated that defining a disease requires that there are
specific problems related to that disease. Other than by testing for IGT
itself, there are no symptoms of IGT in a patient. It is unknown what
complications, if any, are associated with IGT. In discussing
biomarkers, the speaker noted that they had not discussed the question
of what biomarkers are pathogenic and what markers are not. In IGT,
there is a glucose abnormality that associates with cardiovascular
disease. The question is whether or not IGT is the cause of early
cardiovascular disease or just a marker for it. It was suggested this
was the type of question that an NIH study could address. To call IGT a
disease, it would have to be shown that in itself IGT causes morbidity,
not that it is just associated with another disease. Biomarkers have to
be identified as to whether they are a cause of a disease or whether
they are an association of the disease. Which raises the question about
obesity. Is obesity a disease? Or is it only associated with disease.

Dr. Shamoon responded that he had no doubt that obesity is a disease.

On the other hand, Dr. Eckel said he would call obesity a disorder, a
physiology of an expanded fat mass, the consequences of which are
diseases such as hypertension, dyslipidemia, glucose intolerance,
diabetes, obstructive sleep apnea, pulmonary hypertension, and so forth.
There is reasonably good evidence that in the early 20^th^ century,
through World War I and World War II, being fatter allowed for greater
survival when famine ensued. As a survival advantage, obesity has gone
astray today because people live so much longer.

Dr. Orloff remarked that the overall goal for all those
present---industry, academia, advocacy groups, and the government---was
to extend life and to improve health for type 1 and type 2 diabetes
patients. Based on the recurrent message heard at today's meeting that
tools currently available were not being used optimally, he asked those
present if they felt an NIH consensus conference on prevention would now
be appropriate to address the issues raised in this meeting. Dr. Orloff
commented that unconflicted, NIH consensus conferences had historically
been successful in moving fields forward at a practical level in
instructing physicians in how to manage their patients and use the tools
that they had available.

Dr. Saudek agreed that consensus was particularly needed regarding what
to do about the metabolic syndrome and about IGT. He added that it would
take a good deal of work to arrive at such a consensus.

Dr. Fradkin explained that, in general, consensus conferences are held
when the data is at a point to ensure a consensus can be reached. She
said she believed that many of the important questions raised in today's
meeting needed to be addressed and answered before there would be
sufficient clear data for a consensus conference on, for example,
longer-term transplants. The joint ADA-NIH group that looked at
interpreting the DPP essentially was a consensus conference that
assessed the current state of the data. There really has not been much
additional data beyond the DPP at this point that would justify holding
a consensus conference.

Dr. Taylor agreed that there are many questions left to be answered
about current and potential future therapies and suggested that there
would be some value in reaching consensus on what are the most important
questions to ask. This would help in developing a plan for obtaining
answers. Dr. Fradkin agreed that clarifying the questions and the steps
needed to answer them would be a good approach before trying to arrive
at consensus on therapies based on current answers.

Dr. Orloff and Dr. Fradkin thanked the speakers, panelists, organizers,
and participants for their contributions to an excellent and successful
meeting.

The meeting was adjourned at 12:40 p.m.