DEPARTMENT OF HEALTH AND HUMAN SERVICES
                 NATIONAL INSTITUTES OF HEALTH
           NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
                                
            NHLBI SPECIAL EMPHASIS PANEL (SEP) ON: 
   PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASE IN DIABETES
                           MELLITUS
                                
                                
                       MINUTES OF MEETING
                         Sept. 19, 1997
                                

PANEL MEMBERS PRESENT:

Drs. Robert Frye (chair), Lewis Kuller, Carlos Abraira, Steven
Haffner, Curt Furberg, Burton Sobel, Luther Clark, Barbara
Howard, George Sopko, Patrick O'Connor, Sanford Garfield

MEMBERS OF THE PUBLIC PRESENT:

Drs. Katherine Detre, Salim Yusef, Frederick Dunn, David
Billheimer

FEDERAL EMPLOYEES PRESENT:

Drs. Lawrence Friedman (Director, DECA), Peter Savage, Jeffrey
Cutler, Dean Follman, Denise Simons-Morton, Eva Obarzanek, Elaine
Stone, Lawton Cooper, David Gordon (from NHLBI), Richard Eastman,
Maureen Harris, Catherine Cowie (from NIDDK),

The meeting of the Special Emphasis Panel on Prevention and
Treatment of Cardiovascular Disease in Diabetes Mellitus was
convened on September 19, 1997 at 8:00 a.m. at the Rockledge II
Building, 6701 Rockledge Dr., Rockledge, MD.  In accordance with
Public Law 92-463 the meeting was open to the public.  Dr. Robert
Frye presided as Chair.

OPEN MEETING:

I. Call to Order

Drs. Savage and Sopko called the meeting to order by a brief
statement of the purpose of the meeting which was 1) to review
current knowledge on factors contributing to the excess of
cardiovascular disease associated with diabetes and 2) to
recommend future directions for NHLBI research on prevention of
cardiovascular complications of diabetes.  

II. Review of Confidentiality and Conflict of Interest Procedures

Dr. Savage reviewed the policies and procedures regarding
confidentiality and avoidance of conflict-of-interest situations. 
The panel members signed the requisite form.

III. Discussion of current knowledge, ongoing studies, and
research needs

This Special Emphasis Panel was convened to evaluate current
information on the risk of cardiovascular complications
associated with diabetes mellitus and to determine whether NHLBI
should initiate clinical trials in this area.  The group reviewed
the problem of cardiovascular disease (CVD) in diabetic patients
and the factors that may account for its variation across
populations.  They emphasized that much remains unknown about the
way diabetes increases the risk for CVD but that several new
therapeutic interventions have recently become clinically
practical. Major opportunities now exist to reduce the rates of
CVD in diabetic patients but the relative efficacy and cost of
these interventions is largely unknown.  Clinical trials are
needed to determine the best methods to reduce
diabetes-associated cardiovascular complications.  Since this
area has been neglected relative to the intensive intervention
studies onother major CVD risk factors, the NHLBI was urged to
develop a plan for trials in this area.  Two major areas were
identified as having high priority for new initiatives in the
near future 1) a clinical trial to assess the importance of
controlling glucose levels in diabetic patients without
clinically symptomatic CVD and 2) a clinical trial to compare
early surgical intervention with intensive medical management in
diabetic patients with symptomatic CVD.  Several recommendations
were made to optimize study designs which are outlined below.

BACKGROUND 

Most of the excess morbidity and mortality associated with
diabetes results from its chronic macrovascular and microvascular
complications.  Macrovascular complications are the leading cause
of morbidity and mortality in diabetic patients. Approximately
50-60 percent of diabetic patients die of cardiovascular
diseases, and this appears to be mainly due to an acceleration of
atherosclerosis.  Although rates of CVD vary in diabetic patients
around the world, they have a two to four-fold increased risk of
coronary heart disease compared to nondiabetic members of their
group and similar increases in rates of other vascular diseases. 
In general, the increase in risk of CVD is relatively greater in
diabetic women than men.  CVD rates among diabetic patients from
some U.S. minority groups appear higher than those seen in
non-Hispanic whites. 

HYPERGLYCEMIA, INSULIN, INSULIN RESISTANCE

The exact role of hyperglycemia in the pathogenesis of
macrovascular disease is controversial.  It has been more
difficult to show a relationship between glucose levels and
cardiovascular complications than to show this relationship with
microvascular complications.  The benefit of improved glucose
control on rates of microvascular complications has been
conclusively demonstrated in Type 1 (insulin dependent) diabetic
patients in the Diabetes Control and Complications Trial (DCCT).  

In limited studies undertaken to date, no significant benefit of
glucose control on macrovascular complications has been
demonstrated, raising questions about whether this is because of
the suboptimal glucose control in these studies, inadequate
differences between the control and intervention groups, the type
of hypoglycemic drugs used, or due to indirect effects of
hyperglycemia on the pathogenesis of macrovascular complications. 
In recent years, elevated levels of insulin and/or insulin
resistance have been implicated in the pathogenesis of
macrovascular disease.  This is potentially important since more
aggressive insulin therapy is needed to obtain ideal glycemic
control.  The recent availability of drugs that lower insulin
resistance and reduce insulin requirements make it possible to
test different approaches to controlling hyperglycemia and the
possible role of specific abnormalities in the development of
target-organ damage.  While it appears that the benefits of
glucose control on microvascular complications will be applicable
to Type 2 as well as Type 1 diabetic patients, it is less certain
that the impact of therapy on macrovascular complications can be
extrapolated between these two major types of diabetes.   
Planning for future studies will also have to take into account
improved treatments of other common CVD risk factors in diabetic
patients such as blood pressure and dyslipidemia which should
lower overall CVD event rates.  Moreover, there is no current
evidence that strict glucose control in Type 2 patients can be
achieved by oral agents alone over a prolonged period of time,
raising the problem that a significant percentage of patients
will require multiple drug therapy including exogenous insulin
over the course a standard clinical trial.  However, combination
therapy with new oral agents is more effective than single drug
therapy and may postpone the need for insulin. 

DYSLIPIDEMIA

Multiple recent studies have demonstrated significant benefits of
lipid lowering on  cardiovascular event rates and some have
included substantial numbers of diabetic patients.   While the
numbers are still limited, the beneficial impact of treating
elevated cholesterol appears at least of the same magnitude, if
not larger, for diabetics compared to nondiabetic patients. There
are several large ongoing studies sponsored by the pharmaceutical
industry evaluating the impact of aggressive lipid lowering on
major cardiovascular events which will provide additional data on
diabetics.  Given existing treatment guidelines and available
data, the panel expressed the belief that it would not be ethical
to conduct a trial comparing lipid lowering vs. placebo in
diabetic patients in the U.S.  However,  a trial comparing lipid
lowering to different targets may be useful since current advice
to lower lipids more aggressively in diabetic than in otherwise
comparable nondiabetic patients is based upon expert opinion
rather than solid data.  Treatment of the specific diabetic
dyslipidemia, elevated triglycerides and lowered HDL-
cholesterol, also needs to be evaluated but the drugs available
for this appear to be less effective or have more toxicity so
potential benefits are less certain.

HYPERTENSION/MICROALBUMINEMIA

Concomitant hypertension increases the risk of CVD in patients
with diabetes.  Risk of CHD increases remarkably once
microalbuminuria occurs.  In addition to indicating renal
disease, microalbuminuria may reflect susceptibility to vascular
damage.  There are two major unanswered questions about optimal
treatment of hypertension in diabetes.  The first is whether some
classes of antihypertensive drugs have greater benefit in
diabetics.  A number of antihypertensives were reviewed.  ACE
inhibitors delay development of microalbuminemia in Type 1
diabetes, however, there are no similar data for Type 2 diabetes. 
Some of the adverse effects ascribed to calcium channel
antagonists may be due to a higher frequency of adverse effects
among diabetics.  A recent study conducted by NIDDK in
hypertensive diabetic patients, comparing nisoldipine (a calcium
channel blocker) vs. lisinopril (an ACE inhibitor) was terminated
early due to poorer outcomes with nisoldipine.   Results from the
ALLHAT study should provide important data relevant to this
question since approximately 10,000 ALLHAT participants will have
diabetes.  The second question is whether goals for blood
pressure reduction should be lower in diabetic than in
nondiabetic patients.  Some study of this is currently sponsored
by NIDDK.  This issue is difficult to address since the magnitude
of blood pressure differences attainable within the normal range
without side effects is relatively small and a systematic study
would require a large sample size.

RACE AND GENDER 

The burden of micro- and macrovascular complications associated
with diabetes is greater in several nonwhite minority groups than
in the non-Hispanic white U.S. diabetic population. While there
is little doubt that rates are elevated, this seems to be more
related to the increased prevalence of diabetes and other CVD
risk factors in these groups than to differences in the effects
of diabetes itself. The contribution of differences in obesity
among groups to complications is unclear.  Although not
universally found, the relative increase in CVD associated with
diabetes appears to be greater in women then in men and
cardiovascular mortality is higher in women.  Risk factor
abnormalities are more frequent in women, including alteration in
hemostatic factors such as increased levels of fibrinogen. 
Hormonal replacement therapy appears to provide similar benefit
for diabetic and nondiabetic women.  There is little reason for
more work in this area until results of large, currently ongoing
studies are available.  If not already collected, however, the
Women's Health Initiative should consider measurement of fasting
glucose concentrations or some alternate measure of glucose
tolerance so that future analyses comparing diabetic and
nondiabetic subgroups will be possible.

HEMOSTASIS

Factors related to increased thrombosis and decreased
thrombolysis were reviewed.  Experimental data show increased
PAI-1 with elevated insulin and proinsulin levels.  In Type 2
diabetes, obesity, and other nondiabetic states associated with
insulin resistance, PAI-1 antigen and activity are increased. 
Similarly, in patients with CAD and diabetes increased levels of
PAI-1 and decreased levels of uPA were noted.  In both
experimental and human data, hyperglycemia alone does not appear
to increase PAI-1, but hyperinsulinemia, including elevated
proinsulin, correlated with elevated PAI-1.  These data suggest
derangement in fibrinolytic system is closely related to insulin
levels which may then contribute to atherosclerosis progression
and eventual clinical CVD events.  It was suggested that within
physiologic levels of insulin,  PAI-1 may not play a significant
role.  Increased fibrinogen is also associated with diabetes. 
However, it has been proposed that the levels of
hyperfibrinogenemia observed in diabetes may be marker for
inflammation rather than reflect thrombosis.  

THE ROLE OF REVASCULARIZATION 

The risk factors for a clinical CVD event and the most
appropriate preventive treatments are not necessarily the same
for all diabetic patients.  Recent clinical trial data suggest
surgical treatment of CHD needs to be modified in the diabetic
patient.  Nearly 1,000,000 coronary bypass surgeries and
angioplasties are performed on CHD patients each year in the
United States.  Many thousands of these revascularizations
involve diabetic patients with vascular disease.  The five-year
follow-up results of the NHLBI-funded Bypass Angioplasty
Revascularization Investigation (BARI) study comparing balloon
angioplasty vs. coronary bypass surgery were recently published.
An unexpected finding of the BARI was the significantly improved
five year survival of diabetic patients with multivessel coronary
disease treated with internal mammary-coronary artery bypass
grafts (CABG) compared to those treated with percutaneous
transluminal coronary angioplasty (PTCA).  These studies
highlight the need to learn more about the optimal treatments of
diabetic patients with advanced atherosclerosis, indicating an
area where benefits from clinical trials in nondiabetic patients
may not be directly applicable to a diabetic with similar acute
ischemia.  Although diabetics are known to have a higher
mortality compared to non-diabetic patients, these benefits
associated with coronary surgery were not previously known or
even anticipated.

The optimal management of symptomatic coronary artery disease in
diabetic patients who don't require urgent surgical intervention
represents an important and unresolved clinical question. 
Aggressive implementation of proven medical therapies may
decrease mortality and prevent or substantially delay myocardial
infarction.  Alternatively, given the exceptionally high risk of
this group, early invasive revascularization combined with
aggressive medical therapy may result in enhanced long-term
survival and fewer cardiac events than an initial strategy of
medical therapy alone.  Reducing hyperglycemia may have important
effects on vascular pathology including rates of restenosis. 
Evaluation of these approaches requires clinical trials to avoid
biases in patient selection commonly seen in clinical data.  In
addition to evaluating treatment benefits, such studies  may lead
to a better understanding of mechanisms of accelerated
atherosclerosis and restenosis associated with diabetes.  With
advances in technology, new adjunct procedures and drugs are
being developed and tested to accompany percutaneous
revascularization.  One of these examples is stent placement.
Stenting frequently improves short term outcomes of
revascularized vessels, including reducing restenosis.  However,
it is currently unknown whether these new approaches may also
improve long-term outcomes, including survival in CHD patients
with diabetes.

CLINICAL TRIALS

The problem of diabetes associated CVD is increasing as the U.S.
population ages, becomes more obese, and the percentage of
minority citizens increases since diabetes is more frequent in
all of these groups.  Diabetes is a major CVD risk factor in the
elderly ranking second behind elevated blood pressure in the
ongoing Cardiovascular Health Study.  Far less is known about the
cardiovascular benefits of reducing hyperglycemia and other
diabetes-associated metabolic alterations (such as
hyperinsulinemia, increased insulin resistance, etc.) than is
known about the impact of correcting other major CVD risk
factors.  The number of diabetics in reported clinical trials
focusing on cardiovascular interventions is limited and most, if
not all, ongoing studies seem to be targeting a particular
intervention without attempting to optimize control of other
known CVD risk factors.  In general, data indicate that diabetic
patients behave in a similar manner to nondiabetic patients in
response to treatment of dyslipidemia and hypertension.  Benefits
of aspirin also were similar but were greatest among those at
highest risk of a CVD event and aspirin use in primary prevention
must be weighed against the increased risk of stroke associated
with therapy.  Since CVD event rates are increased in diabetic
patients, the absolute benefit of a given intervention should be
greater in a diabetic group.  Because of the strong association
of Syndrome X (the insulin resistance syndrome) with Type 2
diabetes, the risk factors most important for cardiovascular
complications (and the benefits of their control) may differ
somewhat between insulin dependent (Type I) and non-insulin
dependent (Type II) diabetic patients. 

Ongoing studies supported by NIDDK and the Veterans
Administration (VA) were reviewed to see if they will answer some
of the questions related to macrovascular complications.  The
DCCT was not designed to assess prevention of macrovascular
disease but did show a marginally significant benefit of
intensive glucose control on a combined (soft and hard) total CVD
end point.  The original DCCT cohort is being followed in the
Epidemiology of Diabetes Intervention and Complications Study
(EDIC) to evaluate the benefit of a sustained period of intensive
glucose control on subsequent carotid atherosclerosis.  The major
relevant study is the ongoing Diabetes Prevention Study designed
to prevent Type 2 diabetes (DPT 2), a study of interventions to
prevent evolution of Type 2 diabetes from impaired glucose
tolerance.  This will generate data on CVD in the cohort but the
sample size is not sufficient to give solid data on ability to
prevent CVD, given the relatively low event rates in patients
with mild glucose abnormalities and recent onset diabetes.  This
study, however, will provide important information on the safety
and long term efficacy of Troglitazone, the newly available
thiazolidinedione that reduces levels of insulin and insulin
resistance. The Veterans Administration recently completed a
pilot study of intensive glucose control in a group of long-term
Type 2 diabetic patients.  While therapy successfully lowered
glucose without inducing substantial weight gain, there was no
short term reduction in CVD among the intensively treated group. 
In fact, CVD rates in this group exceeded those of the
conventional treatment group. The United Kingdom Prospective
Diabetes Study, a twelve year study of the benefits of
controlling glucose and blood pressure levels in recent onset
Type 2 diabetic patients, is scheduled to report its findings in
the fall of 1998 and these results should be considered in the
design of future trials.   

There was unanimous agreement that clinical trials are urgently
needed to answer the many questions about the optimal treatments
to prevent or postpone cardiovascular complications of diabetes. 
It was noted that, unlike for hypertension and
hypercholesterolemia, there is to date no clear evidence that any
of the drugs commonly used to treat hyperglycemia will reduce
rates of cardiovascular disease.  The recent FDA approval of a
new class of drugs (thiazolidinediones) that reduce insulin
resistance and hyperinsulinemia provides a new therapeutic
approach to improving glucose and several other
diabetes-associated metabolic abnormalities which will induce
metabolic
changes which previously could only be attained by substantial
and sustained weight loss.  

The panel discussed possible designs and priorities for clinical
trials, considering type and duration of diabetes as well as
associated complications, new therapies for control of glucose
and the most appropriate treatment of other established CVD risk
factors.  They also considered the impact of changing health care
economics and organization of health care delivery on attempts to
implement improved treatment of a complex disease such as
diabetes, with particular emphasis on prevention of its
macrovascular complications.   Trials should attempt to quantify
both the participant burden and the cost of any  interventions as
well as the clinical outcomes.  Overt diabetes differs from other
risk factor abnormalities since in addition to hyperglycemia, the
diabetic state is associated with adverse changes in several
other known CVD risk factors.  A strong argument was made that
studies to evaluate methods of delivery of care to diabetic
patients can go ahead concomit-antly with other studies to
evaluate the efficacy of a particular intervention since much
needs to be learned about how to optimally deliver treatments we
already expect to be beneficial.  Lessons learned in developing
control programs for other CVD risk factors should be applied to
the diabetes-CVD area so that clinical application of new
information will not be unnecessarily delayed.

Several issues related study design were discussed including
standardization of nomenclature and disease classification, use
of surrogate CVD endpoints, enhancement of CVD risk in the study
group by identification of subclinical disease, need for blinding
in glycemic intervention arms, the optimal subgroups of diabetic
patients for study, and the type of glycemic control.  Current
hypoglycemic drugs approved by FDA on basis of control of
glycemia may have different long term effects on morbidity or on
total or cardiovascular mortality. 

The panel agreed that two areas of investigation have the highest
priority and, since they deal with different questions in
different subgroups of the diabetic population, intervention
studies could proceed simultaneously:  

1. In the area of primary prevention, the primary goal should be
testing the safety and efficacy of strict glycemic control in
conjunction with aggressive conventional CVD risk factor
modification.  The target population should have a high risk of
incident events.  It was suggested that patients be selected with
evidence of subclinical vascular disease (diagnosed by low
ankle-arm index, wall thickening on carotid ultrasound, etc.) and
possibly microalbuminuria.  Discussion also centered on the issue
of the safety and efficacy of agents classified as "insulin
sensitizers" vs. " those classified as "increasing insulin
levels".  If it is possible to maintain similar major improvement
in glucose levels for sustained periods with different
pharmacologic approaches, testing the relative benefits would be
an important addition to data from any trials undertaken so far.  
Some members of the panel urged a study design that would enable
comparison of the relative benefits of different treatments
(treatment of glucose, blood pressure, lipids, possibly
coagulation, etc.) to reduce CVD risk in diabetic patients,
pointing out that this type of study is unlikely to be undertaken
by the pharmaceutical industry.  Given established guidelines,
this would involve evaluation of standard vs. more aggressive
treatment of established risk factors such as cholesterol and
blood pressure in addition to the glucose lowering intervention.

2. In the area of secondary prevention the goals would be
different.  Based on BARI data, early revascularization in
diabetics with symptomatic coronary artery disease may provide a
significant survival benefit since they may have different risk
related to specific treatment strategies compared to nondiabetic
patients with CAD.  Since recommendations from trials in
nondiabetic CVD patients may not be directly extrapolatable to
diabetic patients, additional studies are necessary to determine
the optimal time and method of coronary intervention in diabetic
patients with clinical CVD.  The value of aggressive medical
therapy, both in lieu of and after surgical intervention on
preventing CVD events needs to be determined.  One potential
design would be to test the benefits on total and cardiovascular
mortality of strict glycemic control, in addition to aggressive
risk factor modification, and early vs. delayed
revascularization.  Impact on major cardiovascular events would
be also studied. 

The meeting was adjourned at 3:45 p.m. on September 19, 1997. 

CERTIFICATION:

I certify the foregoing minutes are accurate and complete.

________________   ___________________    ___________________
Robert Frye, M.D.  Peter J. Savage, M.D.  George Sopko, M.D.
Chairman           Co-Executive Secretary Co-Executive Secretary 
Special Emphasis   Special Emphasis       Special Emphasis
Panel              Panel                  Panel