CSP #465FS - VA Diabetes Trial Long Term Follow-up Study
Conditions: Diabetes, Glycemic Control
Sponsor: VA Office of Research and Development

The VA Diabetes Trial 
Follow-up Study  
(VADT-FS) 
CSP #465-F 
VA Diabetes Trial Follow-up Study (VADT-FS) 
July 6, 2017 
Version 4.1 
Submitted by: 
  Peter Reaven, M.D. 
Nicholas Emanuele, M.D. 
Rodney Hayward, M.D. 
Gideon Bahn, M.S., Ph.D. 
PRIVILEGED AND CONFIDENTIAL – NOT TO BE DISSEMINATED BEYOND OFFICIAL 
USE 
CSP #465-F Protocol 4.1
July 6, 2017

Study Co-Chairperson 
Phoenix VAMC 
Study Biostatistician / Epidemiologist 
Hines CSPCC 
Study Project Manager 
Hines CSPCC 
Study Co-Chairperson 
Hines VAMC 
Study C -Ch 
son 
Ann Arbor e er of Excellence 
"VA Diabetes Trial Follow-up Studv"Protocol / Version 4.1 
Approval Confirmation 
This document has been reviewed for study content and found acceptable for distribution. Any 
questions or comments pertaining to this document should be addressed to: Tamara Paine, the 
Study Project Manager, at tamara.paine@vagov, 708-202-5785 for attention. 
PETER D. 
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Date: 201707.17 160006 .0500' 
This document has been summarized for my review by the CSPCC study team. I am aware it is 
being distributed at this time. I require a brief review of the following sections of the document 
by the person(s) indicated below before distribution: 
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Distributed on 
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CSP #465-F Protocol 4.1
July 6, 2017

CSP 465-F Protocol Changes 4.1 
 
 
 
CSP 
465-F 
Protocol 
4.0 
Changes  to  CSP 465-F Protocol 4.0 – 4.1 
 
From 4.0 
To 4.1 
Cover 
page 
 
Version 4.0 
November 
26, 2013 
Version 4.1 
July 6, 2017 
 
 
Page 34 
 
Added Early Analysis 
The major protocol amendment for the VADT-F was that a mid-point 
analysis would be conducted and reported, which was made and published 
as planned.  We now plan for an early analysis to take place shortly before 
data is fully completed with adjudicated outcomes and locked. There is to 
prepare to submit an important presentation in time to take place at the 
American Diabetes Association (ADA) 2018 which is planned to be made 
in conjunction with publication of the corresponding manuscript. Below 
we provide the full justification for this analysis. 
A major concern about an early analysis of clinical trials is that it can 
potentially bias investigators involved in the study protocol and thus 
integrity of reported data.  However, this concern does not apply to this 
proposed early VADT-F analysis. As active intervention ceased 10 years 
ago at the conclusion of the VADT, and there are no longer research 
personnel that have clinical contact with the study subjects, there is no 
way for investigators to influence patient care or outcomes. The outcomes 
are being collected through database search and surveys. In addition, the 
investigators will be still blinded to the individual treatment level data, 
which will become available for analyses before the final presentation. 
Thus, the potential for bias is not a threat to the VADT-F. 
On the other hand, there will be substantial benefit to the diabetes 
community as we present in a timely manner this important study about 
whether or not there is a delayed effect of the intensive treatment, and all 
presentations and papers will use fully completed and locked data. 
We therefore believe that the benefits of an early analysis provide 
substantial benefit to the diabetes community and do so at essentially no 
risk to the integrity of the VADT-F 
 
CSP #465-F Protocol 4.1
July 6, 2017

VA Diabetes Trial Follow-up Study (VADT-FS) 
CSP #465-F 
Table of Contents 
Protocol 4.1 
 
 
Preface .................................................................................................................................1 
Abstract ................................................................................................................................2 
Background and Significance ..............................................................................................3 
            Cardiovascular Outcomes ........................................................................................4 
            Microvascular Outcomes .........................................................................................7 
            Objectives ................................................................................................................9 
Research Design and Methods .............................................................................................9 
Study Subjects ..........................................................................................................9 
            VADT Protocol and Subject Follow-up ................................................................12 
            VADT-FS Recruitment ..........................................................................................13 
VADT-FS Retention and Completion of Follow-up .............................................15 
Data Collection Sources .....................................................................................................15 
Self Report .............................................................................................................16 
Assessment of VA electronic medical information system files ...........................16 
            Medicare data .........................................................................................................17 
Mortality records ....................................................................................................18 
Measuring Endpoints .........................................................................................................19 
Primary study endpoint ..........................................................................................21 
Major secondary endpoints ....................................................................................22 
Healthcare Utilization and Cost Data ................................................................................22 
Study Organization and Administration  ...........................................................................23 
Study Co-Chairs .....................................................................................................23 
The Cooperative Studies Program Coordinating Center .......................................23 
The Clinical Data Collection Center ......................................................................25 
Executive Committee .............................................................................................26 
The Data Monitoring Committee ...........................................................................26 
Endpoint Evaluation Committee ............................................................................26 
Analysis Plan .....................................................................................................................27 
Statistical Power.....................................................................................................27 
Early Analysis ........................................................................................................29 
Other Analysis Considerations ..............................................................................29 
Interaction (Subgroup) Effects ...............................................................................29 
Evaluation of Mechanisms of Action ....................................................................30 
Missing Data ..........................................................................................................30 
Study Significance .............................................................................................................31 
References ..........................................................................................................................32 
 
 
CSP #465-F Protocol 4.1
July 6, 2017

 
 
Appendices 
Appendix A: Published Manuscripts for VADT ...............................................................41 
Appendix B: VADT Endpoint Definitions ........................................................................47 
Appendix C: Human Subjects ............................................................................................51 
Appendix D: Survey Letter and Questionnaire ..................................................................62 
Appendix E: Opt-in Letter & Opt-out letter .................................................................... ..74 
CSP #465-F Protocol 4.1
July 6, 2017

 
 
The VA Diabetes Trial Follow-up Study (VADT-FS) 
CSP #465-F Protocol 4.1
July 6, 2017

 
PREFACE 
CSP #465, “Glycemic Control and Complications in Diabetes Mellitus Type 2,” was a 
randomized unblinded clinical trial comparing tight glycemic control to standard glycemic 
control and was conducted at 20 VA medical centers. One thousand seven hundred and 
ninety one patients were randomized over the 2 ½  year accrual periods and then followed 
for an additional 5 years. Follow-up averaged between 5 and 7 years depending upon when 
the patient was enrolled in the study. Patients were seen on average every three months in 
the VA Outpatient Clinics. Hypertension and hyperlipidemia were aggressively treated in 
patients in both treatment arms. Education regarding diet, exercise, smoking cessation 
and management of hyper and hypo-glycemic reactions was also provided. Data were 
collected throughout the study on the patients’ physical status, adverse and serious adverse 
events, concomitant medications, and study end points including mortality. The study 
was conducted under an FDA IND and consisted of broad use of all anti-diabetic 
treatments commercially available between 2000 and 2008 including oral medications 
and insulin. Study required medications and all study clinic visits were provided free of 
the usual VA co-pay. Active clinical follow-up of the sample ended on May 31, 2008. 
With the end of the clinical trial the patients were transitioned back to usual patient care 
services.  
It is important to clarify that with the completion of the active clinical trial and transitioning 
of patients to this observational trial, all responsibility for the care, treatment and 
oversight of the study patients became the responsibility of the patients’ Primary Care 
Physician. The VA Diabetes Trial Follow-up Study (VADT-FS)is not collecting adverse or 
serious adverse events, is not required to file FDA reports or actively treat or have any 
“hands-on” care responsibility for the study participants. 
The ongoing VADT-FS consists of centralized computer database searches and annual 
survey questionnaires related to quality of life and self-reported events pertinent to the 
CSP #465 study. 
The VADT-FS is very limited in scope compared to the clinical trial and is restricted to 
the activities stipulated in the proposal contained on the following pages. 
 
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VADT Follow-up Study (VADT-FS) 
Abstract:  
Diabetes affects nearly 1 in 10 Americans over the age of 45 and is associated with a 
doubling of mortality compared to age-adjusted controls, with about 75% of these deaths 
being due to cardiovascular (macrovascular) disease. With the high life-time risk of 
hyperglycemia-related diabetic retinopathy, nephropathy and neuropathy (the so called 
“microvascular” complications of diabetes), there is a consensus that striving for tight 
glycemic control should be a high priority for individuals with early onset diabetes (i.e., 
onset before age 40 with a life expectancy of more than 20 years). However, there is 
considerable controversy over the importance of routine tight glycemic control in those 
with later onset disease, since these patients have a relatively low life-time risk of major 
microvascular complications but a very high risk of cardiovascular events and mortality. 
Certainly, glycemic control, as measured by A1c, has been associated with an increased 
risk in macrovascular complications in many observational studies, however evidence from 
randomized controlled trials on the effectiveness of intensive glycemic control in reducing 
macrovascular complications in those with type 2 diabetes is lacking. Therefore, for the 
majority of people with diabetes in the US (over age 50 without known microvascular 
complications), it remains controversial as to how much effort, cost, patient burden and 
exposure to unknown long-term complications of newer medications is justifiable in the 
pursuit of tight glycemic control. 
Therefore, in 1999 the Veterans Administration Diabetes Trial (VADT) was funded, a 
randomized controlled trial designed to answer the question, “Does intensive glycemic 
management using the most effective hypoglycemic medications available result in 
decreased cardiovascular morbidity and mortality.” The VADT was highly successful 
in recruiting and retaining study subjects and in implementing its study protocol. In 
particular, the VADT maintained a median A1c in the intensive therapy arm that has 
averaged 1.6 points lower than that in the conventional treatment group. The clinical trial 
ended in May 2008. The main results of the VADT were presented at the American 
Diabetes Association Annual Scientific Meeting in June 2008 and published in the New 
England Journal of Medicine in January 2009. During the main trial, intensification of 
glycemic control did not reduce cardiovascular events implemented in people with excellent 
non-glycemic risk factor control. However, there is reason to believe that many of the 
macrovascular and microvascular complications potentially prevented by the 5-8 years of 
good glycemic control achieved in the VADT will occur years after completion of the 
VADT experimental protocol. This could result in the initial results of the VADT 
providing an incomplete picture of the true overall benefits of intensive glycemic control. In 
particular, the results of the United Kingdom Prospective Diabetes Study (UKPDS) follow-
up and EDIC study (the follow-up of the DCCT study population) make a compelling 
argument for continued follow-up of the VADT study population, in that they suggest that 
cumulative years of tight glycemic control may have a multiplicative effect on later CV risk 
(like compound interest). If this is true, then long-term follow-up would likely be necessary 
in order to fully appreciate the importance of intensive glycemic treatment. Therefore, the 
VADT study group proposed a longitudinal observational follow-up study of the VADT 
with the following objective: 1) to determine the long term effects of intensive glycemic 
control in type 2 diabetes on major cardiovascular complications (primary outcome), and 
2) to determine the long term effects of intensive glycemic control in type 2 diabetes on five 
secondary outcomes: a) cardiovascular mortality, b) major microvascular complications, 
c) health-related quality of life, d) total mortality, and e) major microvascular or 
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macrovascular (end-stage renal disease, amputation for either ischemic or non-ischemic 
gangrene, CV-related death, or nonfatal MI, stroke, or new CHF).This began in mid-2008 
with funding through 2012. In December 2011, additional funding through 2018 was 
requested and was received. 
 
Background and Significance 
Diabetes is a highly prevalent disease that has a profound impact on premature disability 
and mortality in the Western world (Camacho, 2000; CDC, 2005; Haffner, 1998; 
Ryerson, 2003). Diabetes affects nearly 1 in 10 Americans over the age of 45, is 
associated with a doubling of mortality compared to age-adjusted controls, and accounts 
for roughly 15% of all health care expenditures in the US (Druss, 2002; Hogan, 2003; 
Ryerson, 2003). Of the over 5 million veterans served by VHA, almost 20% have diabetes 
(VA Achievements in Diabetes Care, VA Fact Sheet, February 2006; Miller, 2004).  In 
FY1998, the total cost of VA inpatient and outpatient use by veterans with diabetes was 
over $1.6 billion and VA patients with diabetes received 30% of all VA pharmacy 
prescriptions, accounting for approximately 28% of all pharmacy dollars expended, in 
FY2000 (Kupersmith, 2007; Miller, 2004; Maciejewski, 2004; Weinstein , 2004). The 
prevalence of diabetes (both diagnosed and undiagnosed cases) has also reportedly 
increased by 4- to 8-fold over the past 25 years, and the current epidemic of obesity 
guarantees that this trend will continue (Honeycutt, 2003). Better understanding how to 
optimize care of diabetes is therefore one of the most important medical and public health 
priorities of today. 
Whether tight glycemic control reduces major cardiovascular complications is a critically 
important unanswered clinical question. There is a clear consensus that if tight glycemic 
control is shown to reduce major cardiovascular complications over a 15-year period, then 
health systems and clinicians should prioritize achieving tight glycemic control in almost 
all patients with diabetes since 75% of people with diabetes die from cardiovascular 
disease (Vijan, 1997; Honeycutt, 2003; Engelgau, 2004). Microvascular complications of 
diabetes (nephropathy, retinopathy, and neuropathy), which are already known to be 
reduced by improved glycemic control, can be devastating as well, and there is strong 
evidence in type 1 diabetes and new onset type 2 diabetes that intensive glycemic control 
reduces microvascular complications and may reduce long-term CV events. However, it 
has, as outlined in detail below, become quite clear that these results may not apply to 
today’s typical type 2 diabetes patient, who is often older and has multiple comorbidities.  
In particular, recent results from large randomized studies (including the Veterans Affairs 
Diabetes Trial ,VADT) in more advanced type 2 diabetes patients indicate that modest 
microvascular benefit and no overall  CV benefit results from improved glycemic control 
during the 3.5-5 year  time frame of the studies. Therefore, the critical question of 
whether tight glycemic control (HbA1c < 7.0) reduces clinically relevant microvascular 
disease and CV events in patients receiving current day standard excellent blood pressure 
and lipid management is only partially answered; and thus remains one of the most 
important clinical and public health questions of today.  
What is clear from several early studies of glycemic control is that some of the most 
interesting and important benefits resulting from improved glucose lowering on both 
macrovascular and, to a lesser extent, on microvascular outcomes have come long after 
the initial period of glycemic intervention, at a time when there was no longer any 
difference in glycemic separation between study groups. This concept of vascular 
metabolic memory or the “legacy effect” is of critical importance in light of less 
impressive results in the shorter-term that were recently reported in The Action to Control 
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Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: 
Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and the 
VADT.  Unfortunately, the important long-term findings from The Diabetes Control and 
Complications Trial (DCCT) and The United Kingdom Prospective Diabetes Trial 
(UKPDS) became apparent after the design and initiation of each of the more recent 
randomized trials - which were only 3.5-5.5 years in length.  Fortunately, plans for a 
longer and relatively inexpensive observational follow-up of the VADT were put in place 
and preliminary data from the first phase of this study demonstrate the feasibility of 
obtaining 15 year follow-up data and adequate statistical power to detect a clinical 
meaningful reduction in major cardiovascular complications. Continued follow-up of this 
VADT cohort is crucial since this would provide the only data regarding the long-term 
effect of a glycemic intervention which was aggressive yet relatively safe (as the 
ACCORD study increased mortality) and undertaken in people with advanced type 2 
diabetes with a heavy cardiovascular burden. 
 
Cardiovascular Outcomes 
 
What have we learned from controlled clinical trials? 
Most, but not all, observational studies have demonstrated that glycemic control is 
associated with reduced risk of both microvascular and CV complications (Selvin, 2004; 
Stratton, 2000; Adler, 1999; Haffner, 1998; Kirkman, 2006; Meigs, 1997; Reaven, 2005). 
As summarized below, evidence from randomized controlled trials on whether tight 
glycemic control results in a reduction of CV complications in those with diabetes is 
mixed at best. 
 
The Diabetes Control and Complications Trial (DCCT) 
In this landmark trial of young people (age 13-39 years old at entry) with type 1 diabetes, 
good glycemic control led to impressive microvascular benefit with reduced albuminuria, 
retinopathy progression and neuropathy (DCCT, 1993). Although there was a trend 
towards improved CV outcomes, the number of events was small and there was no 
significant CV benefit during the course of the trial. 
 
The United Kingdom Prospective Diabetes Trial (UKPDS) 
The UKPDS, conducted in newly diagnosed type 2 diabetes with an average age 53, 
found a small but not statistically significant decrease in cardiovascular outcomes over a 
9-10 year period in the overall treated vs. control group.  However, a smaller subset of 
more overweight subjects treated with metformin did demonstrate a significant reduction 
in CV events (UKPDS, 1998a, UKPDS, 1998b).  
 
The Veterans Affairs Diabetes Trial (VADT), Action to Control Cardiovascular Risk in 
Diabetes (ACCORD), and Action in Diabetes and Vascular Disease: Preterax and 
Diamicron Modified Release Controlled Evaluation (ADVANCE) 
Similar to the UKPDS, more recent trials in type 2 diabetes have also found no clear CV 
benefit over a 4-6 year time period. The VADT, ACCORD, and ADVANCE studies 
examined type 2 diabetes populations who were in general receiving excellent 
management of other CV risk factors.  Achieved glycemic control was also substantially 
better in the intensive groups of each of these studies than in the UKPDS, although only 
the VADT achieved superior glycemic separation between standard and intensive groups. 
While the UKPDS involved individuals with newly diagnosed diabetes, VADT patients 
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had an average duration of diabetes of 11.5 years at entry; ACCORD, 10 years; and 
ADVANCE, 8 years. All participants had either prevalent CV or substantial CV risk at 
entry. The VADT (median follow-up 5.6 years), ACCORD (median follow-up 3.4 years), 
and ADVANCE (median follow-up 5 years) showed no cardiovascular benefit of more 
intensive glycemic control (Duckworth, 2009; ACCORD Study Group, 2008; ADVANCE 
Collaborative Group, 2008). In fact, the glycemic arm of ACCORD was stopped 18 
months early because the intensive glycemic control arm, which achieved an A1c of 
6.4%, was associated with a 22% increase in all cause mortality and a 35% increase in 
cardiovascular mortality (ACCORD Study Group, 2008).  Publication of these 3 landmark 
studies so close in time also stimulated several meta-analyses of these and other major 
trials of glycemic control.  Overall, the meta-analyses found modest benefits of glycemic 
control on myocardial infarction, but not on stroke, cardiovascular mortality, or all-cause 
mortality (Turnbull, 2009; Ray, 2009; Montori, 2009). A fourth recently published meta-
analysis reached essentially the same conclusion (Boussageon, 2011). Probably because 
of the increased mortality risk of very aggressive control seen in ACCORD, one of the 
meta-analyses concluded that "…the possibility of harm with more-intensive glycaemic 
treatment cannot be ruled out." (Turnbull, 2009). Therefore, the risk/benefit ratio of 
intensive glycemic control in people with type 2 diabetes of longer duration and with 
greater prevalence of CV disease over the typical 3-5 year study time frame is far from 
clear. 
 
What have we learned from post-trial observation of patients who had been in controlled 
clinical trials? 
Despite these largely negative results during the interventional phase of the trials, long 
term observational follow-up studies have provided a substantially different, and more 
complex understanding of improved glycemic control and CV complications, at least in 
type 1 and earlier stages of type 2 diabetes. 
 
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions 
and Complications (DCCT/EDIC) 
The DCCT/EDIC study was an observational follow-up study of the DCCT, in which type 
1 diabetes participants continued to be carefully monitored for diabetes complications 
after completion of the active intervention trial phase was completed.  During this follow-
up phase, A1c levels in both treatment groups approached each other and were not 
significantly different throughout the follow-up period.  Thus, the extended follow-up was 
largely monitoring development of complications resulting from the prior reductions in 
glycemia. The main long-term study results were published when mean total follow-up 
(including the active trial phase) was ~17 years, and showed that the intensive glycemic 
group had a 42% reduction in CV events (Nathan, 2005). It is important to note that no 
statistically significant CV benefit was seen during the 6.5 years of the active DCCT.  If 
there had not been a long term post-trial observational period, the conclusion would have 
been that good glycemic control had no CV benefit. In fact, this was not the case, but 
instead, emergence of benefit was delayed. This long-term benefit due to previous 
intensive glycemic therapy is often referred to as “metabolic memory”.  
The United Kingdom Prospective Diabetes Trial (UKPDS) 
As in the follow-up of type 1 diabetes patients, data from a 10 year observational follow-
up of the type 2 diabetes UKPDS cohort also revealed delayed benefits of improved 
glycemic control (Holman, 2008). These benefits, as in the DCCT/EDIC occurred despite 
relatively similar A1c levels in both groups following completion of the active trial phase. 
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During the interventional part of the trial, the benefits of glycemic control were most 
evident for microvascular endpoints. However, during the 10 year observational follow-
up, other consequences of good glycemic control emerged, including reduced incidence of 
diabetes-related death, myocardial infarction and death from any cause. Importantly, 
reductions in hard outcomes required time to become apparent. The myocardial infarction 
and mortality benefits did not appear until about the 6th and 9th year of post-trial follow-
up, respectively. These important findings suggested that the phenomenon of "metabolic 
memory" is seen in type 2 as well as in type 1 diabetes.  Moreover, as was true for the 
DCCT/EDIC, if there had not been a long term post-trial observational period in the 
UPKDS, the conclusion would have been that good glycemic control had no clear CV 
benefit. In fact, this was not the case since there was a substantial benefit, but again, its 
emergence was delayed.  
 
Why is long term observational follow-up of the VADT cohort crucial?  
The lessons of the DCCT/EDIC and the UKPDS follow-up studies are that some of the 
most important findings come long after the initial intervention. The important CV 
benefits of glycemic control in type 1 diabetes in DCCT/EDIC were seen after about 17 
years of follow-up (including 12 years after the end of the intervention trial).  The 
important CV benefits of glycemic control in type 2 diabetes in the UKPDS Follow-up 
were seen after about 20 years of follow-up (including 10 years after the end of 
intervention). Observational periods need to be long, or incomplete, indeed erroneous, 
conclusions can be reached. The practical implications are enormous. The major killer of 
people with type 2 diabetes is CV disease. Intensive glycemic control is expensive, 
increases risk for hypoglycemia and requires substantially more effort on the part of the 
patient and the physician than non-glycemic pharmacologic prevention/treatment of CV 
disease. Therefore, extended follow-up of the VADT cohort is crucial since it will answer 
whether or not the very large human and financial investment in attaining meticulous 
glycemic control to an A1c < 7% actually reduces vascular outcomes over the long-term 
in patients with advanced type 2 diabetes and excellent non-glycemic risk factor control.  
By the end of the current funding of the VADT follow-up study in mid 2012, there will be 
only 4 years of follow-up. The experience of DCCT/EDIC and UKPDS Follow-up 
Studies has shown this is not long enough. Indeed, because of inherent delay in data 
capture in several national databases, our 4 year follow-up actually represents far less 
observation time for several major endpoints. For example, recent mortality data have an 
~ 1.5 year delay before they can be accessed in the National Death Index database. 
Therefore, we will have only approximately 2.5 years post-trial follow-up on this 
important endpoint if the VADT-FS is not extended, not nearly enough to ascertain a 
complete and accurate picture of glycemic intervention. 
 
 
 
 
The VADT Follow-up Study will provide unique information, complementary to other 
studies. 
It is essential to note that an extended follow-up of the VADT cohort is not redundant 
with other studies. Indeed, it will be complementary. The DCCT/EDIC studied young 
participants with type 1 diabetes with few comorbidities not older type 2 diabetes patients. 
There are also many differences between the UKPDS and the VADT. First, the UKPDS 
was conducted in newly diagnosed type 2 individuals with little CV disease; while the 
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VADT enrolled people with diabetes diagnosed on average 11.5 years previously and 
with prevalent CV disease or substantial CV risk factors. Second, the A1c separation 
between intensive and control groups (1.5%) was nearly twice as large in the VADT 
compared to the UKPDS (0.9%) on average. Moreover, the glycemic separation in the 
VADT was achieved within 6 months and maintained for the duration of the study. In the 
UKPDS, A1c levels in the “intensive” treatment arm rose steadily throughout the study 
and had reached an A1c of about 8-8.2 % by the time the study concluded. Third, in 
contrast to UKPDS, both treatment groups in VADT maintained mean LDL cholesterol, 
triglycerides, and blood pressure levels below the target levels of the American Diabetes 
Association. The UKPDS patients had less than optimal lipid control (LDL-C about 127 
mg %) and, arguably, less than optimal systolic blood pressure (~ 137 mmHg) (Holman, 
2008). This will allow the VADT Follow-up to answer a question which the UKPDS 
could not answer, namely whether or not, over a prolonged post-trial observation period 
intensive glycemic control produces benefits beyond that achieved by optimal treatment 
of other CV risk factors (Duckworth, 2006; Duckworth, 2009: Meyers, 2006; Riche, 
2007). Fourth, the UKPDS was predominantly a study of monotherapy, without the use of 
modern glycemic treatment regimens, such as combination therapy with glitizones.  
The ACCORD study group is also conducting a follow-up study, but this does not render 
the VADT-FS unnecessary. Indeed, the results from these two follow-up studies will 
undoubtedly be complementary and provide a more complete understanding of the long-
term effects of improved glycemic control. Although study participants were relatively 
similar in age, duration of diabetes and CV risk, there were substantial differences in 
study design and conduct.  Within the VADT, A1c separation was greater than in 
ACCORD (1.5% difference versus 1.1%) and occurred over different A1c ranges. In 
ACCORD, the standard group achieved a median A1c of 7.5%; the intensive group, 6.4%. 
In the VADT, the standard group achieved a median A1c of 8.4%; the intensive, 6.9%. 
The VADT trial was longer (5.6 years) than the glycemic arm of ACCORD (3.4 years). 
While there was excellent and essentially identical non-glycemic risk factor management 
in VADT, the ACCORD study, by design, was a multifaceted trial which also compared 
blood pressure target levels and lipid control strategies.  Finally, while the long term data 
from ACCORD will be extremely interesting and important, it is unlikely that the 
ACCORD protocol will ever be recommended for use in practice given its significant 
22% increase in all-cause mortality found in short-term follow-up. Thus, the VADT 
Follow-up Study is the only study in progress that can provide critical information on 
long-term CV effects (or lack of them) of an aggressive, but reasonably safe, glycemic 
intervention in those with advanced diabetes. 
 
Microvascular Outcomes 
 
Although the primary outcome assessed in this application has been, and will continue to 
be, a composite of cardiovascular outcomes, a secondary outcome includes microvascular 
disease, so it is appropriate to consider that as well. 
 
What have we learned from controlled clinical trials? 
Follow-up of the VADT cohort will also permit assessment of long term impact on 
glycemic control on microvascular endpoints, for which there is limited randomized 
controlled trial data. Diabetes is the leading cause of irreversible blindness, renal failure 
and amputation in adults in the US, and each of these microvascular complications are 
strongly associated with poor glycemic control (CDC, 2005).  Randomized controlled 
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July 6, 2017

trials in both type 1 and type 2 diabetes have produced grade A evidence that improved 
glycemic control reduces onset of early microvascular findings (such as new retinopathy 
and proteinuria) and progression from early to moderate disease (e.g., progression from 
background retinopathy to requiring retinal photocoagulation [laser therapy]) (DCCT 
Research Group, 1993; UKPDS Study Group, 1998a; Duckworth, 2009; ACCORD Eye 
Study Group, 2010). This is supported by findings from most, but not all, older, smaller 
trials from Norway, Denmark, Sweden, Japan, the Kroc Foundation and by the VA 
Cooperative Study in Diabetes Mellitus (VACSDM), the feasibility trial for the VADT 
(Kroc Collaborative Study Group, 1984; Dahl-Jorgensen, 1988; Feldt-Rasmussen, 1991; 
Reichard, 1993; Shichiri, 2000; Levin, 2000; Beulens, 2009). Although the UKPDS found 
a statistically significant reduction in the need for retinal photocoagulation,  no 
randomized clinical trial has reported any improvement in patient function (such as 
vision, pain or health-related quality of life), end-stage events (such as end-stage renal 
disease or amputations) or diabetes-related mortality over 8 months to10 years  (Kroc 
Collaborative Study Group, 1984; Dahl-Jorgensen, 1988; Feldt-Rasmussen, 1991; 
Reichard, 1993; DCCT Research Group, 1993; UKPDS Study Group, 1998a; Shichiri, 
2000; Levin, 2000; Duckworth, 2009; ACCORD Eye Study Group, 2010). Demonstrating 
improvements in these clinically relevant outcomes however is the most important 
measure of the value of improved glucose control. However, progression of microvascular 
complications to clinical endpoints is slow and as with CV disease, long-term follow-up is 
essential to firmly establishing a causal link. Unfortunately, as noted above, the VADT, 
ACCORD and ADVANCE study durations were only 3.5 to 5.6 years, much shorter than 
needed to observe differences in transition to end-stage complications.   
 
 
What have we learned from post-trial observation of patients who had been in 
controlled clinical trials? 
 
The extraordinary importance of long term follow-up to determine benefits of glucose 
lowering on microvascular complications is well illustrated by the DCCT/EDIC study. 
While there was an effect of blood glucose improvement on a surrogate renal outcome 
(proteinuria) in DCCT, there was no demonstrable benefit on a hard outcome like 
glomerular filtration. However, the DCCT/EDIC did demonstrate that those individuals 
who had had good control during the DCCT had kidney protection at 17 years of follow-
up, a dozen years after the interventional trial ended, evidenced by fewer patients with 
creatinine > 2 mg/dl (Nathan, 2005). It is also important to note that no hard renal 
endpoint benefit was noted in an earlier EDIC/DCCT publication, with a four year post-
trial observation period, so it takes substantial time for this to emerge (DCCT/EDIC 
Research Group, 2000).   
 
To our knowledge, there is very little other clinical trial data on long term impact of 
glycemic control on hard microvascular endpoints. The UKPDS reported a sustained 
benefit on a composite microvascular endpoint, but this was solely due to a reduction in 
retinal photocoagulation  (Holman, 2008). Although this outcome may establish the 
physiological effects of glycemic control, retinal photocoagulation is a low-risk outpatient 
procedure and most patients who undergo appropriately timed photocoagulation do not 
have diabetes-related short-term visual impairment. Furthermore, retinal photocoagulation 
was not a pre-specified outcome in the original UKPDS protocol. Finally, the VADT had 
much better blood pressure control than the UKPDS.   Since improved blood pressure 
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control substantially reduces renal and retinal diabetes complications, the impact of 
intensive glycemic control on even the intermediate outcome of photocoagulation may 
now be substantially less, especially in older patients like those in the VADT. In contrast, 
it could be greater since a greater proportion of VADT patients began the study with early 
diabetic retinopathy. 
 
This suggestion of delayed hard endpoint microvascular benefit in DCCT/EDIC and the 
lack of other clear clinical trial hard endpoint data in those with type 2 diabetes will make 
the VADT Follow-up even more valuable. 
 
Objectives 
CSP #465-F is an observational follow-up study of the surviving VADT cohort (the 
VADT-FS), which has two major objectives: 
 
1.  To determine the long term effects of intensive glycemic control in type 2 
diabetes on major cardiovascular complications (primary outcome), and  
 
2. To determine the long term effects of intensive glycemic control in type 2 diabetes 
on five secondary outcomes: a) cardiovascular mortality, b) major microvascular 
complications, c) health-related quality of life, d) total mortality, and e) major 
microvascular or macrovascular (end-stage renal disease, amputation for either 
ischemic or non-ischemic gangrene, CV-related death, or nonfatal MI, stroke, or 
new CHF).  
Research Design and Methods: 
Study Subjects. 
VADT Recruitment & Baseline Information: To be eligible for the VADT, subjects had to 
be over 40 years old, have type 2 diabetes and be non-responsive (A1c > 7.5%) to a 
maximum daily dose of one or more oral agents or on insulin. Any of the following 
conditions resulted in exclusion of the patient from enrollment in the VADT: 
● angina pectoris, Canadian Class I-II 
● congestive heart failure, Class III-IV 
● stroke, incapacitating or in last 6 months 
● AMI or invasive cardiovascular procedure within the past six months, 
● ongoing diabetic gangrene, 
● BMI > 40, 
● hemoglobinopathy that interferes with A1c monitoring, 
● serum creatinine > 1.6 mg/dL, 
● fasting C-peptide < 0.21 pmol/ml, 
● ALT > 3 times normal or serum bilirubin > 1.9 mg/dL, 
● malignancy or noncardiac life-threatening diseases making life expectancy < 5 years, 
● autonomic neuropathy, 
● symptomatic pancreatic insufficiency (endocrine or exocrine), 
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● recurrent seizures within the past year, 
● hypopituitarism, 
● pregnancy, lactation, or planning a pregnancy, 
● active psychosis or substance abuse, 
● lack of access to a person who can assist or be called in an emergency, 
● underlying conditions that in the site PI’s judgment may prevent adherence to 
protocol, 
● current participation in another clinical trial. 
Almost 18,000 patients were pre-screened using medical record review and those who 
appeared potentially eligible after pre-screening were contacted for detailed screening. 
1,791subjects were enrolled into the VADT over a 30-month period. The most common 
reasons for exclusion were A1c < 7.5% (34%), not on insulin or a maximum dose of an 
oral agent (16%), unwilling to participate (12%), renal insufficiency (8%), PI did not 
approve patient (5%, with the most common reasons given being patient lives too far 
away, has multiple comorbid conditions, or has history of frequent no-shows), and BMI> 
40 (5%). The baseline characteristics of the 1,792 subjects enrolled are shown below in 
Table 1. 
 
VADT-FS Main Cohort 
In brief, subjects have been recruited to receive periodic surveys and to have VA 
EMR data collected centrally, as well as allow reviewing their non-VA hospital 
records. Consented subjects are very similar to surviving VADT not-consented 
subjects on a host of baseline attributes, demonstrating the sample is highly 
representative.  
 
VADT-FS Mortality Analysis Cohort 
In addition to the VADT-FS Main Cohort, the Ann Arbor Center has received IRB 
approval to conduct long-term mortality analyses on all original VADT subjects 
except for the 152 subjects who withdrew consent during the VADT (N=1639, 
91.5% follow-up). The VA Ann Arbor IRB granted a “HIPAA waiver” in July 
2011 that permits determination of cause of death using National Death Index data 
using a special analytic protocol that protects patient anonymity. Investigators at 
the Ann Arbor VA HSR&D are very experienced in conducting such analyses. Per 
IRB protocol, these analyses will be conducted in a fully blinded fashion (ie, the 
data manager accessing the follow-up mortality information will merge this 
information to the VADT unique ID, but will not have access to the VADT dataset 
itself, and the investigators and data analyst will not have access to subject’s true 
identity or treatment arm. Below, we refer to this cohort as the “VADT-FS 
Mortality Analysis Cohort” to distinguish it from the Main Cohort. VA Ann Arbor 
HSR&D will send the data to Hines CSPCC in a secure way following VA 
regulations for the interim and final analyses.  
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Table 1. Baseline characteristics of VADT enrollees (N =1,791) 
Age (yrs) 
60.5 ± 8.7 
Duration of diabetes (yrs) 
11.5 ± 7.5 
Men 
1,736 (96.9%) 
Race/Ethnicity 
Non- Hispanic White 
1,112 (62.1%) 
Non- Hispanic Black 
299 (16.7%) 
Hispanic 
291 (16.2%) 
Other 
90 (5.0%) 
Currently employed 
735 (4 1%) 
College graduate 
367 (20%) 
Previous macrovascular 
event 
724 (40.4%) 
Current cigarette smoker 
257 (14%) 
Hypertension 
1293 (72%) 
Diabetic neuropathy 
761 (43%) 
BMI (kg/m2) 
31 ±4 
A1c(%) 
9.4±1.4% 
Systolic BP (mmHg) 
132 ± 17 
Diastolic BP (mmHg) 
76 ± 10 
Total cholesterol (mg/dL) 
183 ± 47 
LDL cholesterol (mg/dL) 
108 ± 32 
HDL cholesterol (mg/dL) 
36± 10 
Triglycerides (mg/dL) 
212 ± 275 
 
The intervention and control subjects were similar in major demographic characteristics, 
baseline metabolic control and in key CV risk factors, suggesting that randomization 
was successfully achieved. 
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VADT Protocol and Subject Follow-up: 
Detailed information on the VADT protocol can be found in the main manuscript 
published in January, 2009, in the New England Journal of Medicine (Abraria et al., 
2009), however, here we include some background and key aspects relevant to the 
VADT-FS. The VADT was designed to do the best job possible of isolating the effects of 
hyperglycemia in patients with type 2 diabetes. In order for the study to address different 
levels of glycemic control, and minimize potential medication specific effects, the 
protocol strove for both treatment groups to receive near-equal distribution of therapeutic 
classes (insulin segretagogues and sensitizers, exogenous insulin) with ultimately, the 
main difference between treatments arms expected to be related to the dose of insulin. In 
addition, the VADT protocol tried to achieve optimal management of all other CV risk 
factors in both intervention and control patients to answer the question, “What is the 
incremental benefit of intensive glycemic control once blood pressure, lipids and other 
CV treatments are optimized. 
The success of the VADT protocol in achieving the above goals has been impressive and 
is a tribute to the hard work and dedication of the VADT site investigators, and 
especially, the nurse coordinators. The VADT achieved and has maintained substantial 
A1c separation since year 1 1/2 of the trial (averaging a 1.5 point A1c median 
separation, with the A1c being 6.9in the intensive arm and 8.4% in the standard treatment 
arm. 
The goal of complete matching of the standard and intensive arm subjects with respect to 
the number of hypoglycemic medications has not been completely achieved. However, 
the two groups are much more similar in this regard than might be expected given the 
1arge A1c separation. In year 5 of follow-up, the average number of glycemic 
medications was 2.6 in the standard treatment arm and 3.4 in the intensive treatment arm. 
Most of this difference is due to a higher use in the intensive arm of glimepiride (Amaryl) 
(45% vs. 5 8%), rosiglitazone (Avandia)(54% vs. 66%), and precose (Acarbose)(2% vs. 
15%). In year five of the study, 75% of standard therapy patients were on insulin 
compared to 88% of the intensive therapy patients (Duckworth et al., 2009 ). 
Treatment of CV risk factors in the VADT has been superb in both treatment arms as per 
protocol. For example, in year 5 of follow-up, 95% of patients were on aspirin or some 
other anti-platelet/anti-coagulant, 84% were on a statin, and the mean blood pressure was 
126/70mmHg. Each of the above have been achieved almost identically in the standard 
and intensive therapy arms. With regard to lipid levels, in year five the VADT study 
population had a mean LDL cholesterol of 84mg/dL ±29 and a median of 77mg/dL, with 
almost 80% of the study population having levels < 1 00mg/dL. Intolerance of statin 
therapy was the main reason for not achieving an LDL < 100mg/dL(Duckworth et al., 
2009 . 
 
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VADT-FS Recruitment 
All active VADT study subjects will be approached for participation in the VADT-FS. 
To maximize retention it was imperative that consent for VADT-FS be initiated prior to 
May 2008, when the study protocol ended, subject contacts with the nurse coordinators 
ended and patients returned to routine primary care. Therefore, we planned to initiate the 
IRB approval process in Fall 2007 in anticipation of beginning the consent process in Spring 
2008. We planned to utilize the then current site coordinators to inform subjects of the 
purpose, procedures and requirements of the VADT-FS, and obtain informed consent. 
Some of the study sites were unable to complete recruitment by the conclusion of the 
main study protocol and their funding for the nurse coordinator have stopped. Due to little 
local study activity and/or regulatory issues at the local sites, five of the twenty sites were 
prematurely closed. For similar reasons, other sites are considering closing in the future. A 
sixth site was suspended (due to issues having nothing to do with the VADT or the 
VADT-FS). In order to prevent losing the consented patients at these sites and for the 
smooth continuation of the currently consented patients, several strategies were planned 
and have been undertaken. These are under the direction of the follow-up study’s new Co-
Chairmen at the Hines and Phoenix VAMCs and the two national coordinating centers, Ann 
Arbor VA HSR&D (AA HSR&D) Center of Excellence and The Hines VA Cooperative 
Studies Program Coordinating Center (Hines CSPCC) as follows.  
 
Currently, there are three groups of patients. Group #1 consists of those VADT patients 
who consented to participate in VADT-FS but who are at sites where the VADT-FS has 
been closed.  Group #2 consists of those VADT patients who consented to participate in 
VADT-FS and who are at sites where the VADT-FS is still open.  Group #3 consists of 
individuals who were in VADT, but never consented to the VADT-FS. The requested 
process for each group would be different. 
 
Group #1 
For this first group, those VADT patients who consented to participate in VADT-FS 
but who are at sites where the VADT-FS has been closed, the VADT-FS consent form 
is no longer active. We plan to take either of two approaches.  In one approach, we 
plan to contact these individuals regarding their local site study closure. We will invite 
them to continue participation, and have the informed consent process handled 
centrally by the national study staff (who will be located at Hines); Hines would also 
become the sole IRB for the VADT-FS.  
 
The process would be as follows: 
 
1.   National study staff at Hines will obtain participant contact information from the 
Ann Arbor HSR&D and the Hines CSPCC.   
2. National study staff will mail a cover letter addressing local site closure and the 
informed consent forms (including HIPAA) to all patients at closed sites whose 
initial consent forms are no longer valid. The cover letter would explain that 
the study was closed at their hospital, but that oversight would be transferred 
to Hines, and inviting them to continue participation. The complete consent 
form would have this change (i.e, transfer of oversight to Hines IRB) 
highlighted. 
3. Seven to fourteen days after the mailing, the National study staff will attempt to 
contact the individual by phone to see if he or she has any questions about the 
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study or forms. 
4. After approximately two weeks, those who have not yet responded will undergo a 
repeat mailing and follow-up phone contact by the National study staff. 
5. Those who do not respond after two rounds of contact will be considered 
passive refusals for re-entry into the study. 
A second approach would be to work with formerly local PIs at closed sites to re-open 
those sites and consent patients locally. Those patients would then be transferred to the 
supervision of the Hines IRB, as described under Group #2, below. 
 
Group #2 
For this second group, those VADT patients who consented to participate in VADT-
FS and who are at sites where the VADT-FS is still open, we plan to transfer oversight 
to the Hines IRB which would become the sole IRB for the VADT-FS.  
 
The process would be as follows: 
 
1. National study staff at Hines will obtain contact information from the Ann Arbor 
HSR&D and the Hines CSPCC.   
2. National staff will mail an explanatory and “opt-out” letter to all VADT-FS 
participants at open sites. The letter would explain that the study was continuing 
unchanged except that oversight would be transferred to Hines. It would give them 
an opportunity to opt-out of further participation, should they choose not to be 
“transferred”. 
3. If the subjects do not respond two weeks after the initial mailing, they will be mailed 
the letters again. 
4. After the second mailing and no response in two weeks, the subjects are considered 
enrolled under the oversight of the Hines IRB since they have had the opportunity to 
opt out and did not do so.  
5. Then local sites can be closed out with instructions from the Project Manager. 
 
 
 
Group #3 
For this third group, those VADT patients who had never previously consented to 
participate in VADT-FS and who are at sites where the VADT-FS is still open, we 
plan to recruit potential participants in a non-targeted fashion and subsequently 
transfer oversight to the Hines IRB (as with group #2) which would again become the 
sole IRB for these VADT-FS participants.  
 
1. Local staff would use non-targeted recruitment approaches similar to a newspaper 
or flyer advertisement that are consistent with Hines IRB policy. These flyers, ads 
or information sheets would include contact information for the VADT-FS study. 
2. Once consented, these subjects would fall into Group #2 category and would be 
handled in a similar fashion as that group. 
 
 
 
The local site investigators, their ACOS for R & D, and the Chairperson of the local IRB 
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will be informed of all these processes, and may contact the National Co-Chair’s Office 
with questions.  
 
Therefore, in the consent process we ask permission for conducting an annual survey and 
allowing the research team to follow their future health care and outcomes using a variety 
of data sources, including inspection of their VA and non-VA medical records, data from 
the Centers for Medicare and Medicaid Services (CMS), and VA and US death records (see 
Data Collection section below). We inform them that they will receive a small payment of a 
$10 gift card for completion of the questionnaire and that the questionnaire has been pilot 
tested to make sure that it usually takes no longer than 30 minutes to complete. Subjects 
are also informed that they can choose to complete the questionnaire by phone if they 
prefer. Each subject is asked to assign a surrogate authorized to report vital status or health 
events (and provide a release of information) if the study subject is unable to do so. Of 
course, subjects are also informed that participation in the VADT-FS is completely 
voluntary and that they can revoke their consent at any point in the future. 
We cannot be certain what will happen to the risk factor management of the VADT 
cohort once they return to routine VA primary care. If the previous experience of the 
DCCT-EDIC (Nathan, 2005) and the UKPDS Cohort hold true, then eventually both arms 
may converge toward a median A1c of about 7.8 – 8.0%. We suspect that the two study 
arms will have excellent and similar CV risk factor management during the observational 
follow-up period. Blood pressure and LDL levels are currently comparable in the two 
study arms, and based upon current VA-wide levels, we expect that blood pressure and 
LDL will remain generally well controlled during follow-up, at least compared to 
national averages.(Kerr, 2004; Asch, 2004; Kupersmith, 2007; Saydah, 2004) 
VADT-FS Retention and Completion of Follow-Up 
Consented VADT-FS study subjects will be followed until the end of the study unless 
they withdraw their consent. The VADT-FS will also utilize several techniques to 
maximize a high level of study subject retention. For example, subjects who do not 
respond to the 3 mailed survey contacts will be contacted by phone and if that is not 
successful we will then try to contact their designated surrogate. If a subject does not 
complete the survey in a given year, the following year we will once again attempt to 
contact them as outlined above, unless they have withdrawn their consent. In addition to 
obtaining contact information on the study subject and their surrogate at the time of 
recruitment, we will obtain contact information for someone not living with the study 
subject who the study subject feels is likely to know how to contact the study subject over 
the next 10 years. 
 
Data Collection Sources: 
In order to ensure the integrity of the data a new unique ID number has been assigned to all 
patients involved in the VADT-FS. The unique ID consists of a five-digit number 
randomly assigned and has no reference to the original study ID or study site. The Hines 
CSPCC retains the cross-link between the Long Term Follow-up ID and the CSP #465 
Study ID. 
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a) Self Report. All consenting subjects have been given a toll free number and a return 
prepaid envelope to use to notify the Clinical Data Collection Center in Ann Arbor when 
any of the following occurs: 1. self-reported health status, 2. occurrence of study end-points 
(see below), and 3. outpatient visits, hospitalizations and procedures, including whether this 
care was provided inside or outside of VHA (names of hospitals and permission for medical 
record release will be obtained if non-VA inpatient care or procedures were received in the 
prior year in those not Medicare eligible (age <65). The initial mailed survey instrument is 
accompanied by a $10 gift card, and we will follow the modified-Dillman protocol thereafter 
(Dillman, 2007). A thank-you/reminder letter will be sent within 2 weeks of the first 
mailing. This letter will serve to thank those who have responded and encourage non-
responders to submit their survey questionnaires. Individuals still not responding within 2 
weeks of the post-card mailing date will be sent a second survey packet. One month 
following the 2nd mailing, a final mailing packet will be sent to those individuals who 
have not responded to the earlier mailings. Address information will be updated 
continuously during the trial; the main source of new address information will be the U.S. 
post-office. The addresses will be stored and updated by Hines CSPCC or Ann Arbor HSR&D 
via an electronic database behind the VA firewall (SharePoint). Access to this database will 
be limited to study personnel at each site that have a need to know. At 3 months we will 
attempt to contact subjects by phone, and if after intermittent attempts over 4 weeks do not 
succeed in reaching the subject, they will be considered a non-responder for that contact 
period. 
 
Updates 
The survey response rate was 83.6% in 2009, 81.2% in 2010, and 82.7 in 2011. 
Other than informing the Ann Arbor site about events that require adjudication, 
VADT-FS investigators are blinded to survey results. However, preliminary survey 
results and other endpoint data are periodically compiled by the Hines statisticians 
and presented to the DMC. 
 
Assessment of VA electronic medical information systems files. We expect most VADT-FS 
patients will continue to get the majority of their care within VHA. In addition to VA’s current 
central inpatient, outpatient, pharmacy and lab data repositories, newer data sources such as the 
Corporate Data Warehouse and National Diabetes Cube are expected to serve as a source for other 
important clinical information such as blood pressure. 
We have obtained signed informed consent from most of the study subjects for access to their 
EMR during the informed consent process. We will continue to attempt to consent those who, 
for whatever reason, did not consent in the first place, we may have to re-consent those at sites 
where the VADT-FS has closed unless the site can be re-opened (see above). The Data 
Coordinating Center at Hines will be in charge of accessing information from the VA’s central 
data repositories every 6 months (such as the Medical SAS datasets at Austin, which 
contain inpatient and outpatient data, and the DSS lab and pharmacy National Data 
Extracts). The Data Collection Center in Ann Arbor will be in charge of obtaining medical 
record information on selected patients with potential primary endpoints for adjudication by the 
Endpoint Committee. Both Hines and Ann Arbor have extensive experience with these 
respective activities in their past work, and have approved procedures for high-level data 
security. The VA diabetes registry and VA-CDC TRIAD study (which were collected and 
administered by the proposed Clinical Data Collection Center in Ann Arbor) revealed a 
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substantial portion of VA patients get their eye care, emergency care (such as heart attacks and 
strokes) and some elective procedures outside of VHA, requiring us to not rely solely on VA 
information systems, which is why we plan to collect information on non-VA events and obtain 
non-VA medical records for those reporting hospitalization and possible non-fatal primary 
endpoints for those patients younger than 65 (CMS data will be used for those> 65). 
 
Updates 
Our survey results have found that 92% of VADT-FS patients report getting the 
majority of their care within VHA and out-of-VA use has been much less than 
anticipated, thereby allowing excellent capture of patient information from central 
VA sources. Previous estimates were based on results found in the typical veteran 
utilizing the VA, whereas, the VADT appears to have recruited a sample with less 
dual-use. In the first 3 years of the VADT-FS, of the 54 self-reported new study 
end-points requiring adjudication (MI, stroke, CHF or amputation by patient 
survey) only 15 have required obtaining outside hospital records for adjudication. 
As outlined in the original protocol above, obtaining outside records is still 
required for those under age 65 reporting an MI or stroke patients at non-VA 
facilities and for those reporting amputations at outside facilities regardless of age, 
and we have had 100% success rate in obtaining non-VA records to date.  
The Ann Arbor Center has IRB and VA CO permission to access the electronic 
medical record of VADT subjects at all study sites, so transfer of VA records to the 
Ann Arbor is unnecessary. This has greatly improved the efficiency and 
completeness of records available for review and adjudication. Although the 
process of obtaining records from non-VA facilities is very time consuming, the 
number of records that we need to obtain has been less than anticipated. In the first 
2 years of the VADT-FS only 15 of the 130 (11.5%) self-reported new study end-
points (MI, stroke, CHF or amputation by patient survey) have required obtaining 
outside hospital records.  This and utilizing remote electronic access to VA EMR 
records has allowed for some reductions in the budget, particularly important in a 
time of increasing budget constraints.  
c) Medicare data: Most subjects upon VADT completion were eligible for Medicare. By 
agreement between the VA and CMS, data on use of Medicare resources for medical services 
and records are available through the VIREC located at the Hines VA. VADT-FS 
investigators at the Clinical Data Collection Coordinating Center in Ann Arbor have 
previously worked with this database, which provides fairly comprehensive information 
on inpatient and outpatient utilization, diagnoses, procedures and outcomes for those 
veterans 65 years or older. Approval to access this information is included in the informed 
consent process. There was one caveat however − there was currently a hold on release 
of CMS information to VA investigators, due to a recent highly publicized data breech. It 
was a temporary situation, and that permission to access these data will be granted as it 
has been in our past studies. However, if access to CMS data on the subset of patients age 
65 or older is not possible in the future, we would return to Cooperative Studies to 
expand our budget to allow seeking outside records for all non-fatal possible primary 
endpoints reported occurring at non-VA facilities. 
 
Update 
Medicare data for VA patients was not available during the first 2.5 years of the 
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VADT-FS, but it is now available. The Ann Arbor Center recently obtained IRB 
permission to obtain these data. Ann Arbor investigators are in the process of 
obtaining the data for the VADT-FS subjects aged 65 or older dating back to the 
start of the original VADT. From this point forward, the Medicare data for 
subjects will be updated as soon as it becomes available and will be combined 
with the VADT-FS data, along with information from the VA SAS Medical 
Datasets, maintained by the Austin Information and Technology Center. Past 
research has demonstrated that the combined Medicare/VA dataset is very 
accurate for major outcomes (Petersen 1999; Kiyota 2004), and we will use these 
data to identify subjects inside and outside of VA who have heart attacks, strokes, 
amputations, CHF admissions and dialysis based on diagnosis (ICD-9 codes) and 
procedure codes (CPT codes). 70.1% of VADT-FS subjects will be aged 65 or 
older at the beginning of this renewal, June 2012. 
d) Mortality records. Mortality data will be obtained from the VA Vital Status files, 
which combine death dates from all sources currently available to VA researchers, 
including the Medical SAS Inpatient Datasets, the Veterans Benefits Administration’s 
(VBA) Beneficiary Identification and Resource Locator System (BIRLS), the Medicare 
Vital Status file, National Death Index (NDI) and the Social Security Administration (SSA) 
death file. Since the Vital Status file contains Medicare data, as noted above, it is now 
currently available for research purposes. However, if the Vital Status file is not available 
in a timely fashion we will obtain mortality information from other accessible VA data 
sources including BIRLS, the Medical SAS Inpatient Datasets and the SSA death file. 
BIRLS, which is a primary data source for death information, contains approximately 10.7 
million records and has an estimated 94.5% to 96.5% sensitivity (Fisher, 1995). A review of 
major US mortality databases found that the BIRLS-Death File had a high accuracy rate 
(Dominitz, 2001) and compares favorably with other national mortality databases. For 
classification of cause of death, hospital records and NDI will be obtained from 
individual hospitals and adjudicated by the Endpoint Committee (since cardiovascular 
death is a primary study end-point). 
Update 
In addition to Medicare data (see above), we are now obtaining data on fatal 
cardiovascular events from the NDI, which is maintained by the National Center 
for Health Statistics of the Centers for Disease Control and Prevention. The 
Serious Mental Illness Treatment Resource and Evaluation Center (SMITREC), a 
unit housed within Ann Arbor’s COE HSR&D, maintains NDI data on all VHA 
users nationwide. The Ann Arbor Coordinating Center has an existing agreement 
with SMITREC to acquire the NDI information for our sample without charge. At 
present, SMITREC has NDI data available up until December 2008 and we expect 
to obtain 2009 data soon. There is an 18-24 month delay in obtaining NDI data, but 
this will still allow us to have at least 13 years of follow-up of disease-specific 
mortality by the end of the VADT-FS. If obtaining NDI data from SMITREC 
becomes problematic in the future, the Ann Arbor site will obtain these data 
directly from the NDI or from the VA appointed NDI data steward. 
The lag for the VA Vital Status files is only about 6-12 months so this file will 
allow us to have 1 year additional follow-up for total mortality than we will have 
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for disease-specific mortality. Therefore total mortality will be obtained from the 
VA Vital Status files, which combine death dates from all sources currently 
available to VA researchers, including the Medical SAS Inpatient Datasets, the 
Veterans Benefits Administration’s (VBA) Beneficiary Identification and 
Resource Locator System (BIRLS), the Medicare Vital Status file, and the Social 
Security Administration (SSA) death file. A review of major US mortality 
databases found that these sources are quite accurate for mortality (Dominitz, 
2001). 
Measuring Endpoints: 
The following endpoints will always be adjudicated: 1) non-fatal cardiac-related 
admissions to non-VA hospitals in those which hospital discharge data are not available 
(those <65 years old who report such events on the survey), and 2) all amputations (to 
determine if the amputation was ischemic [a primary endpoint], non-ischemic gangrene 
[a secondary endpoint] or traumatic [neither a primary nor secondary endpoint]). Death 
and hospital discharge records will be relied upon for other endpoints at VA facilities 
(using central VA data) and CMS data will be used to capture events at non-VA facilities for 
over 65. Past experience has shown that discharge diagnosis for MI and stroke are highly 
accurate that the patient has truly had these events, and therefore such designations are 
generally relied upon in observational studies. This of course is not done in experimental 
studies in which investigators in the field may bias endpoint determination, a concern that 
does not exist in this observational follow-up study with central data collection. 
 
When endpoint assessment and adjudication is needed, this will be conducted by the 
Endpoints Committee using an approach almost identical to the process used in the 
VADT study protocol. (Goldman, 2006) The Endpoints Committee will be comprised 
of a four person team to include two cardiologists, a neurologist, and a vascular 
surgeon, each of whom will be masked to subject’s previous treatment assignment in 
VADT. There will be no changes from the VADT protocol in the process for adjudicating 
primary endpoints, but some “softer” endpoints will be dropped from the primary composite 
outcome (see below). As per the current end-point evaluation process, all reported 
hospitalizations, deaths or new symptoms or diagnoses that are even remotely suggestive of a 
primary endpoint, will have summary clinical information prepared for review by the 
Endpoint Committee. These clinical summaries of potential study endpoints will be 
prepared by the staff at the Ann Arbor Clinical Data Collection Site, under the direction of 
Rod Hayward, MD and Sarah Krein, PhD, RN. All Ann Arbor personnel and the Endpoints 
Committee will be blinded as to the subjects’ previous randomized treatment status. Data 
sources for identification of potential end-points can be detected by patient self-report, by VA 
or CMS electronic information system data, or through death indices. The clinical summary 
information will be reviewed by the Endpoints Committee, who can render a decision or 
request additional information. 
Endpoints that will be collected include: 
(1) Mortality: categorized as, a) deaths secondary to cardiovascular disease including 
sudden death not otherwise explained, b) deaths secondary to neoplasm, c) deaths 
secondary to other causes, d) undetermined. 
(2) Major cardiac events: categorized as, a) acute myocardial infarction resulting in 
hospitalization, b) stroke, c) new onset congestive heart failure, d) other. 
CSP #465-F Protocol 4.1
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July 6, 2017

(3) Other cardiac event: categorized as, a) cardiac surgery, b) cardiac angioplasty, c) 
other. 
(4) Peripheral vascular disease: categorized as, a) surgical amputation for ischemic 
diabetic gangrene, b) arteriovascular events requiring bypass or angioplasty. 
(5) Renal Insufficiency: categorized as, a) estimated GFR* 16 to 30 w/o dialysis (stage 4 
chronic kidney disease), b) End-stage renal disease (ESRD) defined as GFR<15, 
dialysis or kidney transplantation. 
(6) Severe Visual Impairment: defined as poor or worse visual function on the general 
visual function question on the National Eye Institute Visual Function 
Questionnaire.(Mangione, 2001; Naeim, 2006; Raphael, 2006) 
(7) Other major procedures/diagnoses: categorized as, a) photocoagulation or 
vitrectomy, b) amputation. 
(8) Self-reported health status: diabetes-related quality of life, using an instrument 
adapted for type 2 DM patients from the DCCT (Duckworth, 1998; Saudek 1996). This 
survey tool has been used since the inception of the VADT and will be continued in the 
annual survey. 
 
 
* GFR (mL/min/1.73 m2) = 175 × (Cr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American)
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July 6, 2017

As mentioned previously, the composite endpoint of the VADT-FS is somewhat more 
restrictive than that for the VADT.  However, the protocol for determining all components 
of the VADT-FS’s composite endpoint will be identical to that used during the VADT 
(outlined in Appendix B), with two exceptions. Due to the absence of routine study 
examinations in the VADT-FS, we do not have standard collection of periodic 
electrocardiograms, visual acuity, or retinal examinations after May 2008, the end of the 
VADT. By VADT protocol, new ECG findings consistent with a myocardial infarction 
(such as new q-waves) could have resulted in a determination of the subject reaching the 
AMI endpoint even in the absence of symptoms, hospitalization or a clinical diagnosis. 
However, in the absence of standard collection of ECG’s from study subjects, we feel that 
to use ECG’s ordered for clinical indications as part of the primary composite endpoint could 
introduce substantial ascertainment bias (only those having ECG’s ordered by their 
providers can meet the primary endpoint through this criterion). In addition, although this 
endpoint has been shown to be diagnostically valid (high specificity for the subject having 
truly had a sub-clinical AMI), the clinical implications of these subclinical events are less 
clear. For example, the economic costs and patient morbidity are minimal to none in the 
short-term and the long-term morbidity and mortality risk implications of these 
subclinical infarctions have not been well studied. Therefore, since the VADT-FS proposes 
dropping “softer” endpoints from the primary composite outcome (see below), 
dropping subclinical heart attacks could be justified on those grounds alone. For the 
above reasons, only acute myocardial infarctions that result in hospitalizations will be 
considered as part of the primary composite endpoint for the VADT-FS.  
Although eye disease is not a component of the VADT-FS’s primary outcome, it is a very 
important component of a secondary outcome (major microvascular events). As above, 
the discontinuation of standard routine physical examinations makes continuation of 
visual acuity and retinopathy stage determinations problematic. Fortunately, there is now 
available a patient self-report visual function tool that has been developed with NIH 
support.(Mangione, 2001; Naeim, 2006; Raphael, 2006) This National Eye Institute 
Visual Function Questionnaire includes a validated single question for general visual 
function, and those reporting poor or worse function on this item have been validated to 
have substantial functional impairment impacting their quality of life (Mangione, 2001 
and personal communication with Dr. Carol Mangione in January 2007). Although 
caution is always advised when including a new measure during the course of a 
longitudinal study, we feel that the adoption of this validated item measuring marked 
visual impairment is preferable to dropping measures of visual function altogether. 
Patients with reported visual problems will be informed that they can complete their 
surveys either using the assistance of their designated surrogate or by telephone, 
whichever they prefer. 
Primary study end-point: 
Major CV events (non-fatal MI resulting in hospitalization, non-fatal stroke, new CHF, 
amputation for ischemic diabetic gangrene, or CV-related death). 
The proposed primary end-point of the VADT-FS is slightly more restrictive than the 
primary end-point of the VADT [excluding some CV procedures and subclinical AMI’s 
based upon ECG changes alone] because the increased statistical power of the VADT-FS 
will allow greater focus on major clinical outcomes and avoid outcomes that are more 
difficult to discern (e.g., worsening of symptoms) or are more discretionary (e.g., cardiac 
CSP #465-F Protocol 4.1
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July 6, 2017

procedures). 
Major secondary end-points: 
1. CV mortality 
2. Major microvascular complications (end-stage renal disease, or amputation for 
non-traumatic, non-ischemic diabetic gangrene). 
3. Health-related quality of life (as measured by the modified DCCT tool on a 0-100 
point scale) 
4. Total mortality 
 
Update 
We have revised the composition of our adjudication team, which now includes 2 
hospitalist physicians and a cardiologist. This change was made because fewer 
neurological and cardiac outcomes are being adjudicated in the VADT-F than in 
the original VADT, making hospitalists an excellent choice for the adjudication 
committee. 
 
We propose adding a fifth secondary end-point: Major microvascular or 
macrovascular complication (end-stage renal disease, amputation for either 
ischemic or non-ischemic gangrene, CV-related death, or nonfatal MI, stroke, or 
new CHF).” This secondary endpoint was added for two reasons.  First, this is a 
composite of all major micro- and macro-vascular endpoints and therefore has 
better statistical power and great clinical importance. Second, this also helps 
when making direct comparisons with other trials. The addition of this outcome 
was recommended by the Executive Committee, who is blinded to all outcome 
data in the VADT-FS and therefore this recommendation was made without any 
knowledge of results to date. (Note: New CHF will be determined by a subject 
having either: 1. A hospital stay with a primary discharge diagnosis of CHF, or 2. 
chart review finding an ejection fraction on echocardiogram estimated as being 
below 40%.) 
Healthcare Utilization & Cost Data 
Initial collection of recent data on healthcare utilization and costs incurs a fairly modest 
cost, but such data collection can be much more expensive when done retrospectively. 
Therefore, we will obtain permission to collect this data, but no initial funds are being 
requested for data cleaning and analysis. (Barnett, 2003; Wagner, 2003; Phibbs, 2003) 
Funds for analysis of data on total direct healthcare costs will be requested in a separate 
proposal, and funds for formal cost-effectiveness analysis will only be requested if the 
intervention is eventually shown to produce statistically significant benefit. This is 
similar to incurring the small costs of storing extra sera to be analyzed as indicated. We 
estimate that the cost to obtain and store this data at the same time that we obtain 
information on potential outcomes to be < $10,000 a year. 
 
Update 
 We propose stopping the collection of full cost data, in part to trim the budget 
during a time of increased budgetary constraints, but also because we feel that we 
now have adequate data for cost accounting. If future cost analyses are needed, the 
costs associated with study events to date (i.e. amputations, renal failure, visual 
CSP #465-F Protocol 4.1
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July 6, 2017

impairment, MI, etc) can be used to estimate the costs of subsequent events. 
However, in addition to the major complications and procedures listed above in 
the Endpoints Section, we will also continue to collect information on the number 
of outpatient visits, hospital and ICU days, and total pharmacy costs, since these 
are easily collected centrally and account for the majority of medical care costs 
associated with diabetes care and complications. 
Study Organization and Administration: 
Study Co-Chairs  
Central Office had approved a change in co –Chairmanship from Drs. Abraira and 
Duckworth who will continue to serve as the co-Chairs Emeritus of the study to Drs. Reaven 
and Emanuele. The co-Chairs will have primary responsibility for oversight of the study, 
in close collaboration with the Executive Committee, the Cooperative Studies Program 
Coordinating Center at Hines and the Clinical Data Collection Center in Ann Arbor. They 
will also serve as the Co-Chairs of the Executive Committee. 
 
The Cooperative Studies Program Coordinating Center  
The Hines Cooperative Studies Program Coordinating Center (CSPCC) will continue to 
serve as the Data Coordinating Center for the study. The Hines CSPCC will coordinate 
all administrative activities for the study. The Hines CSPCC will have principal 
responsibility for all analyses. They will also prepare the endpoint analyses needed for 
interim reports and will be responsible for archiving and documentation of all study data at 
completion of the study. 
The study subjects will be contacted annually, with the initial contact scheduled that 
began in June 2009 so as to establish a baseline for the quality of life data. Responders data 
will be received by the Ann Arbor who will send the data to Hines CSPCC, at the Ann 
Arbor the surveys will undergo an initial visual edit and then forwarded for data entry and 
verification before being added to the Master Study Data Base. Response information will be 
provided to the Ann Arbor VAMC to allow for repeat mailings and reminders to be sent to 
non-responders. The anticipated data flow is presented in Figure 1. 
Although all data will eventually reside at the Hines CSPCC, personnel at the Ann Arbor 
VAMC will be responsible for updating the patient’s contact information so as to 
facilitate the annual survey mailings. The Hines CSPCC will forward any updates in 
contact information that they receive to Ann Arbor for incorporation in the Contact Data 
Base. Ann Arbor VAMC will periodically (at least annually) provide the Hines CSPCC 
with a copy of the most recent Contact Data Base. At Hines CSPCC the Contact Data 
Base will be stored in a computer directory separate from the study data, the file will be 
encrypted and password protected. 
Computer programs developed by the Ann Arbor will evaluate the health survey 
responses received to determine if a new end point has been reported or is suspected. 
Ann Arbor VAMC will be provided information on any endpoints that need further 
investigation, i.e. collection of non-VA medical record information and adjudication, 
blinded to the treatment. 
CSP #465-F Protocol 4.1
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July 6, 2017

Figure 1. Data Flow 
Contact information bearing new unique ID 
number provided to Ann Arbor 
 
Cover letter and questionnaire mailed to sample by 
Ann Arbor 
Responses received by Ann Arbor COE, then 
forwarded to Hines CSPCC to undergo a 
visual edit, data entry and blind verification are 
performed and a computer text file created. 
 
The database programmer reads the computer text 
file and merges the data into the LTF Master File 
(ASCII Flat File). SAS reports are generated 
providing the ID numbers of responders and 
identifying endpoints needing investigation and the 
contact information for obtaining non-VA Health 
Care clinical records. 
 
The reports are provided to Ann Arbor as needed 
basis in order for them to update their mailing sample 
and 
investigate endpoints and coordinate 
Endpoint Review. 
Study form reporting results of Endpoint Review 
received at Hines CSPCC, visual edit and data entry 
performed prior to being merged into LTF Master 
File. 
 
Beginning in December 2008 and annually thereafter, Hines CSPCC will perform 
searches of centralized databases to identify any new endpoints including deaths that 
may have occurred, potentially, reducing the number of mailings that need to be 
performed by Ann Arbor. 
 
Endpoint 
Review 
Performed 
CSP #465-F Protocol 4.1
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July 6, 2017

The adjudication form for each event investigated will be forwarded to the Hines CSPCC 
for data entry and inclusion in the Study Master File. 
The Clinical Data Collection Center  
The Ann Arbor HSR&D Center of Excellence (COE) will have principal responsibility for 
centralized data collection of medical record information necessary for adjudicating 
endpoints (data not readily available from national data sources) and providing this data 
to the Data Coordinating Center at Hines for integration with the comprehensive study 
database. The Clinical Data Collection Center will also have principal responsibility for 
informing the Hines CSPCC of updated contact information on study subjects and 
answering patient questions related to the study. Further, this site will continue to collect 
resource utilization and cost information, as it has since the beginning of the VADT. 
Finally, they will be in charge of obtaining and preparing clinical summaries for endpoint 
adjudication by the Endpoint Committee, completing the final adjudication form and 
forwarding it to Hines CSPCC for inclusion in the Master File. 
Update 
Ann Arbor Coordinating Center: During the course of data collection for the 
VADT-FS thus far, it has become clear that there are clear advantages to having 
the VA Ann Arbor HSR&D Center of Excellence take over all central data 
collection activities. The Ann Arbor Center was in charge of many of these 
activities from the outset of the VADT-FS, so this is just a consolidation of data 
collection activities. The Ann Arbor Center has extensive experience and ongoing 
studies that utilize all of the datasets being used for central data collection in the 
VADT-FS. In addition to improved economies of scale, consolidating all these 
activities at the Ann Arbor Center will decrease the chances of confusion or 
miscommunication that can occur when responsibilities are divided across 
Centers. The Ann Arbor HSR&D Center will access the information from VA’s 
central data repositories every 6 months (such as the Medical SAS datasets at 
Austin, which contain inpatient and outpatient data, the DSS lab, the Pharmacy 
Benefits National Data Extracts, and Medicare files) and review medical record 
information on selected patients with potential primary endpoints for adjudication 
by the Endpoint Committee (see below). They will also continue to conduct the 
patient survey. The Ann Arbor Center will then deliver these data to the Hines 
Cooperative Studies Center for data analysis, along with full documentation of 
data collection details. Dr. Hayward will lead this effort and be directly 
responsible for oversight and coordination of these data collection activities. All 
investigators and staff in Ann Arbor are working with fully blinded data except for 
the data manager, who needs access to unique patient identifiers to allow her to 
obtain new follow-up data from central databases. Jennifer Davis is an 
experienced and expert data manager, but she has no access to other VADT or 
VADT-FS data, and has no other role in the VADT-FS other than the initial data 
pull and is blinded to treatment arm. 
Hines VA Coordinating Center: The Hines Cooperative Studies Center will 
continue to be in charge of all statistical analyses, including verification that all 
primary analyses conducted are fully prespecified. All analyses must be initially 
approved by the Hines statistician and final analyses and output verified by Hines 
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statistician(s). 
Executive Committee  
The Executive Committee will be the major decision-making body with primary 
responsibility for study management. The committee will direct operational aspects of 
the study, decide on all proposed changes in the protocol, and decide on all uses of 
study data. In the latter role, the committee will make all decisions regarding publication 
policies and will review all manuscripts and abstracts from the study and approve these for 
submission. Initially, the Executive Committee will have monthly conference calls, with 
the frequency of ongoing conference calls to be decided by the Executive Committee 
members. 
 
Data Monitoring Committee: 
Since the VADT-FS is an observational study and includes no research related clinical 
interventions, the main task of the Data Monitoring Committee will be to assure data 
quality, ongoing blinding of the study results, adherence to the pre-specified analysis plan, 
overall study progress and whether assumptions regarding statistical power are met. In 
addition to overseeing the integrity of scientific quality of data, this committee will 
examine unblinded analyses of primary and secondary endpoints every year. Since the 
intervention will no longer be in effect there will be no interim monitoring rule. The 
study biostatistician will present the Committee with interim reports and unblinded 
outcome data annually. The study Chairs and other Executive Committee members will 
not be privy to these interim reports. The previous CSP #465 Data Monitoring 
Committee was asked to participate and continues to serve as the DMC for the follow-up 
study. 
Endpoint Evaluation Committee  
The composition and procedures of this Committee were outlined above under 
Measuring Endpoints. 
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Analysis Plan. 
Statistical power 
We considered a 20% reduction in primary events to be a reasonable goal of intensive 
glycemic control over the anticipated 15-year study time period. This effect size was 
chosen by taking into consideration both the probability of observing an effect of that 
size given the level of achieved A1c separation, and the perceived value to the patient of 
this level of benefit relative to the risk and burden of intensive glycemic control. In 
addition, a 20% reduction is consistent with the lower limits of the 95% confidence 
intervals of the level of association between A1c and cardiovascular events reported in 
observational analyses (Nathan, 2005; Selvin, 2004). 
Given the current rate of overall events observed in the VADT, Table 2. below shows the 
expected statistical power that the VADT-FS will have for its primary and secondary 
outcome measures. As a continuous measure, statistical power for health related quality 
of life will be even better. 
Table 2. Power Calculations for VADT-FS* 
Overall Study 
Event Rate 
At 6 year 
Follow-up 
(end of VADT) 
At 10 year 
Follow-up† 
At 15 year 
Follow-up† 
(events per 1000 
person-years) 
Statistical Power to detect a Hazards Ratio of 0.8* 
CV events 
(Primary Outcome)‡ 
51.9 
0.93 
0.98 
0.99 
CV Mortality 
5.5 
0.00 
0.08 
0.31 
Micro-vascular 
events§ 
31.4 
0.00 
0.35 
0.71 
Total Mortality 
13.7 
0.00 
0.14 
0.43 
* All power calculations are for 2-tailed testing and assume α=0.05. 
† Estimates assume 85% retention of study subjects from the VADT and attrition due to mortality. 
‡ Major CV events include: non-fatal heart attack, non-fatal stroke, new CHF, amputation for ischemic diabetic gangrene, or CV 
death). 
§ Microvascular events include: end-stage renal disease, irreversible severe visual impairment [i.e., excludes visual acuity problems 
correctable by cataract surgery], or amputation for ischemic diabetic gangrene). 
 
Update  
 
Given the achieved sample size of the VADT-FS Main Cohort (N= 1031 as of July 
31, 2011), the updated power at 15-year follow-up is now 86.3%, which is still 
excellent. Based on additional information, the power for detecting effects for CV 
and total mortality are better than what we previously thought but are still under 
30%.  Although power for mortality is still poor, these results will be useful for 
inclusion in future meta-analyses. 
Objective #1: To determine the long term effects of intensive glycemic control in type 2 
diabetes on major cardiovascular complications (primary outcome). 
The primary outcome measure is the time to the first of any of the following events: 
nonfatal heart attack, nonfatal stroke, new congestive heart failure, amputation for 
ischemic gangrene, or cardiovascular death. The assessment of endpoints comparing the 
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original study glycemic treatment arms will be analyzed as per original intent-to treat 
using methods identical to the current VADT study. Life table methods and the log-rank 
test will be used to compare complication-free survival between the two treatment 
groups. (Halpern, 1987) Preliminary analyses suggest that the treatment groups were quite 
similar on important factors at baseline, so we do not anticipate needing to use Cox 
proportional hazards regression to control for baseline confounding.(Halpern, 1987) 
However, Cox proportional hazards regression methods will be used to perform a time-
dependent covariate survival analysis of the primary outcome. This analysis will adjust 
for risk factors post intervention such as A1 c, weight, BMI, SPB, DBP, cholesterol, HDL, 
LDL, use as time dependent covariates. The progress report will include these post-
intervention risk factors summarized over time as available through database 
search. 
 
Objective #2. To determine the long term effects of intensive glycemic control in type 2 
diabetes on four secondary outcomes: a) cardiovascular mortality, b) major 
microvascular complications, c) health-related quality of life, d) total mortality, and e) 
major microvascular or macrovascular (end-stage renal disease, amputation for either 
ischemic or non-ischemic gangrene, CV-related death, or nonfatal MI, stroke, or new 
CHF). Statistical analyses for secondary outcomes will be identical to those used for the 
primary outcome, with the exception of microvascular complications and health related 
quality of life. Since one of the microvascular complications, severe visual impairment, 
is from the annual survey, survival analysis is not appropriate for the inaccuracy of the 
time of the record but logistic regression analysis. Since health related quality of life is 
a continuous measure, survival analysis will not be appropriate for this secondary 
outcome. The Student t-test will be used to evaluate for differences in mean quality-of-life 
scores in the two treatment arms, with use of robust methods if there is evidence that 
variance estimates vary between the two groups. It is well known that if there is a 
substantial difference in survival between intervention groups, health related quality of life 
results can be misleading unless the survival differences are accounted for. Therefore, if there 
are substantial differences in survival between treatment groups, an alternative analysis 
accounting for missing data due to mortality is a Bayesian imputation approach.(Revicki, 
2001) Again, since substantive differences in baseline attributes did not occur, we do not 
feel that controlling for potential confounders using ordinary least squares regression is 
necessary. 
Update 
We have added a composite measure “Major Microvascular & Macrovascular 
Events, which is simply an aggregate of the primary outcome with the secondary 
outcome  for microvascular outcomes.  Statistical analyses for secondary outcomes 
will be identical to those used for the primary outcome, with the exception of 
health related quality of life.  Since health related quality of life is a continuous 
measure, survival analysis will not be appropriate for this secondary outcome. The 
Student t-test will be used to evaluate for differences in mean quality-of-life scores 
in the two treatment arms, with use of robust methods if there is evidence that 
variance estimates vary between the two groups. It is well known that if there is a 
substantial difference in survival between intervention groups, health related 
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July 6, 2017

quality of life results can be misleading unless the survival differences are 
accounted for. Therefore, if there are substantial differences in survival between 
treatment groups, an alternative analysis accounting for missing data due to 
mortality using a Bayesian imputation approach (Revicki, 2001), which will be 
done by Ann Arbor according to their IRB permission on mortality data collection 
on all VADT population except the terminated. Again, since substantive 
differences in baseline attributes did not occur, we do not feel that controlling for 
potential confounders using ordinary least squares regression is necessary. For the 
quality of measure, we will deal with confounding due to systematic mortality 
differentials between treatment arms by using selection models, as recommended 
in Assessing Quality of Life in Clinical Trials: Methods and Practice (eds. Fayer 
P, Hays R, April 2005.) 
Update: (Early Analysis)  
The major protocol amendment for the VADT-F was that a mid-point analysis 
would be conducted and reported, which was made and published as planned.  We 
now plan for an early analysis to take place shortly before data is fully completed 
with adjudicated outcomes and locked. There is to prepare to submit an important 
presentation in time to take place at the American Diabetes Association (ADA) 
2018 which is planned to be made in conjunction with publication of the 
corresponding manuscript. Below we provide the full justification for this analysis. 
A major concern about an early analysis of clinical trials is that it can potentially 
bias investigators involved in the study protocol and thus integrity of reported 
data.  However, this concern does not apply to this proposed early VADT-F 
analysis. As active intervention ceased 10 years ago at the conclusion of the 
VADT, and there are no longer research personnel that have clinical contact with 
the study subjects, there is no way for investigators to influence patient care or 
outcomes. The outcomes are being collected through database search and surveys. 
In addition, the investigators will be still blinded to the individual treatment level 
data, which will become available for analyses before the final presentation. Thus, 
the potential for bias is not a threat to the VADT-F. 
On the other hand, there will be substantial benefit to the diabetes community as 
we present in a timely manner this important study about whether or not there is a 
delayed effect of the intensive treatment, and all presentations and papers will use 
fully completed and locked data. 
We therefore believe that the benefits of an early analysis provide substantial 
benefit to the diabetes community and do so at essentially no risk to the integrity 
of the VADT-F. 
Other Analysis Considerations  
Interaction (Subgroup) Effects 
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The improved statistical power of the VADT-FS allows us more freedom to examine 
interaction effects (subject baseline attributes that modify the treatment effect) than is 
possible in the VADT. However, our only a priori hypotheses regarding biological 
factors that may modify the treatment effect relate to patient attributes that affect the 
likelihood of the outcomes. As has been recently reported, in such instances it is 
preferable to combine risk factors into a risk score whenever feasible (which will 
generally dramatically improve statistical power as well as diminish problems inherent in 
multiple comparisons)(Brookes, 2004; Hayward, 2005). Therefore, rather than look at 
cardiovascular risk factors in isolation, we will combine these risk factors into the 
Framingham risk score (Hayward, 2006). As reported by Brookes et al, statistical power 
for such interaction effects is further improved if these interaction effects are examined as 
continuous variables using Cox proportional hazard modeling, rather than subdividing the 
risk score into categories.(Brookes, 2001) Consequently, we will examine whether the 
treatment effect is modified by a subject’s 10-year risk of CV events (as predicted by a 
subject’s baseline Framingham score), which will test whether the hazard ratio varies 
conditional on baseline overall CV risk.(Wilson, 1998) Similarly, we will conduct 
regression analyses examining for interaction effects between treatment arm and a study 
subject’s risk of major microvascular complications, using the prediction model 
discussed above (Vijan, 1997). 
Evaluation of Mechanisms of Action 
In addition to examining interaction effects (factors that modify the intervention’s effect), 
we will examine factors that are hypothesized to mediate the interaction effect. Whereas 
interaction effects are part of the experimental analysis (examining baseline [pre-
randomization] subject attributes that identify individuals or groups who will benefit 
more or less than average), examination of potential mediating factors are observational 
analyses (examining factors post-treatment but prior to the occurrence of an outcome 
trying to better understand the treatment’s mechanism(s) of action).(Hayward, 2006) 
There are two principle hypothesized mechanisms of action for why improved metabolic 
control may reduce CV events: 1) direct effects of hyper-glycemia on blood vessels and 
atherosclerotic disease, and 2) decreasing the prevalence of diabetic nephropathy and 
proteinuria (microvascular complications known to increase with hyperglycemia), which 
in turn reduces risk of CV events. We will examine these two factors following the 
methods used in the DCCT/EDIC.(Nathan, 2005) The variable examining direct 
hyperglycemic effects will be based upon the log of cumulative average A1c (previous 
observational analyses have consistently reported a log-linear association between A1c 
and adverse outcomes), which will be updated annually for all subjects who have not yet 
reached the endpoint. Markers for diabetic nephropathy previously reported to be 
associated with CV risk, include presence of proteinuria and estimated GFR. In addition 
to the log of cumulative average A1c, proteinuria and GFR, this analysis will control for 
a subject’s other CV risk factors. (Fleiss, 1986) Cox proportional hazards regression will 
be used for these analyses, except for the visual impairment outcome which was not 
collected during the original VADT. Since time of the event is not available, logistic 
regression will be used for this outcome.  
Missing Data 
In longitudinal studies relying on survey or tests ordered in routine clinical practice, 
problems of missing data will almost always increase. Fortunately, our primary outcome 
and three of our four secondary outcomes do not rely on these data sources. However, our 
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analysis of health related quality of life will be limited to those subjects who have 
answered the survey. For those analyses of interaction effects and potential mechanisms 
of action, outlined above, standard multiple imputation techniques will be utilized so as 
to prevent diminished sample size and potential response bias due to dropping subjects 
with missing data on covariates.(King, 2001; Revicki, 2001; Caroll, 1995) Imputed 
values for a given covariate will be informed by an individual’s values for all other 
observed covariates to be used in the regression model, as well as temporal trends in the 
study population and previous values for that covariate in the individual. Multiple 
imputation is preferable in such instances, since it accounts for the degree of precision in 
imputed values and therefore provides better variance estimates for all regression 
coefficients. (King, 2001; Clayton, 1991; Caroll, 1995; Gatsonis, 1995; Oppenheimer, 
1999) 
 
Updates 
There are no anticipated changes in the planned analyses, other than the addition 
of the new composite secondary endpoint, “Major Microvascular & 
Macrovascular Events” (see Endpoints Section) except severe visual impairment, 
which will be analyzed independently from other outcomes using only data 
collected through self-administered survey questionnaire during this follow-up 
period since 2009.  
 
Study Significance. 
The proposed extension of the VADT Follow-up Study (VADT-FS) would capitalize on a 
unique opportunity to examine factors that are associated with long-term complications and 
mortality for people with one of the most important conditions in modern medicine, a 
disease that will continue to grow dramatically if current epidemiological trends continue. 
Given the results of the UKPDS Follow-up Study and the DCCT-EDIC study, the objectives 
of the VADT-FS are important to answer in order to better assess possible multiplicative 
temporal effects and to obtain adequate statistical power to assess mortality benefits 
directly. It will also provide an opportunity to assess the long-term impact of tight 
glycemic control on vision and renal insufficiency when tight blood pressure control is 
achieved, a question unanswered by previous studies. 
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Appendix A 
Published Manuscripts for VADT 
 
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-Abraira C: Tight control of Blood Glucose for Cardiovascular Risk Reduction? - Syllabus, 3rd Annual  
  National VA Diabetes Symposium, Alexandria, VA (Sierra Military Health Services, Baltimore, MD) 2001 
(Also abstracted in Veterans Health Journal 6:14-21, 2001). 
 
-Duckworth W, McCarren M, Abraira C: The Department of Veterans Affairs Diabetes Trial., Diabetes Care   
24: 942-945, 2001.  
                            
-Abraira C, Duckworth W. The Need for Glycemic Trials in type 2 Diabetes (Featured article). Clinical  
  Diabetes, 21: 107-111, 2003. 
 
-Abraira C, Duckworth W, McCarren M, Emanuele N, Arca D, Reda D, Anderson W for the participants of 
the VA Cooperative Study of Glycemic Control and Complications In Diabetes Mellitus Type 2. Design of  the 
Cooperative Study on glycemic control and complications in Diabetes Mellitus type 2: the VADT.  Journal of 
Diabetes and its Complications, 17: 314-322, 2003. 
 
 
-Reaven PD, Sacks J and VADT investigators. Reduced Coronary and abdominal   
      Artery Calcification in Hispanics with type 2 Diabetes. Diabetes Care 27:1115-1120, 2004. 
 
 
-J. Shah, S. Kirkman, C. Wendell, McCarren M., W. Duckworth, C. Abraira and the VADT group. Baseline 
Macrovascular Disease Correlates in Older Type 2 Diabetic Patients in US Veterans Affairs Diabetes Trial 
VADT).  Proceedings, 12th International Congress of Endocrinology- Lisbon. :Medimond, Bologna-Italy,   
2004, pp 653-658. 
 
 
 
-  C. Abraira, J. Sacks, N. Emanuele, R. Klein, W. Duckworth and the VADT Group. Retinopathy   
Associations in the V.A. Diabetes Trial.  Proceedings, 12th International Congress of Endocrinology-   
Lisbon. Medimond, Bologna, 2004, pp. 435-439. 
   
-C. Abraira, contributor.  CADRE: Type 2 Diabetes Outcomes Trials on the Horizon. Reprint Lecture Kit,  
 Volume 3. (http://www.cadre-diabetes.org) Council for the Advancement of Diabetes Research and 
Education.  New York, 2004. 
 
- Emanuele N, Sacks G, Klein R, Duckworth W, Abraira C (corresponding author) and VADT Group.    
  Ethnicity, Race and Basal Retinopathy Correlates in the Veterans Diabetes Trial.  Diabetes Care.    28: 
1954-1958, 2005. 
 
- Reaven PD, Sacks J, Investigators for the VADT Coronary artery and abdominal  aortic calcification are 
associated with cardiovascular disease in type 2 diabetes. Diabetologia,  48:379-385, 2005.   
 
-  Duckworth W, McCarren M, Abraira C., VADT investigators, Control of Cardiovascular Risk Factors in the 
A Diabetes Trial in Advanced type 2 Diabetes.  Endocrine Practice, 12 (Suppl. 1), 85-88, 2006. 
 
-. Kirkman MS, McCarren M, Shah J, Duckworth W, Abraira C, The association between metabolic control  
and prevalent cardiovascular disease in type 2 Diabetes. The VA Cooperative Study in Diabetes.  J Diab 
Compl, 20: 75-80, 2006. 
  
-Meyers CD, McCarren M, Wong ND, Abraira C, Duckworth W, Kashyap M, VADT Group. Baseline  
 achievement of lipid goals and usage of lipid medications in the VA diabetes trial.  Am. J. Cardiology,   
98:63-65, 2006. 
 
- Abraira, C: The VA Diabetes Trial, Design and Update. In, Alan J. Garber, Hertzel C. Gerstein, Steven M.  
Haffner, MD and Carlos Abraira: What Impact Will Major Clinical Trials Have on Type 2  Diabetes? Satellite 
Symposium to ADA meeting, Washington DC, 2006.   Medscape- Diabetes and Endocrinology, August 1, 
2006. www.medscape.com/viewprogram/5528?rss (accessed October23, 2006). 
 
 
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- Reaven P, Emanuele N, Moritz T, Klein R, Davis M, Glander K, Duckworth W, Abraira C. Proliferative  
   Diabetic Retinopathy is Strongly Related to Coronary Artery Calcium in the Veterans Affairs Diabetes   Trial 
(VADT). Diabetes Care, 31:952-957, 2008. 
 
- Zimering M, Anderson RJ, Luo P, Moritz TE and VADT Investigators .Increased plasma basic fibroblast 
growth factor immunoreactivity in adults In the Veterans Affairs Diabetes Trial: correlation with plasminogen 
activator inhibitor-1. Metabolism 57: 1487-1624, 2008. 
 
- Saremi A, Anderson RJ, Luo P, Moritz TE, Schwenke DC, Allison M, Reaven PD; for the VADT 
Association between IL-6 and the extent of coronary atherosclerosis in the veterans affairs diabetes trial 
(VADT).  Atherosclerosis. 2009 Apr;203(2):610-4. 
 
- Emanuele N, Klein R, Moritz M, Davis M, Glander K, Anderson R, Reda D, Duckworth W, Abraira C   
 (corresponding author) for the VADT group. Comparison of Dilated Fundus Examinations with 7-Field 
Stereo Photographs in VA Diabetes Trial.  J Diab. Comp. 23:323-329,2009. 
  
- Abraira C, Duckworth W, Moritz T for the VADT group. Glycemic Separation and Risk Factor Control in the 
Veterans Affairs Diabetes Trial: An Interim Report. Diabetes, Obesity and Metabolism, 11: 150–156, 2009.  
 
-  Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N et al., VADT investigators: Glucose Control and  
Complications in the VA Diabetes Trial (VADT). N Eng J of Med 360:129-139, 2009. 
 
-  Zimering M, Anderson R, Moritz T, Ge L, Investigators for the VADT :Low plasma  
basic fibroblast growth factor is associated with laser photocoagulation treatment in adult type 2 diabetes 
mellitus from the Veterans Affairs Diabetes Trial. Metabolism 58: 393-400, 2009. 
 
-Duckworth W, Moritz T and Abraira C: Glucose control and vascular complications in Type 2 diabetes.      
Reply to readers comments, New Eng J of Med 360: 2032, 2009. 
 
- Zimering M, Pan Z : Autoantibodies in Type 2 Diabetes induce stress fiber formation and apoptosis in 
endothelial cells in VADT. J Clin Endocrinol Metab, 94(6): 2171-2177, 2009. 
 
- Reaven P, Moritz T, Schwenke D, Anderson R, Criqui M, Detrano R, Emanuele N, Kayshap M, Marks J, 
Mudaliar S, Rao R, Shah J, Goldman S, Reda D, McCarren M, Abraira C,  Duckworth W, for the  
VADT. Intensive Glucose Lowering Therapy Reduces Cardiovascular Disease Events in Those with  Lower 
Calcified Coronary Atherosclerosis: A sub study of the Veterans Affairs Diabetes Trial (VADT).  Diabetes, 58: 
2642-2648, 2009. 
    
- Zimering MB, Anderson RJ, Moritz TE, Ge L, investigators for VADT2009. Endothelial cell inhibitory 
antibodies are associated with laser coagulation in adults from the     
Veterans Affairs Diabetes Trial, Metabolism, 58:882-87, 2009. 
 
- Emanuele N, Moritz T, Klein, R, Davis M, Glander K, Khanna A, Duckworth W, Abraira C (Corresponding  
Author). Clinically Significant Macular Edema Is Associated With Ethnicity and Hemodynamic-
Vascular.Factors at Baseline in the Veterans Affairs Diabetes Trial (VADT). Diabetes Res and Clin. Practice, 
86: 104-110, 2009. 
 
- Moritz T, Duckworth W, Abraira C. Veterans Affairs Diabetes Trial—Corrections, N Eng J of Med, 
361:1024-1025, 2009 (Additional corrections in Page 1028, same issue). 
 
 - Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, Evans GW, Gerstein 
HC, Holman RR, Moritz TE, Neal BC, Ninomiya T, Patel AA, Paul SK, Travert F, Woodward M.  Intensive 
glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia, 52 (Nov):2288-2298, 2009. 
 
- Andreas Liebl, Guy Rutten, Carlos Abraira: “Treat early, treat appropriately”, Primary Care Diabetes      4, 
suppl. 1 (2010) S3–S10.  
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- Saremi A, Allison M, Ditomasso D, Moritz T, Ge L, Anderson R, Duckworth W, Abraira C, Reaven P, for he 
VADT. Hepatic Fat and Inflammation in Type 2 Diabetes. Metabolism. Mar;59(3):430-2, 2010 
 
-Nicholas Emanuele, MD, Thomas Moritz, MS, Ronald Klein, MD, Matthew D. Davis, MD, Kathleen 
Glander, Anuradha Khanna, Lizy Thottapurathu, MS, Gideon Bahn, MS, William Duckworth, MD, 
Carlos Abraira, MD, and the VADT Study Group, (2009) Ethnicity, Race, and Clinically Significant 
Macular Edema in the Veterans Affairs Diabetes Trial (VADT) Diabetes Research and Clinical Practice 
 
- Saremi, Aramesh; Moritz, Thomas; Anderson, Robert J.; Abraira, Carlos; Duckworth, William C.; 
Reaven, Peter D.; on behalf of the Veterans Affairs Diabetes Trial (VADT).  Rates and Determinants of 
Coronary and Abdominal Aortic Artery Calcium Progression in the Veterans Affairs Diabetes Trial 
(VADT).  Diabetes Care (2010) Dec;33(12): 2642-2647. 
 
- Anderson, Robert J.; Bahn, Gideon; Kaufman, Derrick; Moritz, Thomas; Abraira, Carlos; Duckworth, 
William.  Letters to the Editor/Observations - Blood Pressure and Cardiovascular Disease Risk in the 
Veterans Affairs Diabetes Trial (VADT).  Diabetes Care, 34:34-38, 2011. 
 
-Agrawal,L, Azad, N, Emanuele, N., Bahn, G., Kaufman, D., Moritz, T., Duckworth, W., Abraira, C., 
and the VADT Study Group.  Observation on Renal Outcomes in the Veterans Affairs Diabetes Trial.  
Diabetes Care 34: 1-5, 2011. 
 
-Duckworth, W. C., Abraira, C., Moritz, T. E., Davis, S. N., Emanuele, N., Goldman, S., &  Zieve, F. J. (2011). 
The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes 
Trial. Journal of Diabetes & Its Complications, 25(6), 355-361.  
-Azad N, Agrawal L, Emanuele NV, Klein R, Bahn GD, McCarren M, Reaven P, Hayward R, Duckworth W 
and the VADT Study Group. “Association of PAI-1 and Fibrinogen with Diabetic Retinopathy in the Veterans 
Affairs Diabetes Trial (VADT) Diabetes Care. (Published online before print October 7, 2013, doi: 
10.2337/dc13-1193)  
- Mark B. Zimering, Robert J. Anderson, Ling Ge, Thomas E. Moritz, and Investigators for the VADT: 
Increased plasma basic fibroblast growth factor is associated with coronary heart disease in adult type 2 
diabetes. Metabolism Clinical and Experimental 60(2): 284-291, 2011.  
-Nalurporn, C. Ability of Indices of Cardiovascular Disease (CVD) Risk and Comorbidity To Predict CVD 
Outcomes with Intensive Gluscose Control in the VADT.  Abstract presented at 71st Scientific Sessions on 
06/25/2011. 
-Aramesh Saremi, MD1, Gideon Bahn, PhD2, Peter D, Reaven, MD1 for VADT investigators.  Progression of 
Vascular Calcification Is Increased With Statin Use in the Veterans Affairs Diabetes Trial (VADT).  Diabetes 
Care 35.11  (Nov 2012): 2390-2. 
-Lopes-Virella MF, Hunt KJ, Baker NL, Virella G, Moritz T; VADT Investigators. The levels of MDA-LDL in 
circulating immune complexes predict myocardial infarction in the VADT study. Atherosclerosis. 2012 
Oct;224(2):526-31. 
-Koska J, Saremi A, Bahn G, Yamashita S, Reaven PD for the VADT Investigators. The Effect of Intensive 
Glucose Lowering on Lipoprotein Particle Profiles and Inflammatory Markers in the Veterans Affairs Diabetes 
Trial (VADT).  Diabetes Care. 2013 published ahead of print March 27, 2013, doi:10.2337/dc12-2082. 
- Mark B. Zimering, Thomas E. Moritz, Robert J. Donnelly. Anti-Neurotrophic Effects from Autoantibodies in 
Adult Diabetes Having Primary Open Angle Glaucoma or Dementia. Front Endocrinol (Lausanne). 2013; 4: 
58. 
-Bhensdadia NM, Hunt KJ, Lopes-Virella MF, Michael Tucker J, Mataria MR, Alge JL, Neely BA, Janech MG, 
Arthur JM. Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes.  
Kidney Int. 2013 Jun;83(6):1136-43.  
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-Alele JD, Luttrell LM, Hollis BW, Luttrell DK, Hunt KJ; VADT Study Group.  Relationship between vitamin D 
status and incidence of vascular events in the Veterans Affairs Diabetes Trial. Atherosclerosis. 2013 
Jun;228(2):502-7.  
- Madona Azar, Timothy J. Lyons, Petar Alaupovic, Julie A. Stoner, Carmen Quiroga, Derrick G. Kaufman, 
Maria Lopes-Virella, Richard L. Klein, Alicia J. Jenkins, VADT Study Group.  Apolipoprotein-defined and 
NMR lipoprotein subclasses in the veterans affairs diabetes trial. J Diabetes Complications. 2013 Aug 1. 
doi:pii: S1056-8727(13)00113-X. 10.1016/j.jdiacomp.2013.05.005. [Epub ahead of print] 
- Azad N, Agrawal L, Emanuele NV, Klein R, Bahn GD, Reaven P; VADT Study Group. Association of Blood -
Jenkins, A.J., Fu, D., Azar, M., Stoner, J.A., Kaufman, D.G., Zhang, S.X., Klein, R.L., Lopes-Virella, M.F., 
Ma, J.X. & Lyons, T.J.  Clinical Correlates of Serum Pigment Epithelium-Derived Factor in Type 2 Diabetes 
Patients. J. J Diabetes Complications. 2014 May-Jun;28(3):353-9. doi: 10.1016/j.jdiacomp.2014.01.008. 
Epub 2014 Jan 17. 
-Glucose Control and Pancreatic Reserve with Diabetic Retinopathy in Veterans Affairs Diabetes Trial 
(VADT).  D Diabetologia. 2014 Jun;57(6):1124-31. doi: 10.1007/s00125-014-3199-7. Epub 2014 Mar 6. 
-Anderson, R.J., Bahn, G.D., Emanuele, N.V., Marks, J.B., Duckworth, W.C.,  for the VADT Study Group. 
Blood Pressure and Pulse Pressure Effects on Renal Outcomes in the Veterans Affairs Diabetes Trial 
(VADT).  Diabetes Care. 2014 Oct;37(10):2782-8. doi: 10.2337/dc14-0284. Epub 2014 Jul 21. 
-Saremi A, Schwenke DC, Bahn G, Ge L, Emanuele N, Reaven PD; VADT Investigators. The effect of 
intensive glucose lowering therapy among major racial/ethnic groups in the Veterans Affairs Diabetes Trial 
(VADT).  Metabolism .  2015 Feb;64(2):218-25. doi: 10.1016/j.metabol.2014.10.010. Epub 2014 Oct 17. 
-Florez H, Reaven P, Bahn G, Moritz T, Warren S, Marks J, Reda D, Duckworth W, Abraira C, Hayward R, 
Emanuele N, from VADT Research Group.  Rosiglitazone Treatment and Cardiovascular Disease in the 
Veterans Affairs Diabetes Trial. PubMed – NCBI  Diabetes Obesity and Metabolism. 2015 Oct;17(10):949-
55. doi: 10.1111/dom.12487. Epub 2015 Jun 17. 
-Hayward, R., Reaven, P., Wiitala, W., Bahn, G., Reda, R., Ge, L., McCarren, M., Duckworth, W., and 
Emanuele, N., for the VADT Investigators.  Follow-up of Glycemic Control and Cardiovascular Outcomes in 
Type 2 Diabetes.  New England Journal of Medicine. 2015 June;372(23):2197-2206. doi: 
10.1056/NEJMoa1414266. Erratum in: N Engl J Med. 2015 Jul 9;373(2):198. 
-Hayward, R., Reaven, P., and Emanuele, N., for the VADT Investigators. Follow-up of Glycemic Control and 
Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2015 Sep 3;373(10):978. 
DOI: 0.1056/NEJMc1508386 
-Zimering MB, Behnke JA, Thakker-Varia S, Alder J (2015) Autoantibodies in Human Diabetic Depression 
Inhibit Adult Neural Progenitor Cells In vitro and Induce Depressive-Like Behavior in Rodents. J Endocrinol 
Diab 2(2): 11. 2015, April 25. 
-Zimering, MB, Jeffrey, K, Ge, L, Bahn, G, and VADT Investigators (2016). Predictors of cognitive decline in 
older adult type 2 diabetes from the Veterans Affairs Diabetes Trial. Front. Endocrinol. 7:123. doi: 
10.3389/fendo.2016.00123  
-Azad N, Bahn G, Emanuele N, Agrawal L, Ge L, Reda D, Klein R, Reaven P, Hayward R and the VADT 
Study Group. Association of Blood Glucose Control and Lipids with Diabetic Retinopathy in the Veterans 
Affairs Diabetes Trail (VADT). Diabetes Care, 39: 816-822, 2016  
-Saremi A, Bahn G, Reaven PD; A Link Between Hypoglycemia and Progression of Athrerosclerosis in  the 
Veterans Affairs Diabetes Trial (VADT). Diabetes care, Diabetes Care, 39: 448-54, 2016  
- Maria F Lopes-Virella, M.D., Ph.D., Kelly J Hunt, Ph.D., Nathaniel L Baker, M.S., Gabriel Virella, M.D., 
Ph.D., and the VADT Group of Investigators. High Levels of AGE-LDL, and of IgG Antibodies reacting with 
MDA-lysine epitopes expressed by oxLDL and MDA-LDL in Circulating Immune Complexes Predict 
Macroalbuminuria in Patients with Type 2 Diabetes. Journal of Diabetes and Its Complications. 2016 May-
June;30(4): 693-699. 
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-Aramesh Saremi, Scott Howell, Dawn C. Schwenke, Gideon Bahn, Paul J. Beisswenger, Peter D. Reaven 
(2017) Advanced Glycation End Products, Oxidation Products, and the Extent of Atherosclerosis During the 
VA Diabetes Trial and Follow-up Study Diabetes Care 2017 Feb; dc161875. https://doi.org/10.2337/dc16-
1875 
-Herrington WG, Preiss D. Tightening our understanding of intensive glycaemic control. Lancet Diabetes 
Endocrinol 2017 Jun;5(6):405-407. doi: 10.1016/S2213-8587(17)30095-5. Epub 2017 Mar 30. 
- Zoungas S, Arima H, Gerstein HC, Holman RR, Woodward M, Reaven P, Hayward RA, Craven T, Coleman 
RL, Chalmers J; Collaborators on Trials of Lowering Glucose (CONTROL) group. Effects of intensive 
glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual 
participant data from randomised controlled trials. Lancet Diabetes Endocrinol 2017 Jun;5(6):431-437. doi: 
10.1016/S2213-8587(17)30104-3. Epub 2017 Mar 30. 
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Appendix B 
VADT Endpoint Definitions 
 
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CSP #465 (VADT) Endpoint Definitions 
 
PRIMARY ENDPOINTS  
1. MYOCARDIAL INFARCTION 
Myocardial infarctions will be determined based on the algorithm supplied at the end of 
this appendix. All suspected MI will be evaluated in detail by the Endpoints Committee. 
All supporting documentation, i.e., ECGs, hospital records, laboratory values, etc. needed 
to confirm or rule out the presence or absence of an MI will be obtained by personnel at 
the ECG Laboratory. 
2. CONGESTIVE HEART FAILURE – also see revised definition below: 
Diagnosis of new congestive heart failure (CHF) can be made in the presence of at least 
two major manifestations of CHF or one major and at least two minor manifestations or 
new onset of pulmonary congestion requiring treatment. Treatment with diuretic, 
digitalis glycoside, ACE inhibitor, or hospitalization for management of symptoms of 
CHF would be appropriate. 
Major Criteria: 
1) paroxysmal nocturnal dyspnea 
2) distended neck veins 
3) cardiomegaly and pulmonary hilar congestion on X-ray, or increased heart size 
4) acute pulmonary edema 
5) increased venous pressure 
6) hepatojuglar reflux 
7) documented 10% or greater decrease in ejection fraction to less than 40%. 
Minor Criteria: 
1) bilateral ankle edema 
2) night cough 
3) dyspnea on normal exertion 
4) hepatomegaly 
5) pleural effusion 
Diagnosis of worsening CHF, for patients entering the Study with NYHA Class I or II CHF, will be 
made if there is a 10% (absolute) decrease in LVEF. Baseline assessment of LVEF must be made 
within the six months prior to randomization. 
REVISED CHF DEFINITION: meets all criteria shown above with the additional requirement 
that the patient will have been hospitalized or had an urgent care visit associated with aggressive 
treatment for CHF as part of the event. Aggressive treatment today (2003) primarily includes 
intravenous treatment with diuretics and/or inotropic agents. However, as the study progresses, this 
list may be expanded to include newer oral agents. The aim of this additional condition is to ensure 
that the visit was accompanied by, if not precipitated by, moderate to severe CHF symptoms.” 
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3. STROKE 
Occurrence and documentation (with copies of any hospital admissions) of 
cerebrovascular accident, subject to evaluation by the Endpoints Committee, will be 
counted as a primary endpoint. 
Non-hemorrhagic stroke is defined as the sudden onset of localizing neurologic defect 
(e.g. hemoparesis, aphasia, homonymous hemianopsia) persisting for> 24 hours. 
Intracranial hemorrhage is indicated by headache, change in consciousness, and signs of 
meningeal irritation with a bloody spinal fluid under increased pressure, with or without a 
localizing neurologic defect. Embolic stroke is indicated by the presence of an embolic 
source (e.g. atrial fibrillation, mitral stenosis, recent myocardial infarction, endocarditis), a 
consistent clinical course (e.g., rapid onset and claring, localized defect, possibly 
bloody spinal fluid) and/or other peripheral emboli. 
Results of imagining procedures, accompanied by a summary of a neurologist’s 
examination or hospitalization work-up are to be included in the endpoint evaluation. No 
other disease process or event such as a brain typor, trauma, subdural hematoma, 
subarachnoid hemorrhage, inflammatory disease, metabolic disorder, or peripheral lesion 
that could cause localized neurological deficit or course will be considered as an 
endpoint. 
4. AMPUTATION 
Amputation due to ischemic gangrene will be counted, with pathological report 
confirming the diagnosis. 
5. CARDIOVASCULAR DEATH 
Cardiovascular death is classified by the Endpoint Committee. An autopsy will be 
performed whenever possible. Major categories are sudden death, coronary heart disease, 
cerebrovascular accident, and other cardiovascular events (e.g. cardiomyopathy). The 
definition of sudden death will be used from the Framinham Study: death within one 
hour from the onset of symptoms, and if the cause of death could not be attributed to 
some potentially lethal disease other than coronary heart disease. Sudden death will be 
further classified as unexpected if the patient did not have a previous history of 
cardiovascular heart disease. 
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New York Heart Association Functional Classification 
CLASS I 
No limitation of physical activity. No dyspnea, fatigue, or 
palpitations 
with ordinary physical activity. 
CLASS II 
Slight limitation of physical activity. These patients have 
fatigue, 
palpitations, and dyspnea with ordinary physical activity, but 
are comfortable at rest. 
CLASS III 
Marked limitation of activity. Less than ordinary physical activity 
results 
In symptoms but patients are comfortable at rest. 
CLASS IV 
Symptoms are present at rest and any physical exertion 
exacerbates the 
symptoms. 
Canadian Heart Classification 
The Canadian Heart Classification is most often used to characterize a patient’s limitation 
from angina pectoris. It is modified slightly from the New York Heart Association 
functional class. 
CLASS I Ordinary physical activity, such as walking and climbing stairs, does 
not cause angina. Angina occurs with strenuous, rapid or prolonged 
exertion during work or recreational activity. 
CLASS II 
Slight limitations of ordinary activity by angina. Angina pectoris 
occur 
when walking or stair climbing, after meals, or in cold, or I wind, or 
under emotional stress, or only during the few hours after awakening. 
Angina pectoris may also occur when walking more than ? blocks on 
the level and climbing more than one flight of ordinary stairs at a 
normal pace and in normal conditions. 
CLASS III Marked limitation of ordinary physical activity. Angina pectoris 
occurs when walking one to two blocks on the level and climbing 
one flight of stairs in normal conditions and at normal pace. 
CLASS IV 
Inability to carry on any physical activity without anginal 
discomfort. 
Angina may be present at rest.   
Reference: Campeau, L: Grading of anginapectoris. Circulation 1976; 54:522-3. 
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Appendix C 
Human Subjects 
 
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Study Title:   VA Diabetes Trial Follow-up Study      
 
Principal Investigator:  Nicholas Emanuele, M.D. 
 
Department of Veterans Affairs Authorization for 
Release of Protected Health Information for Research Purposes 
 
 
You have been asked to be part of a research study under the direction of Dr. Nicholas 
Emanuele and his research team.  The purpose of this study is to help determine allow the 
investigators to determine the long term effects of tight and standard glycemic control 
(diabetes management) on the progression of illness associated with diabetes, i.e.,  coronary 
artery (heart disease) and peripheral vascular disease (stroke, claudication or leg pain), kidney 
disease, vision loss and mortality. 
 
By signing this document, you will authorize the Veterans Health Administration (VHA) to 
provide Dr. Nicholas Emanuele and his research team to use and/or disclose the following 
information about you.  
 
 
Demographic Information:  e.g. Name, Address, Phone Number, Social Security 
Number, Date of Birth 
 
Medical Record:  history and physical exam notes, progress notes, consultation 
reports, laboratory test results, operative reports 
 
Photographs, videotapes, or digital or other radiographic images  
 
Tissue Samples  (specify) 
 
Blood Samples  (specify) 
 
 
The information that will be released may include information regarding the following 
conditions:  
 
 
Drug Abuse 
 
Alcoholism or Alcohol Abuse 
 
Mental or Behavioral Health or Psychiatric Care 
 
Acquired Immunodeficiency Syndrome (AIDS) or Human Immunodeficiency Virus 
(HIV) Infection 
 
Sickle Cell Anemia 
 
The research team may also need to disclose the information to others as part of the study 
process. The others may include representatives of the Hines Cooperative Studies Program 
Coordinating Center and to the Ann Arbor VA Health Services Research & Development 
 
DEPARTMENT OF VETERANS AFFAIRS 
EDWARD HINES, JR. VA HOSPITAL  
CAPT. JAMES A. LOVELL FEDERAL HEALTH CARE CENTER 
 
INSTITUTIONAL REVIEW BOARD 
Building 1, Room C334 
PO Box 5000 (151) 
Hines, IL  60141 
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Center of Excellence. The collected information will be maintained to the highest standards of 
confidentiality as required by VA research.  
 
If you do not sign this authorization, you will not participate in the study. 
This authorization to use your information has no expiration date. 
 
While this study is being conducted, you will not be allowed to see research-related medical 
records about you that are created or obtained by the research team.  You will be able to see 
them again when the study is completed.  This will not affect your doctor’s ability to see your 
records as part of your normal health care. 
 
You can revoke this authorization, in writing, at any time.  Your individually identifiable 
health information that is disclosed in accordance with this authorization may no longer be 
protected by Federal laws or regulations and may be subject to re-disclosure by the non-VA 
recipient.  To revoke your authorization, you must write to the Release of Information Office 
at this facility or you can ask a member of the research team to give you a form to revoke the 
authorization.  Your request will be valid when the Release of Information Office receives it.  
If you revoke this authorization, you will not be able to continue to participate in the study.  
This will not affect your right as a VHA patient to treatment or benefits outside the study.   
If you revoke this authorization, Dr. Nicholas Emanuele and his research team can continue to 
use information about you that was collected before receipt of the revocation.  The research 
team will not collect information about you after you revoke the authorization.  
 
The VHA complies with the requirements of the Health Insurance Portability and 
Accountability Act of 1996 and its privacy regulations and all other applicable laws that 
protect your privacy.  We will protect your information according to these laws.  Our Notice 
of Privacy Practices (a separate document) provides more information on how we protect your 
information.  If you do not have a copy of the Notice, the research team will provide one to 
you. 
 
I have read this authorization form and have been given the opportunity to ask questions.  If I 
have questions later, I understand I can contact Dr. Nicholas Emanuele at 708-202-8387 Ext 
4533. I will be given a signed copy of this authorization form for my records.  I authorize the 
use of my identifiable information as described in this form. 
 
 
 
 
 
 
 
Signature of Participant or Person Authorized                              Date 
to Sign for Participant  
(Attach authority to sign, e.g., Power of Attorney)               
 
 
 
                Print Participant Name 
 
__________________________ Participants SSN (VHA 1605.1 b. 1(a)) 
 
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July 6, 2017

 
Instructions to Investigator:  VHA Handbook 1605.1 14 (d) 
• When Signed, a copy of the signed authorization is required to be given to the 
individual 
 
Written authorization for release of information is valid when signed by: 
• The individual 
• Court appointed guardian (NOT federal fiduciary monetary benefits) 
• Person legally authorized in writing by the individual (or the individual’s legal 
guardian  (i.e. POA) 
• If deceased, then the Executor of Estate 
 
 
CSP #465-F Protocol 4.1
61
July 6, 2017

 
 
Appendix D 
Survey Letter and Questionnaire 
 
CSP #465-F Protocol 4.1
62
July 6, 2017

DEPARTMENT OF VETERANS AFFAIRS 
HEALTH SERVICES RESEARCH & DEVELOPMENT CENTER OF EXCELLENCE 
VA Medical Center 
Ann Arbor, Michigan 
In Reply Refer To: CSP #465-FS 
June 1, 2011                                                                                             #1234 
 
Mr. John Doe 
1234 Main Street 
Any Town, MI 12345 
 
Dear Mr. Doe: 
 
Thank you for your ongoing participation in the VA Diabetes Trial (VADT, CSP #465).  As you know, 
the clinic visits and examination portion of this important study ran from 2000-2008.  We are very 
grateful that in 2008 you agreed to continue to participate in the VADT-Follow-up Study by 
completing an annual survey.  Of course, your continued participation is completely voluntary and 
will not in any way affect your health care or your VA benefits.  However, your ongoing participation 
is very important to the success of this study, and we hope that you will take the time to complete 
this brief annual survey to assist us in this important project.  In order for this study to maintain the 
highest level of scientific accuracy, having information on each participant is extremely valuable and 
important.  The information in this survey will provide useful information that could help us learn how 
to help veterans and other people with diabetes live longer and healthier lives.  Your generous help 
with this study is much appreciated.  As a small token of our thanks, we have enclosed a gift card 
with a value of $10.   
 
Please complete the enclosed survey and return it in the self-addressed, postage paid envelope 
provided.  This survey is designed to take 10-20 minutes of your time.  All responses to the 
questions will be strictly confidential and no information about any individual veteran will be 
released.  If we do not hear from you within the next few weeks, we will contact you again.  If you 
need assistance in completing the questionnaire or have any questions or concerns, you or a 
friend/family member should feel free to contact Douglas Bentley at (800) 753-3357.  Alternatively, 
you can simply indicate on the cover of the questionnaire that you would like to answer the survey 
by phone, and return the uncompleted questionnaire to us in the envelope provided.  We will then 
contact you by telephone to administer the questionnaire or respond to your questions. 
 
We thank you for your time and assistance with the VADT Follow-up Study. 
 
Sincerely, 
 
 
Rodney A. Hayward, M.D. 
Director 
VA Ann Arbor Health Services Research  
 & Development Center of Excellence 
 
Enclosures 
CSP #465-F Protocol 4.1
63
July 6, 2017

The VA Diabetes Trial Foiiow-up Study 
Annyal Syrvey 
Survey Instryctioos 
Please answer ail questions as best you can 
All of your answers will be kept confidential 
Please return the completed questionnaire in the self-addressed, postage-
paid envelope provided 
Thank you s© moch for your time and assisfence! 
Would you prefer that we contact you by phone? 
L _ 
If because of visual problems or any reason whatsoever, you would prefer to 
complete this survey by phone, please contact us at 1-800-753-3357 and 
ask for Doug Bentley. 
starts Approval Expires 
12/16/13 
IRB 
10/06/14 
Edward Hines,Jr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
64
July 6, 2017

CSP #465-F 
VADT Long Term Follow-up © 
Form (70) 
Annual Survey 
General Health Questions: 
1. In general, would you say your health is: 
(Circle one) 
Good 
23 U Excellent 
[1] Very Good 
[I 
H Fair 
[I] Poor 
2. The foilowing questions are about activities you might do during a typical day. Does your health 
now limit vou in these activities? If so, how much? (Circle one) 
a. Moderate activities such as moving a table, pushing 
a vacuum cleaner, bowling, playing golf: _ _ _ _ _ 
b. Climbing several flights of stairs: 
Yes, limited! 
Yes, limited 
No, not 
a lot 
a little 
limited at all 
241 1 
25 
_3_ 
T 
3. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities as a result of vour physical health? (Circle one) 
a. Accomplished less than you would 
like? 
b. Were limited in the kind of work or 
other activities?_ 
_ 
All of 
the time 
271 
Most of 
the time 
_1_ 
T 
Some of 
A little 
the time 
of the time 
2_ 
None 
of the time 
_4_ 
4. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities as a result of anv emotional problems? 
(Circle one) 
a. Accomplished less than you would 
like? 
b. Did work or other activities less 
carefully than usual? 
All of 
the time 
28' 
Most of 
the time 
Some of 
the time 
2_ 
A little 
of the time 
_3_ 
None 
of the time 
(VACO-OMB 
EXEMPT: 
5-7-09) C S P #465-F - Form {70-ENGLISH) - Page 2 of 10 12/10/2013 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward Hines,Jr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
65
July 6, 2017

CSP #465-F 
VADT Long Term Follow-up Study 
Form (70) 
Annual Survey 
5. During tiie past 4 weeks. !iow much did pain interfere with your normal work, (including both 
work outside the home and housework)? 
(Circle one) 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
301 
_1_ 
6. During the past 4 weeks, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting friends, relatives, etc.)? (Circle one) 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
31 0 
7. These questions are about how you feel and how things have been with you during the past 4 
weeks. For each question, please give one answer that comes closest to the way you have 
been feeling. How much of the time durina the past 4 weeks.... (Circle one) 
a. Have you felt calm and peaceful? 
b. Did you have a lot of energy?_ 
c. Have you felt downhearted and 
depressed? 
, 
34 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little 
of the time 
None 
of the tim 
0 
32' 
1 
m 
m 
m 
33m 
m 
m 
4 
T] 
[T 
j4_ 
8. At the present time, would you say vour evesiaht using both eves (with glasses or contact 
lenses, ifyou wear them) is: (Circle one) 
35LIJ Excellent 
I j Good 
LH] Fair 
\A] Poor 
[Z3 Very Poor 
[LI Completely Blind 
9. Is the VA your primary source for diabetes care? (Circle one) 
No 
D l Yes 
36 
(VACO-OMB EXEMPT: 
5-7-09) 
C S P #465-F - Form {70-ENGLISH) - Page 3 of 10 12/10/2013 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward Hines,Jr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
66
July 6, 2017

CSP #465-F 
VADT Long Term Follow-up S' 
Form (70) 
Annual Survey 
11. Hospitalizations and Medical Procedures: 
The following questions ask you about hospitalizations and medical procedures that you may have 
had since June 1, 2013. 
10. Since June 1, 2013, have you had a heart attack, myocardial infarction ("Ml") or 
coronary"? (Circle one) 
37 _2J No (If no, skip to question 11 on next page) 
U J Yes 
If "yes", please list the hospital name, city, state, and admission date (including the year) for each 
hospitalization you had for a heart attack since June 1, 2013: 
1st Admission: 
^ 
Hospital Name: 
40 
City; 
70 
Admitted: 
92 
Month 
/ 94! 
Year 
Is this a VA Hospital? 
oeLLlNo 
LUVes 
State: •90 
Rec 
2nd Admission: 
! 
Hospital Name: 
22 
City: 52 
Admitted: 
74 
Month 
Is this a VA Hospital? 
/ 7& 
78 
Year 
No IJH Yes 
State:72 
3rd Admission: 
Hospital Name: 
221 
City: 52'— 
Admitted: 
741-
Month 
Is this a VA Hospital? 
76 
78 
Year 
E 
No 
Yes 
I State: 72 
CVACO-OMB EXEMPT: 5-7-09) C S P #465-F - Form (70) - Page 4 of 10 (12 10 2013) 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward Hines,Jr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
67
July 6, 2017

CSP #465-F 
VADT Long Term Fotlow-up Study 
Form (70) 
Annual Survey 
R e c j T ] 
11. Since June 1, 2013, iiave you liad a strol<e or "mini-stroke"? Tliese are also called 
cerebrovascular accidents ("CVA"), blood clots in the brains, or transient ischemic attacks ("TIA"): 
. (Circle one) 
21 
No (If no, skip to question 12 on next page) 
Yes 
If "yes", please list the hospital name, city, state, and admission date (including the year) for each 
hospitalization you had for a stroke or mini-stroke since June 1, 2013: 
1st Admission: 
Admitted: 
74^ 
Month 
Is this a VA Hospital? 
76 
Year 
7 8 [ o ] N o 
[DYes 
Hospital Name: 
22 
1 
1 
1 
1 
1 
1 
I
I
I
I 
City: 
' 
52 
1 
1 
1 
1 
1 
1 
1 
State: 72 
1 
RecjTj 
2nd Admission: 
Hospital Name: 
22 
City: 
52 
Admitted 
74 
Month 
Is this a VA Hospital? 
76 
Year 
7 8 [ I ] N o 
[DYes 
state: 72 
3rd Admission: 
Hospital Name: 
22 
City 
5 2 ' 
Admitted: 
74 
Month 
Is this a VA Hospital? 
/ 76 
Year 
7 8 [ £ ] N 0 
Yes 
state: 72L 
(VACO-OMB 
EXEMPT: 
S-7-09) C S P #465-F - Form (70-ENGLISH) - Page 5 of 10 12/10/2013 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward Hines,Jr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
68
July 6, 2017

CSP #465-F 
VADT Long Term Follow-up Si 
Form (70) 
Annual Survey 
Rec 7 
12. Since June 1, 2013, iiave you had a toe, foot, or leg amputation? (Circle one) 
21 £ j No (If no, skip to question 13 on next page) 
LQ Yes 
If "yes", please list the hospital name, city, state, and admission date (including the year) for each 
hospitalization you had for an amputation since June 1, 2013: 
1st Admission: 
Hospital Name: 
22 
City: 
5 2 ' 
Admitted: 
74 
Month 
is this a VA Hospital? 
76 
Year 
7 8 [ £ ] N o 
QIlYes 
State: 72L 
RecfTj 
2nd Admission: 
Hospital Name: 
22 
I 
\ 
T " 
City: 5 2 ' 
Admitted: 
74 
Month 
Is this a VA Hospital? 
76 
Year 
A I n o 
DIlYes 
781 
State:72! I 
3rd Admission: 
Hospital Name: 
22 
City 4 3 ' 
Admitted: 
65 
Month 
Is this a VA Hospital? 
67^ 
Year 
[ U n o 
69 
Yes 
state: es'-
(VACO-OMB EXEMPT: S-7-09) C S P #465-F - Form (70-ENGLISH) - Page 6 of 10 (12 10 2013) 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward Hines,Jr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
69
July 6, 2017

CSP #465-F 
VADT Long Term Follow-up Study 
Form (70) 
Annual Survey 
13. Since June 1, 2013, have you had any of the following procedures done? (Circle one) 
a. Angioplasty or stent or balloon or bypass to unclog 
arteries to your heart? 
Yes 
No 
Unsure 
b. Angioplasty or stent or balloon or bypass to unclog 
y i H " 
arteries to your brain? 
2 
c. Retina eye surgery (such as "laser" treatment or 
M i 
"vitrectomy")? 
2 
d. Cataract eye surgery? 
7 3 E 
2 
e. Either dialysis or kidney transplant for kidney 
r n 
fol 
H" 
failure? 
— ' 
'—' 
'—' 
(VACO-OMB 
EXEMPT: 5-7-09) C S P #4S5-F - Form (70-ENGLISH) - Page 7 of 10 (12 10 2013) 
Starts Approval Expires 
12/16/13 
IRB 
10/06/14 
Edward Hines,Jr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
70
July 6, 2017

CSP #465-F 
VADT Long Term Follow-up Study 
Form (70) 
Annual Survey 
lil. Diabetes & Your Health: 
14. Directions: Read each statement carefully. Please indicate how satisfied or dissatisfied you 
currently are with the aspect of your life described in the statement. CIRCLE the number that 
corresponds to how satisfied or dissatisfied you feel. There are no right or wrong answers to 
these questions. We are interested in your opinion. 
(Circle one number on each line) 
Satisfied 
Dissatisfied 
Very 
Moderately 
Neither 
Moderately 
Very 
75 a. How satisfied are you with the 
amount of time it takes to man-
age your diabetes? 
1 
2 
3 
4 
5 
76 b. How satisfied are you with the 
amount of time you spend 
getting checkups? 
1 
2 
3 
4 
5 
77 c. How satisfied are you with the 
time it takes to determine your 
sugar levels? 
1 
2 
3 
4 
5 
78 d. How satisfied are you with 
your current treatment? 
1 
2 
3 
4 
. 
79 e. How satisfied are you with the 
flexibility you have with your 
diet? 
1 
2 
3 
4 
5 
80 f. How satisfied are you with the 
burden your diabetes is placing 
on your family? 
1 
2 
3 
4 
5 
81 g. How satisfied are you with 
your knowledge about your 
diabetes? 
1 
2 
3 
4 
5 
82 h. How satisfied are you with 
your sleep? 
1 
2 
3 
4 
5 
83 i. How satisfied are you with 
your social relationships and 
friendships? 
1 
2 
3 
4 
5 
(VACO-OMB 
EXEMPT: S-7-09) C S P #465-F - Form (70-ENGLISH) - Page 8 of 10 (12 10 2013] 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward HinesJr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
71
July 6, 2017

CSP #465-F 
VADT Long Term FolSow-up Study 
Form (70) 
Annua! Survey 
ilL Diabetes & Your Health: Continued 
(Circle one number on each line) 
Satisfied 
Dissatisfied 
(Circle one number on each line) 
Very 
j 
Moderately 
| 
Neither 
Moderately 
Very 
j . How satisfied are you with 
your sex life? 
1 
2 
3 
5 
k. How satisfied are you with 
your work, school, and house-
hold activities? 
1 
2 
3 
4 
5 
1. How satisfied are you with the 
appearance of your body? 
1 
2 
3 
4 
5 
m. How satisfied are you with 
the time you spend exercising? 
1 
2 
3 
4 
5 
n. How satisfied are you with 
your leisure time? 
1 j 
2 
3 
4 
5 
0 . How satisfied are you with life 
in general? 
2 
3 
4 
5 
15. D i r e c t i o n s : Read each statement carefully. Please indicate ho 
h a p p e n to y o u . CIRCLE the appropriate number. There are no 
questions. W e are interested in your opinion. 
w often the following events 
right or wrong answers to these 
(.L/ircie one numoer on eacn line) 
, 
- <• 
1 Never 
Very Seldom 
j 
Sometimes 
1 
Often 
1 Ali of the Time 
a. How often do you feel pain 
associated with the treatment of 
your diabetes? 
1 
2 
3 
4 
5 
b. How often are you embar-
rassed by having to deal with 
your diabetes in public? 
1 
2 
3 
4 
5 
c. How often do you have low 
blood sugar? 
1 
2 
3 
4 
5 
d. How often do you feel physi-
cally ill? 
1 
2 
3 
4 
5 
e. How often does your diabetes 
interfere with your family life? 
1 
1 
2 
1 
3 
4 
5 
f. How often do you have a bad 
night's sleep? 
1 j 
2 
3 
4 
[ 
5 
(VACO-OMB 
EXEMPT: S-7-09) C S P #465-F - Form (70-ENGLISH) - Page 9 of 10 (12 10 2013) 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward HinesJr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
72
July 6, 2017

CSP #465-F 
VADT Long Term Follow-up Study 
Form (70) 
Annual Survey 
111. Diabetes & Your Health: Continued 
(Circle one number on each line) 
(Circle one number on each line) 
Never 
Very Seldom 
Sometimes 
Otten 
All of the Time 
| 
96 g. How/ often do you find your 
diabetes limiting your social 
relationships and friendships? 
1 
2 
3 
4 
5 
97 h. 
How often do you feel good 
about yourself? 
1 
2 
3 
4 
5, 
98' i. How often do you feel re-
stricted by your diet? 
1 
2 
3 
4 
5 
99 j . How often does your diabetes 
interfere with your sex life? 
1 
2 
3 
4 
5 
100 k. How often does your diabetes 
keep you from driving a car or 
using a machine (e.g., a type-
writer)? 
1 
2 
4 
5 
101 1, How often does your diabetes 
interfere with your exercising? 
1 
2 
3 
4 
5 
102 m. How often do you miss work, 
school, or household duties 
because of your diabetes? 
1 
2 
3 
4 
5 
Again, thank you very much for taking the time to complete this questionnaire. 
Please return the completed questionnaire 
in the self-addressed, postaae-paid envelope provided. 
(VACO-OMB EXEMPT: 5-7-03) C S P #4S5-F - Form (70-ENGLISH) - Page 10 of 10 (12 10 2013) 
Starts Approval 
Expires 
12/16/13 
IRB 
10/06/14 
Edward HinesJr.VAH/JALFHCC 
CSP #465-F Protocol 4.1
73
July 6, 2017

 
 
Appendix E 
Opt-in Letter and Opt-out Letter 
 
CSP #465-F Protocol 4.1
74
July 6, 2017

DEPARTMENT OF VETERANS AFFAIRS 
 
 
In Reply Refer To: CSP #465-FS 
June 1, 2011                                                                                               #1234 
 
Mr. John Doe 
1234 Main Street 
Any Town, MI 12345 
 
Dear Mr. Doe: 
 
Thank you for your participation in the VA Diabetes Trial (VADT, CSP #465).  As you 
know, the clinic visits and examination portion of this important study ended in 2008.  
The results of this study were very important and helped change the way diabetes is 
treated in the VA and around the world.  
 
We are very grateful that you agreed to continue to participate in the VADT Follow-up 
Study, which only consists of tracking a few parts of your medical history using VA and 
other databases.  This, therefore, requires no action on your part. There may also be an 
occasional voluntary survey to get your opinion on how your health is. 
 
This letter is to inform you about a slight change in the Follow-up Study which will not in 
any way affect what you do to participate, or how you receive your local healthcare. 
Because the VADT Follow-up Study does not require local VA visits, it has been 
administratively closed at your VA hospital. However, the study will now be run centrally 
from the Hines VA Medical Center under direction of Dr. Nicholas Emanuele and Dr. 
Peter Reaven, who helped run the VADT. We are asking that you continue to 
participate in this study by signing and returning two attached forms; HIPAA and 
Informed Consent (postage pre-paid). Again, the only change is the central 
administration of the study by Hines and this point is highlighted in the attached 
documents. 
  
Your ongoing participation is very important to the success of this study, and we hope 
that you will choose to sign and return the forms. Other medical studies have reported 
that some of the most important information comes during these follow-up periods.  In 
order for this study to maintain the highest level of scientific accuracy, having 
information on each participant is extremely valuable and important, and we cannot 
continue to collect that information unless you sign and return the enclosed documents.   
 
For questions about your rights as a research participant or to discuss problems, 
complaints or concerns about the study, contact the Hines IRB Office at 708-202-5701.   
 
 
We thank you for your time and assistance with the VADT Follow-up Study and for 
returning the enclosed forms. 
CSP #465-F Protocol 4.1
75
July 6, 2017

 
Sincerely, 
 
 
 
Nicholas Emanuele, M.D. 
Enclosures 
 
CSP #465-F Protocol 4.1
76
July 6, 2017

DEPARTMENT OF VETERANS AFFAIRS 
 
 
In Reply Refer To: CSP #465-FS 
June 1, 2011                                                                                               #1234 
 
Mr. John Doe 
1234 Main Street 
Any Town, MI 12345 
 
Dear Mr. Doe: 
 
Thank you for your ongoing participation in the VA Diabetes Trial (VADT, CSP #465).  As you know, 
the clinic visits and examination portion of this important study ended in 2008.  We are very grateful 
that you have agreed to continue to participate in the VADT Follow-up Study.  The Follow-up Study 
simply consists of tracking your medical history by study of several databases and requires no 
action on your part. In addition, there is a voluntary annual survey that is performed by mail. 
 
This letter is to inform you about a very slight change in the Follow-up Study which will not in any 
way affect what you do to participate or how you receive your local healthcare. Since the active part 
of the VADT was completed in 2008, the study will now be run centrally from the Hines VA Medical 
Center under direction of Dr. Nicholas Emanuele and Dr. Peter Reaven. Although this change is 
very minimal and will not affect anything that you agreed to previously, we did want to give you a 
chance to ‘opt out’ of the Study. If you do not agree to continue participation (decide you no longer 
wish to continue), please sign the attached page and mail it back in the self-addressed envelope. 
  
Your ongoing participation is very important to the success of this study, and we hope that you will 
choose to remain in the program. Other studies have reported that some of the most important 
information comes during these follow-up periods.  In order for this study to maintain the highest 
level of scientific accuracy, having information on each participant is extremely valuable and 
important.   
 
 For questions about your rights as a research participant or to discuss problems, complaints or 
concerns about the study, contact the IRB Office at 708-202-5701.   
 
 If nothing is returned, we will assume that you wish to continue to allow us to track your medical 
information and receive the mailed questionnaires. 
 
 
We thank you for your time and assistance with the VADT Follow-up Study. 
 
Sincerely, 
 
 
 
Nicholas Emanuele, M.D. 
Enclosures 
CSP #465-F Protocol 4.1
77
July 6, 2017

 
 
 
CSP 465-F 
VA Diabetes Trial Follow-up 
Opt Out  
 
 
 
 
I _________________________________________ do not agree to continue to participation in the
 
(print Name) 
 
 
CSP 465-F “VA Diabetes Trial Follow-up Study under the Hines IRB leadership.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________ 
__________________________ 
 
(sign name) 
 
(date) 
 
 
 
_______________________________________ 
 
 
 
 
 
 
(social security number) 
 
 
CSP #465-F Protocol 4.1
78
July 6, 2017