PREVENTION OF CARDIOVASCULAR DISEASE IN DIABETES MELLITUS This draft document is made available to the public for review in accordance with FAR 5.205 (c). We are disseminating this information pertaining to a possible NHLBI funded clinical trial contract program to allow potential offerors to begin thinking about their responses in advance.




The proposed contract program is for a multi-center clinical trial to prevent major cardiovascular events in Type 2 diabetes mellitus (DM). The specific objectives of the study are to determine if the rate of major cardiovascular events in DM patients can be reduced by:

  1. Intensive glycemic control using a standard drug regimen, compared with conventional glycemic control.

  2. Intensive glycemic control using an insulin-resistance-lowering drug regimen compared with conventional glycemic control.

  3. Intensive glycemic control using an insulin-resistance-lowering drug regimen, compared with intensive glycemic control using a standard drug regimen.

  4. Intensive levels of lipid and blood pressure control compared with standard levels of lipid and blood pressure control.


  1. Background and Rationale

    1. Introduction

      Diabetes mellitus is a common disorder which is frequently misunderstood and often not treated optimally. Although usually thought of in terms of the acute symptoms and long term consequences associated with elevated glucose levels, diabetes is a complex metabolic disorder with abnormalities in carbohydrate, lipid, and protein metabolism. Declines in CVD mortality in this country in the past 30 years have been smaller among diabetics than among non-diabetics. Most diabetic patients die of cardiovascular disease (CVD), with CVD rates in diabetics two to four times those of the non-diabetic population. This increased CVD risk, along with the increasing prevalence of obesity and increasing numbers of elderly and minorities in the U.S. population, means that diabetes-associated CVD will become an even greater public health problem in the future.

      Diabetes can increase the risk of CVD in several ways, including the effects of elevated blood sugar (e.g., acute alterations in blood lipids and coagulation factors, protein glycosylation causing damage to the kidneys and secondary hypertension, direct toxic effects on the vasculature potentiating the development of atherosclerosis), the combination of hyperglycemia with other CVD risk factors to exacerbate the risk for a given profile of non-glucose CVD risk factors, and the worsening of multiple other CVD risk factors levels (insulin resistance syndrome). Due to these complex co-morbid conditions, control of hyperglycemia, although important, may not be sufficient to substantially reduce morbidity and mortality.

      Diabetes is not a single disease and although common forms of diabetes are associated with an increased risk of CVD, the type of diabetes may have implications for the approach to preventing its cardiovascular complications. Current recommendations for CVD prevention generally apply to both Type 1 and Type 2 diabetes. In the U.S., approximately 10 percent of diabetic patients have Type 1 diabetes (previously called insulin dependent diabetes or IDDM) while approximately 90 percent have Type 2 diabetes (previously called non-insulin dependent diabetes or NIDDM). The optimal treatment for the young, Type 1 diabetic patient with severe, labile hyperglycemia may not be the best treatment for the older, Type 2 diabetic with mild, stable glucose elevations. Type 1 diabetes is an immunologic disease characterized by severe insulin deficiency, and restoration of normal glucose levels by intensive insulin therapy may be more successful in reducing risk of all chronic complications of this disorder. Type 2 diabetes, a complex disease with generally elevated levels of insulin resistance and variable levels of circulating insulin, is often accompanied by multiple other CVD risk factor abnormalities. While glucose control also appears important for Type 2 patients, it is critical not to overlook treatment of other associated CVD risk factor abnormalities. For prevention of cardiovascular complications, control of these other risk factors may have a greater effect than glucose control. Nevertheless, several recent studies indicate that in clinical practice, neither hyperglycemia nor other CVD risk factors are adequately controlled in patients with diabetes {Savage 1998}.

    2. Hyperglycemia:

      For decades, the value of "tight control" of glucose levels was debated. The Diabetes Control and Complications Trial provided unequivocal evidence of major reductions in the chronic microvascular complications (nephropathy, retinopathy, and neuropathy) among a group of Type 1 diabetic patients where intensive therapy maintained glucose at near normal levels over a six-year period (mean attained glycosylated hemoglobin [HbA1C] slightly over 7%, compared with about 9% in controls) {DCCT Research Group, 1993}. While a comparable study has not been done in Type 2 patients, there is observational evidence that these microvascular benefits of normalizing glucose will apply to all diabetics {Klein, 1995}. It is less certain, however, that these benefits can be extrapolated to predict reduction in the chronic macrovascular complications of diabetes. The results of the University Group Diabetes Program (UGDP) in the 1960s suggested that treatment of Type 2 diabetes with tolbutamide (a sulfonylurea) may increase the rate of clinical CVD events compared with placebo {UGDP, 1970}. That study and its results remain controversial, but do cast doubt on the macrovascular benefits of standard drug therapy for diabetes. The recent Veterans Affairs Diabetes Feasibility Trial showed a trend towards greater risk of a cardiovascular event in the intensive glycemic treatment arm (mean HgbA1C = 7.1%) than in the standard treatment arm (mean HgbA1C = 9.2%), and lower attained HgbA1C level was an independent predictor of cardiovascular events {Abraira, 1997}.

      While the microvascular complications are essentially unique to diabetes, the macrovascular complications are largely associated with accelerated atherosclerosis, another complex disorder with multiple causes. For macrovascular disease, hyperglycemia or some associated metabolic abnormality may have different effects depending upon the patient's underlying predisposition to CVD. This variable susceptibility may explain why rates of macrovascular complications are more variable than those of microvascular complications among diabetic populations around the world.

      A recent review summarizes the metabolic abnormalities of Type 2 diabetes and discusses currently available treatment strategies. Appropriate diet and exercise are the foundation of all therapy for diabetes. New drugs such as metformin and troglitazone may permit a higher percentage of diabetics to attain good glucose control without undue risk of hypoglycemic episodes. {Dagogo-Jack and Santiago 1997}

      Some questions about the benefit of glucose control in Type 2 diabetic patients may be resolved soon. Results of the U.K. Prospective Diabetes Study are scheduled to be released in 1998 {UKPDS 1991}. With an average 11-year follow-up of newly diagnosed Type 2 diabetic patients randomized to different combinations of sulfonylureas, metformin, and insulin, this study will add important information to current knowledge. However, it is not clear whether the separation in HbA1c levels between control and intervention groups achieved in that study is adequate to definitively test the hypothesis that intensive glucose control can reduce the incidence of macrovascular disease. Also, that study is not examining the benefit of lowering glucose using drugs that lower with regard to insulin resistance.

    3. Hyperinsulinemia and Insulin Resistance

      Elevations in circulating insulin level have been associated with an increased risk of CVD in some but not all studies. A direct causal role of insulin has been questioned due to the inconsistency of evidence from population studies. In recent years it has become more common to ascribe the primary defect to an increase in resistance to insulin action. A recent study has shown an association of insulin resistance with carotid atherosclerosis {Bonora 1997}. Dyslipidemia, blood pressure elevations, and abnormalities in hemostasis have been associated with this state and a common cause has been postulated (Syndrome X, multiple CVD risk factor syndrome, insulin resistance syndrome). Clarification of the importance of hyperinsulinemia and insulin resistance is important for several reasons including: 1) if hyperinsulinemia stimulates progression of atherosclerosis, the intensive therapy needed to achieve glucose control in many patients could increase the risk of CVD; and 2) if elevated insulin resistance is a primary cause of multiple CVD risk factor abnormalities, treatment of this defect might be a simpler way to reduce CVD risk.

      Recently, a new class of drugs that reduce insulin resistance, the thiazolidinediones, has opened new approaches to the treatment of diabetes {Johnson 1998}. Troglitazone, the only drug of this class approved for use in the U.S., could be a potent new tool for improving diabetes management. In addition to reducing insulin resistance and its accompanying hyperinsulinemia, it has variable effects on other CVD risk factors associated with Syndrome X. However, isolated reports have appeared of severe liver toxicity associated with its use, and the drug has been removed from the market in Europe. It remains to be determined whether this problem will prove sufficient to limit the usefulness of this agent. Newer drugs in the same class are expected to be approved within the next two years, and they may have less of a problem with liver toxicity.

    4. Hypertension

      A subgroup analysis of diabetics in the Systolic Hypertension in the Elderly Program (SHEP) showed a similar relative benefit for CVD events of treatment in diabetics and non-diabetics {Curb 1996}. The revised guidelines for the treatment of hypertension by the Joint National Committee (JNC VI) recommend that blood pressure in diabetic patients be treated to a goal of 130/85 mm Hg, a level lower than previously advocated. This level, however, is not based on clinical trial data, and the level of blood pressure needed for maximal prevention of CVD is still unresolved. Diabetics (N approx.=1500) included in the Hypertension Optimal Treatment (HOT) trial showed a 51% reduction in major cardiovascular events in the DBP target group <80 mm Hg compared with the DBP target group <90 mm Hg, but this was a post hoc analysis and the number of events was relatively small {Hansson, 1998}. Some clarification of this issue may be provided by the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, which is designed to compare the effects of intensive with moderate blood pressure control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease and neuropathy in Type 2 diabetes {Schrier 1996}. The ALLHAT study includes approximately 15,000 diabetics, and although it is primarily designed to compare different types of anti-hypertensive drugs, it may provide data on the benefit of different levels of blood pressure control in diabetics. None of these trials or others in progress, however, will provide data on the marginal effect on CVD morbidity and mortality of blood pressure-lowering on top of intensive glycemic control or vice versa, in diabetics.

    5. Dyslipidemia

      Elevated triglycerides and reduced high density lipoprotein cholesterol (HDL-C) levels are the characteristic lipid abnormalities of diabetes. While levels of these lipids are generally correlated with the level of fasting hyperglycemia, control of hyperglycemia does not generally lead to their complete normalization. Current recommendations for treatment of lipid levels in diabetic patients concentrate on reduction of LDL-C to levels recommended for those with additional CVD risk factors (< 130 mg/dl). Some experts favor lowering LDL-C to levels recommended for those with existing CHD (< 100 mg/dl); the rationale is that diabetic patients are a high risk population most likely to benefit from aggressive cholesterol lowering.

      A recent subgroup analysis of data from diabetic patients in the Simvastatin Survival Study (4S) found a reduction in coronary heart disease (CHD) events and suggested that the absolute clinical benefits achieved by cholesterol-lowering in this group may be greater in diabetic than in nondiabetic persons with CHD {Pyorala 1997}. Although there is increasing evidence that cholesterol-lowering is beneficial for diabetic patients, the benefits of more aggressive lowering of cholesterol levels and the optimal target levels remain to be quantified in clinical trials. Large trials are currently underway investigating the effect of statins, fibric-acid derivatives (fibrates, another class of lipid-modifying agents), or a combination of the two on CHD risk in diabetic populations. One of these is the ALLHAT lipid component, which is comparing pravastatin with usual care in persons with an LDL between 130 and 185 mg/dl (between 100 and 129 if CHD is present), and includes about 3,500 diabetics. None of these trials, however, is designed to answer the question of optimal target levels nor the marginal benefit of lipid-lowering on top of intensive glycemic control or vice versa.

    6. Conclusions of Recent Expert Panels

      The report of the Macrovascular Disease Subcommittee of the NIH-sponsored diabetes conference in September 1997 notes that "about 50 percent of excess heart disease in diabetics can be attributed to associated abnormalities in other known CVD risk factors" and that "the same risk factors that predict large vessel disease (i.e. stroke, heart attack and peripheral arterial disease) in the general population also affect the diabetic." This panel "enthusiastically recommended a large scale clinical trial to determine whether the level of glucose control and altering levels of insulin and insulin resistance will decrease the incidence of CHD in a diabetic population." A trial comparing the cost effectiveness of different therapeutic approaches (such as contrasting optimal glucose control with aggressive lipid lowering) was advocated by some members of the panel. The panel also emphasized the importance of selecting diabetics at particularly high risk for developing CVD for inclusion in clinical trials, using such markers as microalbuminuria or carotid artery wall thickness by ultrasound.

      Similar conclusions were reached by the NHLBI Special Emphasis Panel on Prevention and Treatment of Cardiovascular Disease in Diabetes Mellitus in September 1997. Notably, however, a number of panel members recommended testing not only the relative benefit of different diabetic regimens, but also different target levels or intensities of treatment for lipids or blood pressure, using a factorial design. The rational for such a design is that although a number of studies in progress are collectively addressing treatment of lipids, blood pressure or glycemic control in diabetics, none of them will shed light on the comparative benefit of treating hyperglycemia and aggressively treating blood pressure and lipids.

      Additional support for a large clinical trial testing the benefit of tight glycemic, lipid, and blood pressure control as well as insulin resistance lowering therapy was given by an ad hoc advisory group convened by NHLBI in May 1998.

  2. Design of Proposed Initiative

    1. General study design

      The proposed study is a 3-by-2 factorial randomized clinical trial in patients aged 55-75 years with previously diagnosed Type 2 diabetes mellitus. A total sample size of 10,000 is estimated to enable adequate power to test the primary hypotheses (see OBJECTIVES), given an average follow-up time of 5 years. Some marker(s) for subclinical macrovascular disease or other risk factor(s) will be used as selection criteria in younger patients in order to recruit a study population with a composite annual event rate of 4 to 5%; candidates include ankle-brachial index (ABI), microalbuminuria, and carotid intimal-medial wall thickness. The sample size calculation was based on selection by ABI.

      The clinical trial will compare 3 different diabetic treatment approaches, and it will also compare the current recommended treatment for blood pressure and lipids for non-diabetic patients with a more aggressive approach to treating these risk factors.

      The diabetic treatment goals are to compare conventional (CD) with intensive glycemic control using either standard drug therapy (CS) or insulin resistance-lowering or -neutral therapy (CRL), as well as to compare CS with CRL. The 3 diabetic treatment arms will be: 1) conventional glucose control starting with agents that do not work by reducing insulin resistance (e.g., sulfonylureas, insulin); 2) intensive glucose control starting with agents that do not work by reducing insulin resistance; and 3) intensive glucose control starting with agents that reduce or do not affect insulin resistance (e.g., thiazolidinediones, biguanides, and acarbose). A difference in attained HgbA1C of 1.5-2.0% between conventional and intensive glucose control arms is needed to test the hypothesis that intensive control reduces CVD risk. One approach would be to have a target hemoglobin A1C (HgbA1C) level in the range of 8.0 to 8.5% for the CD arm and a range of 6.0 to 6.5% for CS and CRL.

      The target levels for the two blood pressure/lipid treatment arms might be defined as (1) conventional (LDL < 130 if no clinical CHD and < 100 if CHD; SBP < 130); and (2) intensive treatment (LDL < 100 if no clinical CHD and < 75 if CHD; SBP < 120).

      Standard advice regarding diet and physical activity appropriate for diabetics will be provided to all patients.

      The main outcome measure will be a combination of CVD mortality and major morbidity, including MI (clinical and "silent"), stroke, and CVD death.

      The first year of recruitment and follow up will constitute an internal pilot study or vanguard phase, the results of which would determine whether the study will proceed as planned. If a decision is made to proceed with the remainder of the study, the patients already recruited and any endpoint events will be included in the main study. Criteria for deciding whether to proceed would include the success of patient recruitment and the ability to meet treatment targets and obtain separation of the arms.

      Diabetes treatment
      Conventional glucose
      control starting with
      non-insulin resistance
      reducing drugs
      Intensive glucose
      control starting with
      non-insulin resistance
      reducing drugs
      Intensive glucose
      control starting with
      insulin resistance
      reducing drugs
      Pressure Treatment
      Treatment to achieve
      current recommended
      levels (CLB)
      Cell #1 Cell #2 Cell #3
      Treatment to achieve
      more aggressive
      target levels (TLB)
      Cell #4 Cell #5 Cell #6

    2. Inclusion/Exclusion criteria

      The definition of Type 2 diabetes mellitus for purposes of determining eligibility for this study will follow the new American Diabetes Association guidelines (an FPG level >126 mg/dl (7.0 mmol/l) or a 2-h postload value in the OGTT >200 mg/dl, with confirmation by retesting). It is expected that only previously diagnosed diabetics will be included. Persons already on insulin will be excluded because the use of insulin will hamper the study's ability to test the benefit of reducing insulin resistance in the CRL arm. In making sample size estimates for this initiative it was assumed that such persons would be excluded.

      Persons with chronic conditions that would seriously hamper their full participation in the trial for the full follow-up period would be excluded. The age range is assumed to be 55-75 years. The inclusion of younger patients would lower the expected event rates and raise the required sample size, while the oldest patients (over 75 or 80 years) may have more problems with lactic acidosis from biguanides and hypoglycemic complications resulting from intensive glucose lowering. The sample size calculations are based on persons aged 55-75 years. Evidence of subclinical atherosclerosis, and/or other relatively prevalent risk indicators in the presence of which CVD risk is at least doubled, will be used to determine eligibility in order to increase the expected event rates and reduce the required sample size. Patients will need to have blood pressure or LDL-cholesterol above specified levels, at least above the target levels for the intensive blood pressure and lipid treatment arm. Measurements will include blood pressure, HgbA1C, lipids, microalbuminuria, tests to monitor drug side effects (e.g., liver enzymes, potassium), creatinine, blood urea nitrogen, and white blood cells for storage for genetic analyses. The details of the specific eligibility criteria and measurements will be finalized by the investigators during protocol development.

    3. Study organization

      The major organizational components that are traditionally part of a large trial are expected to be part of the structure of this trial: there will be a Data Coordinating Center, a Steering Committee and an NHLBI appointed Data and Safety Monitoring Board. However, the organization of clinical sites may be one of two different models or a hybrid. In one model, six to eight clinical networks, each with a clinical coordinating center, would be identified based on demonstrated scientific leadership, ability to recruit large numbers of diabetic patients, and ability to coordinate activities at other sites. There would be four to six satellite sites subcontracted by each clinical network coordinating center for the express purpose of conducting this trial, with a total for the trial of 40-50 clinical sites. Each clinical site would be expected to recruit a minimum of 200 patients. An alternative model would involve health care institutions able to recruit large numbers of patients, such as HMOs with multiple clinical sites and a readily identifiable pool of eligible participants from their own patient populations. In the latter case, the network (coordinating center and clinical sites) would be part of the same organization, utilizing the already existing coordination structure. A vanguard phase will start with all of the networks in place but a smaller number of clinical sites; additional sites will be added later if the study proceeds further. Skilled diabetes nurses and/or physician assistants or nurse practitioners are expected to be critical to the operation of the clinical sites, with assistance from technicians.

      To facilitate protocol development and study management, given the large study population size and need for a large number of clinical sites, a planning committee of 10-15 persons will be selected, including the study chairperson, network coordinating center and data coordinating center principal investigators, and NHLBI project office staff.

  3. Expected event rates and study power

    For 10,000 persons with NIDDM aged 55 - 75 years, an ankle-brachial index (ABI) below 0.95 or the lowest age-specific quintile for those aged 55 - 65 years, and assuming one half of the persons are aged 65-75 years, in an average of 5 years of follow-up we would expect about 2,000 persons to have a major cardiovascular event, defined as an MI, stroke, or fatal event attributed to CVD. This number of events would be adequate, assuming no interactions and applying a two-sided alpha level of 0.0167 (to adjust for multiple comparisons because of the two glycemic intervention groups), to detect a 20% reduction in event rate in either of the glycemic intervention groups compared with the glycemic control group or a 20% rate difference between the two glycemic intervention groups, with 90% power. This assumes, conservatively, a 30% effect of intensive blood pressure- and lipid-lowering, since the greater this effect the lower the CVD rate in the glycemic control arm (CD in above schemata).

    To detect a 20% reduction in event rate in the blood pressure/lipid (BP/L) intensive intervention group compared with the control group, this number of patients would provide greater than 99% power, at a two-sided alpha level of 0.05.

  4. Feasibility

    It is expected that the clinical sites will recruit and retain approximately two to three hundred or more persons with DM meeting inclusion and exclusion criteria. Enrollment of an average of seven patients per month, in each of the clinical sites, during the time allowed for patient recruitment in this project is highly feasible.

    Another key feasibility issue is the ability to achieve a sufficient separation in HgbA1C between glycemic treatment and control groups. The feasibility trial of the VA Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM) demonstrated that a 2 percentage points lower HgbA1C could be achieved and maintained over one year in the intensive glycemic treatment group compared with the control group (about 7% vs. 9%), with very few episodes of severe hypoglycemia, using insulin as needed.

    A third feasibility issue is cost. It is anticipated that donations of medications will be obtained from the private sector. It is also presumed that NHLBI financial support will not include the "usual cost" of medical care for a comparable population of diabetic patients.

  5. Schedule of main study activities

    A schedule of main activities for the proposed study follows.

    Time Period Main Activities
    September 30, 1999 - May 31, 2000 Protocol development
    Begin pilot testing of forms and procedure
    June 1, 2000 - September 30, 2000 Complete pilot testing of forms
    October 1, 2000 - September 30, 2001 Patient recruitment and follow-up
    Vanguard Phase
    October 1, 2001 - September 30, 2003 Patient recruitment and follow-up, after
    review by DSMB with recommendations to
    the Institute to proceed
    October 1, 2003 - September 30, 2007 Patient follow-up (4 - 6 years, with a mean
    follow-up of 5 years)
    October 1, 2007 - September 30, 2008 Data clean-up
    Data analysis and publication


    The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2000, a PHS-led national activity for setting priority areas. This RFP is related to the priority areas of "Heart Disease and Stroke" and "Diabetes and Chronic Disabling Diseases".


    The ALLHAT Study is testing the effect of different blood pressure agents on CVD event rates in about 40,000 adult patients across the U.S., including about 15,000 diabetics (36%). It does not compare intensive and conventional blood pressure and lipid lowering, and it does not compare different types of glucose lowering therapy.


    It is anticipated that awards will be made to up to eight Clinical Networks and one Data Coordinating Center. The total cost for funding eight network centers that will comprise a total of 50 clinical sites, in addition to a data coordinating center with three subcontracts (an ECG reading center, a core laboratory and a drug distribution center), for a duration of nine years, will be approximately $107.6 million. Open competition for the nine awards will be implemented in fiscal year 1999. The NHLBI estimates yearly total study costs as follows (in thousands):

    FY 99: $3,569 FY 04: $14,096
    FY 00: $12,245 FY 05: $14,481
    FY 01: $18,727 FY 06: $11,546
    FY 02: $16,686 FY 07: $2,641
    FY 03: $13,682


  1. Project Origin and Approval Status

    This project originated in the Clinical Applications and Prevention Program, Division of Epidemiology and Clinical Applications, NHLBI. It stems from the recommendations of the Macrovascular Disease Subcommittee of an NIH-sponsored diabetes conference and the NHLBI Special Emphasis Panel on Prevention and Treatment of Cardiovascular Disease in Diabetes Mellitus, both held in September 1997, and an Ad Hoc Advisory Group for the NHLBI/DECA diabetes initiative held in May 1998. It is also responsive to diabetes as a trans-NIH priority.

  2. Method of Review

    Proposals from individual institutions will be reviewed by institutional review boards at the applying institutions. An ad hoc primary review group, selected based on the known expertise of the reviewers in their respective fields, will be convened by NHLBI. Relevant expertise will be required in clinical diabetology, lipidology, hypertension, clinical trial design, biostatistics, and possibly subclinical atherosclerosis. Proposals deemed to be in the competitive range will be evaluated by a secondary review group composed of relevant NHLBI staff, who will conduct negotiations and select the final proposals to be awarded.

  3. Management Plan
    Division: Division of Epidemiology and Clinical Applications
    Division Program: Clinical Applications and Prevention Program
    Scientific Research Group: Prevention Scientific Research Group

  4. Proposed Schedule
    Submission to Council: September, 1998
    Release of RFP: November, 1998
    Letters of Intent: January, 1999
    Receipt Date for Proposals: March, 1999
    Initial Technical Review: June, 1999
    Secondary Review: July, 1999
    Awards: September, 1999


Abraira C et al: Cardiovascular events and correlates in the veterans affairs Feasibility trial: Veteran Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Intern Med. 1997;157:181-188

Bonora E et al: Intimal-medial thickness of the carotid artery in nondiabetic and NIDDM patients. Relationship with insulin resistance. Diabetes Care 1997;20:627-31

Curb JD et al: Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 1996;276:1886-92

Dagogo-Jack S and Santiago JV: Pathophysiology of type II diabetes and modes of action of therapeutic interventions. Arch Intern Med. 1997;157:1802-1817

DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86

Donahue RP and Orchard TJ: Diabetes mellitus and macrovascular complications. An epidemiological perspective. Diabetes Care 1992;15:1141-55

Hansson L et al: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998;351:1755-62

Johnson MD et al: Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Ann Pharmacother 1998;32:337-48

Klein R: Hyperglycemia and microvascular disease in diabetes. Diabetes Care 1995;18,2:258-68

National Diabetes Data Group: Diabetes in America, 2nd Edition. NIH Publication No. 95-1468; 1995

Pyorala K et al: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614-20

Savage PJ: Treatment of diabetes mellitus to reduce its chronic cardiovascular complications. Curr Opin Cardiol 199;13:131-8

Schrier RW et al: Appropriate Blood Pressure Control in NIDDM (ABCD) Trial. Diabetologia 1996;39:1646-54

UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia 1991;34:877-90

University Group Diabetes Research Group: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: II Mortality results. Diabetes 1970; 19(suppl 2):785-830

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