DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE NHLBI SPECIAL EMPHASIS PANEL (SEP) ON: PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASE IN DIABETES MELLITUS MINUTES OF MEETING Sept. 19, 1997 PANEL MEMBERS PRESENT: Drs. Robert Frye (chair), Lewis Kuller, Carlos Abraira, Steven Haffner, Curt Furberg, Burton Sobel, Luther Clark, Barbara Howard, George Sopko, Patrick O'Connor, Sanford Garfield MEMBERS OF THE PUBLIC PRESENT: Drs. Katherine Detre, Salim Yusef, Frederick Dunn, David Billheimer FEDERAL EMPLOYEES PRESENT: Drs. Lawrence Friedman (Director, DECA), Peter Savage, Jeffrey Cutler, Dean Follman, Denise Simons-Morton, Eva Obarzanek, Elaine Stone, Lawton Cooper, David Gordon (from NHLBI), Richard Eastman, Maureen Harris, Catherine Cowie (from NIDDK), The meeting of the Special Emphasis Panel on Prevention and Treatment of Cardiovascular Disease in Diabetes Mellitus was convened on September 19, 1997 at 8:00 a.m. at the Rockledge II Building, 6701 Rockledge Dr., Rockledge, MD. In accordance with Public Law 92-463 the meeting was open to the public. Dr. Robert Frye presided as Chair. OPEN MEETING: I. Call to Order Drs. Savage and Sopko called the meeting to order by a brief statement of the purpose of the meeting which was 1) to review current knowledge on factors contributing to the excess of cardiovascular disease associated with diabetes and 2) to recommend future directions for NHLBI research on prevention of cardiovascular complications of diabetes. II. Review of Confidentiality and Conflict of Interest Procedures Dr. Savage reviewed the policies and procedures regarding confidentiality and avoidance of conflict-of-interest situations. The panel members signed the requisite form. III. Discussion of current knowledge, ongoing studies, and research needs This Special Emphasis Panel was convened to evaluate current information on the risk of cardiovascular complications associated with diabetes mellitus and to determine whether NHLBI should initiate clinical trials in this area. The group reviewed the problem of cardiovascular disease (CVD) in diabetic patients and the factors that may account for its variation across populations. They emphasized that much remains unknown about the way diabetes increases the risk for CVD but that several new therapeutic interventions have recently become clinically practical. Major opportunities now exist to reduce the rates of CVD in diabetic patients but the relative efficacy and cost of these interventions is largely unknown. Clinical trials are needed to determine the best methods to reduce diabetes-associated cardiovascular complications. Since this area has been neglected relative to the intensive intervention studies onother major CVD risk factors, the NHLBI was urged to develop a plan for trials in this area. Two major areas were identified as having high priority for new initiatives in the near future 1) a clinical trial to assess the importance of controlling glucose levels in diabetic patients without clinically symptomatic CVD and 2) a clinical trial to compare early surgical intervention with intensive medical management in diabetic patients with symptomatic CVD. Several recommendations were made to optimize study designs which are outlined below. BACKGROUND Most of the excess morbidity and mortality associated with diabetes results from its chronic macrovascular and microvascular complications. Macrovascular complications are the leading cause of morbidity and mortality in diabetic patients. Approximately 50-60 percent of diabetic patients die of cardiovascular diseases, and this appears to be mainly due to an acceleration of atherosclerosis. Although rates of CVD vary in diabetic patients around the world, they have a two to four-fold increased risk of coronary heart disease compared to nondiabetic members of their group and similar increases in rates of other vascular diseases. In general, the increase in risk of CVD is relatively greater in diabetic women than men. CVD rates among diabetic patients from some U.S. minority groups appear higher than those seen in non-Hispanic whites. HYPERGLYCEMIA, INSULIN, INSULIN RESISTANCE The exact role of hyperglycemia in the pathogenesis of macrovascular disease is controversial. It has been more difficult to show a relationship between glucose levels and cardiovascular complications than to show this relationship with microvascular complications. The benefit of improved glucose control on rates of microvascular complications has been conclusively demonstrated in Type 1 (insulin dependent) diabetic patients in the Diabetes Control and Complications Trial (DCCT). In limited studies undertaken to date, no significant benefit of glucose control on macrovascular complications has been demonstrated, raising questions about whether this is because of the suboptimal glucose control in these studies, inadequate differences between the control and intervention groups, the type of hypoglycemic drugs used, or due to indirect effects of hyperglycemia on the pathogenesis of macrovascular complications. In recent years, elevated levels of insulin and/or insulin resistance have been implicated in the pathogenesis of macrovascular disease. This is potentially important since more aggressive insulin therapy is needed to obtain ideal glycemic control. The recent availability of drugs that lower insulin resistance and reduce insulin requirements make it possible to test different approaches to controlling hyperglycemia and the possible role of specific abnormalities in the development of target-organ damage. While it appears that the benefits of glucose control on microvascular complications will be applicable to Type 2 as well as Type 1 diabetic patients, it is less certain that the impact of therapy on macrovascular complications can be extrapolated between these two major types of diabetes. Planning for future studies will also have to take into account improved treatments of other common CVD risk factors in diabetic patients such as blood pressure and dyslipidemia which should lower overall CVD event rates. Moreover, there is no current evidence that strict glucose control in Type 2 patients can be achieved by oral agents alone over a prolonged period of time, raising the problem that a significant percentage of patients will require multiple drug therapy including exogenous insulin over the course a standard clinical trial. However, combination therapy with new oral agents is more effective than single drug therapy and may postpone the need for insulin. DYSLIPIDEMIA Multiple recent studies have demonstrated significant benefits of lipid lowering on cardiovascular event rates and some have included substantial numbers of diabetic patients. While the numbers are still limited, the beneficial impact of treating elevated cholesterol appears at least of the same magnitude, if not larger, for diabetics compared to nondiabetic patients. There are several large ongoing studies sponsored by the pharmaceutical industry evaluating the impact of aggressive lipid lowering on major cardiovascular events which will provide additional data on diabetics. Given existing treatment guidelines and available data, the panel expressed the belief that it would not be ethical to conduct a trial comparing lipid lowering vs. placebo in diabetic patients in the U.S. However, a trial comparing lipid lowering to different targets may be useful since current advice to lower lipids more aggressively in diabetic than in otherwise comparable nondiabetic patients is based upon expert opinion rather than solid data. Treatment of the specific diabetic dyslipidemia, elevated triglycerides and lowered HDL- cholesterol, also needs to be evaluated but the drugs available for this appear to be less effective or have more toxicity so potential benefits are less certain. HYPERTENSION/MICROALBUMINEMIA Concomitant hypertension increases the risk of CVD in patients with diabetes. Risk of CHD increases remarkably once microalbuminuria occurs. In addition to indicating renal disease, microalbuminuria may reflect susceptibility to vascular damage. There are two major unanswered questions about optimal treatment of hypertension in diabetes. The first is whether some classes of antihypertensive drugs have greater benefit in diabetics. A number of antihypertensives were reviewed. ACE inhibitors delay development of microalbuminemia in Type 1 diabetes, however, there are no similar data for Type 2 diabetes. Some of the adverse effects ascribed to calcium channel antagonists may be due to a higher frequency of adverse effects among diabetics. A recent study conducted by NIDDK in hypertensive diabetic patients, comparing nisoldipine (a calcium channel blocker) vs. lisinopril (an ACE inhibitor) was terminated early due to poorer outcomes with nisoldipine. Results from the ALLHAT study should provide important data relevant to this question since approximately 10,000 ALLHAT participants will have diabetes. The second question is whether goals for blood pressure reduction should be lower in diabetic than in nondiabetic patients. Some study of this is currently sponsored by NIDDK. This issue is difficult to address since the magnitude of blood pressure differences attainable within the normal range without side effects is relatively small and a systematic study would require a large sample size. RACE AND GENDER The burden of micro- and macrovascular complications associated with diabetes is greater in several nonwhite minority groups than in the non-Hispanic white U.S. diabetic population. While there is little doubt that rates are elevated, this seems to be more related to the increased prevalence of diabetes and other CVD risk factors in these groups than to differences in the effects of diabetes itself. The contribution of differences in obesity among groups to complications is unclear. Although not universally found, the relative increase in CVD associated with diabetes appears to be greater in women then in men and cardiovascular mortality is higher in women. Risk factor abnormalities are more frequent in women, including alteration in hemostatic factors such as increased levels of fibrinogen. Hormonal replacement therapy appears to provide similar benefit for diabetic and nondiabetic women. There is little reason for more work in this area until results of large, currently ongoing studies are available. If not already collected, however, the Women's Health Initiative should consider measurement of fasting glucose concentrations or some alternate measure of glucose tolerance so that future analyses comparing diabetic and nondiabetic subgroups will be possible. HEMOSTASIS Factors related to increased thrombosis and decreased thrombolysis were reviewed. Experimental data show increased PAI-1 with elevated insulin and proinsulin levels. In Type 2 diabetes, obesity, and other nondiabetic states associated with insulin resistance, PAI-1 antigen and activity are increased. Similarly, in patients with CAD and diabetes increased levels of PAI-1 and decreased levels of uPA were noted. In both experimental and human data, hyperglycemia alone does not appear to increase PAI-1, but hyperinsulinemia, including elevated proinsulin, correlated with elevated PAI-1. These data suggest derangement in fibrinolytic system is closely related to insulin levels which may then contribute to atherosclerosis progression and eventual clinical CVD events. It was suggested that within physiologic levels of insulin, PAI-1 may not play a significant role. Increased fibrinogen is also associated with diabetes. However, it has been proposed that the levels of hyperfibrinogenemia observed in diabetes may be marker for inflammation rather than reflect thrombosis. THE ROLE OF REVASCULARIZATION The risk factors for a clinical CVD event and the most appropriate preventive treatments are not necessarily the same for all diabetic patients. Recent clinical trial data suggest surgical treatment of CHD needs to be modified in the diabetic patient. Nearly 1,000,000 coronary bypass surgeries and angioplasties are performed on CHD patients each year in the United States. Many thousands of these revascularizations involve diabetic patients with vascular disease. The five-year follow-up results of the NHLBI-funded Bypass Angioplasty Revascularization Investigation (BARI) study comparing balloon angioplasty vs. coronary bypass surgery were recently published. An unexpected finding of the BARI was the significantly improved five year survival of diabetic patients with multivessel coronary disease treated with internal mammary-coronary artery bypass grafts (CABG) compared to those treated with percutaneous transluminal coronary angioplasty (PTCA). These studies highlight the need to learn more about the optimal treatments of diabetic patients with advanced atherosclerosis, indicating an area where benefits from clinical trials in nondiabetic patients may not be directly applicable to a diabetic with similar acute ischemia. Although diabetics are known to have a higher mortality compared to non-diabetic patients, these benefits associated with coronary surgery were not previously known or even anticipated. The optimal management of symptomatic coronary artery disease in diabetic patients who don't require urgent surgical intervention represents an important and unresolved clinical question. Aggressive implementation of proven medical therapies may decrease mortality and prevent or substantially delay myocardial infarction. Alternatively, given the exceptionally high risk of this group, early invasive revascularization combined with aggressive medical therapy may result in enhanced long-term survival and fewer cardiac events than an initial strategy of medical therapy alone. Reducing hyperglycemia may have important effects on vascular pathology including rates of restenosis. Evaluation of these approaches requires clinical trials to avoid biases in patient selection commonly seen in clinical data. In addition to evaluating treatment benefits, such studies may lead to a better understanding of mechanisms of accelerated atherosclerosis and restenosis associated with diabetes. With advances in technology, new adjunct procedures and drugs are being developed and tested to accompany percutaneous revascularization. One of these examples is stent placement. Stenting frequently improves short term outcomes of revascularized vessels, including reducing restenosis. However, it is currently unknown whether these new approaches may also improve long-term outcomes, including survival in CHD patients with diabetes. CLINICAL TRIALS The problem of diabetes associated CVD is increasing as the U.S. population ages, becomes more obese, and the percentage of minority citizens increases since diabetes is more frequent in all of these groups. Diabetes is a major CVD risk factor in the elderly ranking second behind elevated blood pressure in the ongoing Cardiovascular Health Study. Far less is known about the cardiovascular benefits of reducing hyperglycemia and other diabetes-associated metabolic alterations (such as hyperinsulinemia, increased insulin resistance, etc.) than is known about the impact of correcting other major CVD risk factors. The number of diabetics in reported clinical trials focusing on cardiovascular interventions is limited and most, if not all, ongoing studies seem to be targeting a particular intervention without attempting to optimize control of other known CVD risk factors. In general, data indicate that diabetic patients behave in a similar manner to nondiabetic patients in response to treatment of dyslipidemia and hypertension. Benefits of aspirin also were similar but were greatest among those at highest risk of a CVD event and aspirin use in primary prevention must be weighed against the increased risk of stroke associated with therapy. Since CVD event rates are increased in diabetic patients, the absolute benefit of a given intervention should be greater in a diabetic group. Because of the strong association of Syndrome X (the insulin resistance syndrome) with Type 2 diabetes, the risk factors most important for cardiovascular complications (and the benefits of their control) may differ somewhat between insulin dependent (Type I) and non-insulin dependent (Type II) diabetic patients. Ongoing studies supported by NIDDK and the Veterans Administration (VA) were reviewed to see if they will answer some of the questions related to macrovascular complications. The DCCT was not designed to assess prevention of macrovascular disease but did show a marginally significant benefit of intensive glucose control on a combined (soft and hard) total CVD end point. The original DCCT cohort is being followed in the Epidemiology of Diabetes Intervention and Complications Study (EDIC) to evaluate the benefit of a sustained period of intensive glucose control on subsequent carotid atherosclerosis. The major relevant study is the ongoing Diabetes Prevention Study designed to prevent Type 2 diabetes (DPT 2), a study of interventions to prevent evolution of Type 2 diabetes from impaired glucose tolerance. This will generate data on CVD in the cohort but the sample size is not sufficient to give solid data on ability to prevent CVD, given the relatively low event rates in patients with mild glucose abnormalities and recent onset diabetes. This study, however, will provide important information on the safety and long term efficacy of Troglitazone, the newly available thiazolidinedione that reduces levels of insulin and insulin resistance. The Veterans Administration recently completed a pilot study of intensive glucose control in a group of long-term Type 2 diabetic patients. While therapy successfully lowered glucose without inducing substantial weight gain, there was no short term reduction in CVD among the intensively treated group. In fact, CVD rates in this group exceeded those of the conventional treatment group. The United Kingdom Prospective Diabetes Study, a twelve year study of the benefits of controlling glucose and blood pressure levels in recent onset Type 2 diabetic patients, is scheduled to report its findings in the fall of 1998 and these results should be considered in the design of future trials. There was unanimous agreement that clinical trials are urgently needed to answer the many questions about the optimal treatments to prevent or postpone cardiovascular complications of diabetes. It was noted that, unlike for hypertension and hypercholesterolemia, there is to date no clear evidence that any of the drugs commonly used to treat hyperglycemia will reduce rates of cardiovascular disease. The recent FDA approval of a new class of drugs (thiazolidinediones) that reduce insulin resistance and hyperinsulinemia provides a new therapeutic approach to improving glucose and several other diabetes-associated metabolic abnormalities which will induce metabolic changes which previously could only be attained by substantial and sustained weight loss. The panel discussed possible designs and priorities for clinical trials, considering type and duration of diabetes as well as associated complications, new therapies for control of glucose and the most appropriate treatment of other established CVD risk factors. They also considered the impact of changing health care economics and organization of health care delivery on attempts to implement improved treatment of a complex disease such as diabetes, with particular emphasis on prevention of its macrovascular complications. Trials should attempt to quantify both the participant burden and the cost of any interventions as well as the clinical outcomes. Overt diabetes differs from other risk factor abnormalities since in addition to hyperglycemia, the diabetic state is associated with adverse changes in several other known CVD risk factors. A strong argument was made that studies to evaluate methods of delivery of care to diabetic patients can go ahead concomit-antly with other studies to evaluate the efficacy of a particular intervention since much needs to be learned about how to optimally deliver treatments we already expect to be beneficial. Lessons learned in developing control programs for other CVD risk factors should be applied to the diabetes-CVD area so that clinical application of new information will not be unnecessarily delayed. Several issues related study design were discussed including standardization of nomenclature and disease classification, use of surrogate CVD endpoints, enhancement of CVD risk in the study group by identification of subclinical disease, need for blinding in glycemic intervention arms, the optimal subgroups of diabetic patients for study, and the type of glycemic control. Current hypoglycemic drugs approved by FDA on basis of control of glycemia may have different long term effects on morbidity or on total or cardiovascular mortality. The panel agreed that two areas of investigation have the highest priority and, since they deal with different questions in different subgroups of the diabetic population, intervention studies could proceed simultaneously: 1. In the area of primary prevention, the primary goal should be testing the safety and efficacy of strict glycemic control in conjunction with aggressive conventional CVD risk factor modification. The target population should have a high risk of incident events. It was suggested that patients be selected with evidence of subclinical vascular disease (diagnosed by low ankle-arm index, wall thickening on carotid ultrasound, etc.) and possibly microalbuminuria. Discussion also centered on the issue of the safety and efficacy of agents classified as "insulin sensitizers" vs. " those classified as "increasing insulin levels". If it is possible to maintain similar major improvement in glucose levels for sustained periods with different pharmacologic approaches, testing the relative benefits would be an important addition to data from any trials undertaken so far. Some members of the panel urged a study design that would enable comparison of the relative benefits of different treatments (treatment of glucose, blood pressure, lipids, possibly coagulation, etc.) to reduce CVD risk in diabetic patients, pointing out that this type of study is unlikely to be undertaken by the pharmaceutical industry. Given established guidelines, this would involve evaluation of standard vs. more aggressive treatment of established risk factors such as cholesterol and blood pressure in addition to the glucose lowering intervention. 2. In the area of secondary prevention the goals would be different. Based on BARI data, early revascularization in diabetics with symptomatic coronary artery disease may provide a significant survival benefit since they may have different risk related to specific treatment strategies compared to nondiabetic patients with CAD. Since recommendations from trials in nondiabetic CVD patients may not be directly extrapolatable to diabetic patients, additional studies are necessary to determine the optimal time and method of coronary intervention in diabetic patients with clinical CVD. The value of aggressive medical therapy, both in lieu of and after surgical intervention on preventing CVD events needs to be determined. One potential design would be to test the benefits on total and cardiovascular mortality of strict glycemic control, in addition to aggressive risk factor modification, and early vs. delayed revascularization. Impact on major cardiovascular events would be also studied. The meeting was adjourned at 3:45 p.m. on September 19, 1997. CERTIFICATION: I certify the foregoing minutes are accurate and complete. ________________ ___________________ ___________________ Robert Frye, M.D. Peter J. Savage, M.D. George Sopko, M.D. Chairman Co-Executive Secretary Co-Executive Secretary Special Emphasis Special Emphasis Special Emphasis Panel Panel Panel