Diabetes and Cardiovascular Disease: Quantitative Aspects

An association between overt diabetes and cardiovascular disease has been observed in many studies [2-4]. In the developed world, the risk for cardiovascular disease is increased two- to fourfold among diabetic patients compared with nondiabetic persons within their corresponding population. Among persons with NIDDM in the United States, up to 75% of deaths are attributed to ischemic heart disease or other heart and vascular disease [5]. Although the cardiovascular disease mortality rate has recently decreased in diabetic persons as well as in normoglycemic persons, a higher risk for cardiovascular disease remains a major problem for diabetic patients [6].

The association between milder degrees of glucose intolerance (impaired glucose tolerance and mild diabetes with normal or near-normal fasting glucose concentrations) and cardiovascular disease is less established. Several studies suggest a relatively continuous gradient of increasing risk as glucose tolerance decreases [4, 7]. In contrast, a review of several other studies found a small and inconsistent effect of mild hyperglycemia on cardiovascular disease risk, especially after adjustment for other known cardiovascular disease risk factors [8]. Patients with mild glucose tolerance abnormalities are important because they comprise more than half of those with abnormal glucose tolerance in the U.S. population. In this group, higher risk for cardiovascular disease may be the major adverse effect of hyperglycemia.

There are several reasons macrovascular complications of diabetes are increasing in importance. Diabetes is most common among the elderly, and the number of elderly men and women is increasing rapidly in the United States [9]. Diabetes is associated with a greater relative risk for cardiovascular disease among women than among men, and women make up most of the elderly population. Diabetes is more common in many minority populations, groups whose numbers are increasing rapidly in the United States. Although rates of heart disease vary among diabetic patients from different populations, the relative increase over nondiabetic persons persists. Finally, success in reducing microvascular complications of diabetes will increase the number of persons at risk for macrovascular complications of diabetes.

Several cardiovascular complications have been associated with diabetes. These include increases in both incidence of and patient fatality rates from acute myocardial infarction [2, 4], mortality in the months after discharge from the hospital for acute myocardial infarction [10], unexplained chronic congestive heart failure [11], cerebrovascular disease [12], and peripheral vascular disease [13].

The higher risk for macrovascular disease is shown by findings in two large, longitudinal studies. The Honolulu Heart Study, a prospective study of cardiovascular disease and its risk factors in Japanese-American men, assessed the 12-year risk for fatal and total coronary heart disease in relation to post-challenge glucose levels in 6394 men initially free from known cardiovascular disease, diabetes, and treated hypertension [4] (Table 1). A significant and progressive increase in risk was seen as glucose levels increased, suggesting that even mild, asymptomatic abnormalities in glucose tolerance are important. A more recent report from the Multiple Risk Factor Intervention Trial (MRFIT) examined 12-year mortality in relation to reported history of diabetes in 347000 men [14] (Table 2). The relative risks for total cardiovascular disease, coronary heart disease, stroke, other cardiovascular disease, and all-cause mortality were increased two-to threefold in diabetic patients, even after adjustment for several other known cardiovascular disease risk factors.

The Hypotheses: Causes of the Higher Risk for Cardiovascular Disease in Diabetic Patients

Current evidence suggests there are several reasons for the higher incidence of macrovascular disease found in patients with NIDDM [15]. Both the degree and duration of hyperglycemia may contribute directly to macrovascular complications, although this theory is controversial [16]. In the patient with NIDDM, the likelihood increases that other cardiovascular disease risk factors will be abnormal, and some studies have documented that these abnormalities may precede the development of hyperglycemia [17]. Hyperglycemia may also increase the atherogenicity of other known cardiovascular disease risk factors. Small, dense low-density lipoprotein particles that undergo glycosylation have an enhanced susceptibility to oxidation [18]. Given the complex relations among these factors, it is unsurprising that several discrete interventions tailored to the metabolic profile of each diabetic patient may be necessary to achieve optimal protection against cardiovascular complications.

The importance of normalizing blood glucose levels to prevent complications of diabetes was debated for decades. The recent findings of the Diabetes Control and Complications Trial (DCCT) have established that microvascular complications can be dramatically reduced by intensive glucose control in patients with insulin-dependent diabetes (IDDM) [19]. Little reason exists to doubt that similar benefits will occur in patients with NIDDM. The DCCT, however, did not establish that the macrovascular complications of diabetes, the major cause of death in older diabetic patients, can be reduced by glucose control.

Many questions about the relation of hyperglycemia to risk for cardiovascular disease are unanswered. Early studies of hyperglycemia as a risk factor for cardiovascular disease and of its associations with other cardiovascular disease risk factors used techniques of risk factor and disease measurement that are crude by current standards. In most studies focused on diabetes, measures of vascular disease and cardiovascular disease risk factors were limited. In most studies focused on cardiovascular disease and its risk factors, definitions of diabetes were imprecise or inadequate numbers of diabetic patients were identified for detailed study. In several clinical trials, diabetic patients were either excluded or their numbers were too limited to permit separate analysis. In addition, although other risk factors such as blood pressure and lipid levels were carefully measured, diabetes was often included as a categorical variable, eliminating the ability to assess the cardiovascular disease risk across the spectrum from asymptomatic diabetes to marked fasting hyperglycemia. Lack of quantifying the degree and duration of hyperglycemia precluded studies of whether the rate of progression of macrovascular disease differs at different stages in the development of diabetes. As a result, critical information for developing prevention programs is missing.

Factors other than hyperglycemia appear to explain part of the higher risk for cardiovascular disease in diabetic patients. Abnormalities in several other known cardiovascular disease risk factors are commonly found in association with NIDDM, in part related to the common occurrence of obesity in patients with NIDDM. Diabetes is often associated with elevated blood pressure. Dyslipidemia, especially hypertriglyceridemia and low levels of high-density lipoprotein cholesterol, is common. Several hemostatic abnormalities involving levels of coagulation factors, platelet dysfunction, and increased blood viscosity have been described. This clustering of blood pressure, lipid, and hemostatic abnormalities occurs more frequently than would be expected given the prevalence of other risk factors in the population. This multiple metabolic risk factor syndrome (syndrome X [20]) is associated with hyperinsulinemia and diminished tissue sensitivity to insulin. It is rare in patients with IDDM. Components may differ among patients with NIDDM who are from distinct racial or ethnic groups.

Clinical Trials: What We Know and What We Need To Know

To assess the need for a clinical trial of cardiovascular disease prevention in diabetic patients, several questions unique to diabetic patients were identified. A key question is whether hyperglycemia is the primary risk factor for macrovascular disease and whether alleviating this condition will reduce the risk for cardiovascular disease. Because all agree that diabetic patients with hypertension should be treated, the major remaining questions in this area focus on whether standard treatment goals are adequate or whether additional lowering of blood pressure is beneficial and whether some antihypertensive agents have protective effects in addition to the benefits achieved by lowering blood pressure.

Similar questions can be asked about diabetic dyslipidemia. New agents raise the promise of alleviating multiple risk factor abnormalities by increasing insulin sensitivity, although the benefit of this approach in contrast to specific treatment of the abnormal risk factor is not yet known [21]. The benefits of correcting the coagulation factor abnormalities such as elevated levels of fibrinogen or plasminogen activator inhibitor-1 (PAI-1) are unknown. A recent analysis of results from trials of antiplatelet agents found that the benefits of antiplatelet therapy in diabetic patients were similar to those in nondiabetic patients [22]. Smoking should be strongly discouraged. Finally, it is unclear whether the same approach will be equally successful in patients with IDDM and those with NIDDM. For example, intensive insulin therapy may be effective in patients with IDDM but could stimulate weight gain and worsen other cardiovascular disease risk factors in patients with NIDDM, especially among those with the multiple risk factor syndrome.

Several observations suggest that intensive control of hyperglycemia may not be sufficient to reduce cardiovascular risk to nondiabetic levels. In the University Group Diabetes Program, no clear benefit on cardiovascular disease rates was seen despite significantly better glucose level control in the group treated with variable insulin doses [23]. Despite therapeutic advances, achieving this level of control in the general population with NIDDM will still be difficult. More limited current data are conflicting. In the DCCT, a borderline benefit of intensive glucose control was seen in the reduction of total cardiovascular disease over 6 years (P = 0.07) [19]. However, because this study included only young patients, it was not designed to assess cardiovascular complications. In contrast, a recent pilot study of the Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM (see "The Feasibility of Intensive Insulin Management in NIDDM: Implications of the Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM") on cardiovascular disease prevention in patients with NIDDM found a higher incidence of cardiovascular disease events over a 2-year period in the group receiving intensive glucose control therapy compared with rates in the group receiving standard glucose control therapy [24]. In both studies, the number of cardiovascular events was small, and neither study provided definitive information on this issue. Longer observation in high-risk diabetic patients is necessary. These observations do suggest, however, that the most appropriate therapy for reducing cardiovascular complications is less established than it is for microvascular complications. In support of the multiple risk factor intervention approach, a review of data from the Tecumseh, Michigan, community study [25] suggested that currently feasible control of nonglucose risk factors in diabetic patients could reduce projected cardiovascular disease rates by more than 50%.

Two major clinical trials now under way will answer some, but not all, of these questions. The United Kingdom Prospective Diabetes Study [26], a trial of glucose and blood pressure control in patients with recent onset of NIDDM, should provide important information before the end of the decade. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a comparison of several antihypertensive drugs in high-risk hypertensive patients, includes several thousand diabetic patients and will provide information on the type of antihypertensive agent most beneficial to these patients.

Even once this information is available, additional factors must be considered. In a time of great concern about medical care expenses, the relative efficacy, relative cost, and patient burden of different interventions must be considered in developing a cardiovascular disease reduction program that will be effective for most diabetic patients. A recent survey pointed out that more than 70% of visits to physicians for diabetes are to general internists, general practitioners, or family practice specialists [27]. In addition, the average diabetic patient sees a physician for less than 1 hour per year. Unless a major expansion occurs in care for diabetic patients, this finding places severe limits on the complexity of any program that can be implemented.

If and when a trial of therapy to reduce cardiovascular complications in diabetic patients is initiated, several options should be considered. An intensive glucose control regimen compared with a standard glucose control arm is highly desirable, although the DCCT results raise questions of whether this is still permissible in patients with IDDM [19]. Given the existing data and the cost of a new trial, it would be a mistake to focus all efforts on glucose control. Standard blood pressure control is necessary for all participants, an intervention that in itself will probably substantially reduce the incidence of cardiovascular disease in diabetic patients. The feasibility and benefits of lowering blood pressure below commonly accepted treatment goals are uncertain. Two major options exist for lipid interventions: lowering of low-density lipoprotein cholesterol levels below those recommended for the nondiabetic population (< 2.59 mmol/L) or attempting to correct the diabetic dyslipidemia of hypertriglyceridemia and low high-density lipoprotein cholesterol levels. The latter, while more specifically related to the metabolic abnormalities of diabetes, is more difficult to achieve. Ideally, sufficient numbers of patients with IDDM and NIDDM would be included to distinguish different effects of treatment on the two major types of diabetes. The possibility of different effects in diabetic participants of various minorities should also be considered.

Given the complexity of such a trial and the large amount of existing data on risk factor interventions in nondiabetic patients, a study with an intermediate end point such as progression of carotid atherosclerosis should be considered. This design would be substantially less expensive but would potentially miss adverse effects related to accelerated coagulation.

Conclusions

Diabetic patients have a substantially increased risk for cardiovascular complications, particularly those related to atherosclerosis. The reasons for this increase are less understood than the reasons for cardiovascular disease in patients with hypertension and dyslipidemia. Nevertheless, further understanding of the pathogenesis of the risk is necessary because diabetes will increase in importance as a cardiovascular disease risk factor as the population ages and minority populations increase. Two key questions remain to be answered: Will optimal glucose level control normalize the risk for cardiovascular disease? Is glucose level control the most cost-effective intervention to prevent diabetes-related cardiovascular complications? Neither question can be answered without a new clinical trial. For the present, existing guidelines for control of cardiovascular disease risk factors in diabetic patients should be followed aggressively [28, 29].