CONSENSUS STATEMENT American Diabetes Association Role of Cardiovascular Risk Factors in Prevention and Treatment of Macrovascular Disease in Diabetes iabetes mellitus is a major risk factor for mor- The conference consisted of 19 invited presentations bidity and mortality due to coronary heart dis- and considerable discussion from a large audience of ease, cerebrovascular disease, and peripheral health-care professionals. A consensus panel with ex- D vascular disease in the United States. The prev- pertise in clinical diabetes, clinical investigation, epi- alence of these macrovascular complications is in- demiology, nutrition, cardiovascular diseases (CVD), creased about two- to fourfold in diabetic populations. and lipid and lipoprotein disorders considered a broad In 1987, these macrovascular complications accounted spectrum of issues concerned with macrovascular dis- for most of the hospitalizations for diabetes and contrib- ease in diabetes. The panel reached a consensus on uted substantially to the 20.4 billion dollars spent for answers to the following questions: diabetes care in the United States. Multiple risk factors for macrovascular disease are fre- 1. The commonly identified risk factors for macro- quently found in individuals with diabetes. There is an vascular disease include hypertension, smoking, increased prevalence of hypertension and lipid abnor- and lipid abnormalities. To what extent do these malities in many populations with diabetes. Many in- risk factors operate in people with diabetes? dividuals with diabetes have not stopped smoking 2. Are cardiovascular risk factors and cardiovascular despite evidence that this is a major cardiovascular risk risk the same in all types of diabetes, and are there factor. There are other factors that may be associated other risk factors of importance to people with di- with macrovascular disease in diabetes, including obe- abetes? sity, impaired glucose tolerance (IGT), hyperglycemia, 3. What is the evidence for the value of modifying hyperinsulinemia, microalbuminuria, elevated fibrino- these risk factors in the general population and in gen levels, altered platelet function, and qualitative li- people with diabetes? poprotein abnormalities. 4. What is the treatment of choice for each risk fac- Primary and secondary intervention trials directed at tor, and are there unique issues that should be cardiovascular risk factors in nondiabetic individuals considered in people with diabetes? have been performed and data are now available. Ad- 5. What additional research is needed in this area? vances have also occurred in nutritional management, exercise programs, behavioral approaches, and phar- macological therapy for diabetes and its major risk fac- QUESTION 1: THE COMMONLY IDENTIFIED RISK tors, and advances have been made in our under- FACTORS FOR MACROVASCULAR DISEASE INCLUDE standing of atherogenesis. These developments led the HYPERTENSION, SMOKING, AND LIPID ABNORMALITIES. American Diabetes Association (ADA) to convene a TO WHAT EXTENT DO THESE RISK FACTORS OPERATE IN consensus development conference, on 10-12 May PEOPLE WITH DIABETES? 1989, on the role of cardiovascular risk factors in the prevention and treatment of macrovascular disease in The prevalence of coronary artery disease, stroke, pe- diabetes. ripheral vascular disease, and total mortality are sub- DIABETES CARE, VOL. 12, NO. 8, SEPTEMBER 1989 573 CONSENSUS STATEMENT stantially increased in diabetic subjects, even in the in a markedly increased incidence of coronary heart absence of hypertension, smoking, and lipid abnormal- disease, CVD, and overall mortality in diabetic patients. ities. Diabetes adversely affects both men and women. This relationship is shown for cardiovascular mortality The risk in female diabetic subjects is similar to the risk in Fig. 1. These risk factors maintain predictive value in in nondiabetic males, and the risk in diabetic males is patients who have already had a cardiovascular event. even greater. In most epidemiological studies the major Cross-population studies suggest that not all diabetic risk factors total serum cholesterol and number of cig- subjects are subject to the same increase in cardiovas- arettes smoked per day are similar, whereas mean sys- cular risk. Pima Indian and Japanese diabetic people tolic and diastolic blood pressures are only slightly have lower CVD than White diabetic subjects. These higher in the diabetic population than nondiabetic pop- differences may be due to genetic or environmental fac- ulation. Available data from the Framingham study and tors. Multiple Risk Factor Intervention Trial (MRFIT) suggest Few data are available to differentiate the effects that these risk factors retain the same adverse impact on of various lipoprotein fractions on CVD risk in dia- the development of macrovascular disease in non-in- betic subjects. In diabetic as in nondiabetic subjects, sulin-dependent diabetes mellitus (NIDDM) subjects as CVD risk is directly proportional to low-density lipopro- in nondiabetic subjects. Currently, there are no compar- tein cholesterol (LDL-chol) and inversely proportional able data in insulin-dependent diabetes mellitus (IDDM) to high-density lipoprotein cholesterol (HDL-chol). subjects. Whereas hypertriglyceridemia is common in NIDDM, it Although the relationship between hypertension, is uncertain at present whether triglycerides have inde- smoking, or lipid abnormalities and cardiovascular risk pendent predictive value for macrovascular disease. are not exaggerated by diabetes, the imposition of these Increases in both systolic and diastolic blood pressure factors-on the increased risk inherent in diabetes results have the same adverse effect on macrovascular disease risk in diabetic and nondiabetic subjects; the risk in- creases linearly with elevations in blood pressure in both groups. Cigarette smoking exerts a detrimental effect on macrovascular disease as well. Although the relative risk of smoking may be slightly greater in nondiabetic sub- jects, the CVD mortality in diabetic subjects is signifi- cantly increased by smoking even less than a pack a day. The three major risk factors appear to be additive in their adverse impact on cardiovascular events in di- abetic subjects. QUESTION 2: ARE CARDIOVASCULAR RISK FACTORS AND CARDIOVASCULAR RISK THE SAME IN ALL TYPES OF DIABETES, AND ARE THERE OTHER RISK FACTORS OF IMPORTANCE TO PEOPLE WITH DIABETES? Whereas hypertension, smoking, and lipid abnormali- ties are undoubtedly contributors to the risk of macro- vascular disease among people with and without diabetes, there are numerous other factors that need to 0 12 3 be considered. Among nondiabetic individuals, uncom- NUMBER OF RISK FACTORS plicated obesity has been established as a risk factor for FIG. 1. Effects of three major risk factors (hypercholes- CVD. This risk factor is of special importance in NIDDM terolemia, smoking, and diastolic hypertension) on age- subjects because 60-85% are obese and cardiovascu- standardized cardiovascular disease mortality in 5245 lar events account for most of the fatalities. It is now diabetic subjects (solid line) and 350,977 nondiabetic sub- recognized that the distribution of adiposity has a sig- jects (broken line) between ages 35 and 57 yr and free of nificant impact on cardiac risks. Hypertension, hyper- myocardial infarction at baseline. Follow-up was in 6 yr. insulinemia, diabetes, elevated very-low-density lipopro- On the abcissa are the number of risk factors present. tein cholesterol (VLDL-chol), and low HDL-chol are Number 1 refers to any one of the three, number 2 refers highly associated with upper-body segment (abdominal) to any two of the three, and number 3 refers to all three. obesity, measured as an increased waist-to-hip ratio. (Data adapted from the Multiple Risk Factor Intervention Trial. J. Stamler, personal communication; and Stamler): In contrast, lower-body segment (femoral and gluteal) Epidemiology, established major risk factors, and the pri- obesity appears to have less impact on these risks. mary prevention of coronary heart disease. In Cardiology. Furthermore, it appears that men are less tolerant to the Parmley W, Chatterjee K, Eds. Philadelphia, PA, Lipincott, impact of obesity than women in the general popula- 1987, p. 1-41.) tion, but there are no data on people with diabetes. 574 DIABETES CARE, VOL. 12, NO. 8, SEPTEMBER 1989 CONSENSUS STATEMENT Whether or not recurring or former obesity is a greater renal disease increases this risk to 12 times that of age- or lesser risk remains to be established. matched nondiabetic control subjects. The reason for The role of obesity in predisposing to macrovascular this inordinate risk is enigmatic. disease is complicated by the tendency for a sedentary life-style in obese subjects. Inactivity appears to be a risk factor for macrovascular events. This raises the pos- QUESTION 3: WHAT IS THE EVIDENCE FOR THE VALUE sibility that increasing activity may be beneficial in its OF MODIFYING THESE RISK FACTORS IN THE GENERAL own right as well as an adjunct to weight reduction. POPULATION AND IN PEOPLE WITH DIABETES? IGT has been shown to be a risk factor for macrovas- cular disease in several epidemiological studies. Be- LIPID ABNORMALITIES cause people with IGT are hyperinsulinemic, this raises General population. The evidence that the risk for CVD the question of the role of hyperinsulinemia as a risk can be reduced in the general population by reducing factor for macrovascular disease. Prospective studies plasma