Non-insulin-dependent diabetes (NIDDM) is a major cause of premature morbidity and mortality among adults. Macrovascular disease of coronary and peripheral vessels is the primary cause of death in these patients. Numerous experimental and epidemiologic studies have suggested that hyperinsulinemia accelerates the development of atherosclerosis. In experimental models, insulin promotes diet-induced lesion development and overrides lesion regression and estrogen protection against atherosclerosis. Local hyperinsulinemia induced by selected arterial infusion accelerates atherosclerosis in the perfused artery. Insulin has been shown to stimulate subintimal smooth muscle and fibroblast cells in culture, and to increase the uptake and local synthesis of lipid by these cells. Insulin may also induce inhibition of fibrinolysis. Several prospective studies performed on nondiabetic patients show that either fasting or postprandial insulin levels are a sensitive predictor of the development of coronary disease independent of other risk factors. Two recent studies in NIDDM patients confirm this finding and suggest that glycemic control may not be a significant factor in the development of macrovascular disease. Diseases of carbohydrate tolerance, ie, NIDDM, impaired glucose tolerance, obesity, are frequently associated with elevated circulating insulin levels, either physiologically or secondary to treatment. Given the high prevalence of cardiovascular disease in these populations, modifying therapy to minimize hyperinsulinemia should be an important consideration in a treatment program. Use of oral agents such as glipizide or gliclazide, which induce less diurnal hyperinsulinemia, may be advantageous when compared to traditional oral agent or insulin therapy.