Type 2 diabetes: Overlap of clinical conditions Content Points: This slide depicts the overlap of clinical conditions often seen in day-to-day clinical practice. Type 2 diabetes may be multifactorial with insulin resistance as a major underlying feature.10,11 Such clinical conditions include hypertension as well as dyslipidemia, and excess weight...all of which often coexist in patients with Type 2 diabetes, a disease occurring in patients already at higher risk for cardiovascular disease. Nearly twice as many patients with Type 2 diabetes have a medical history of heart disease vs those without diabetes.

Insulin resistance syndrome Content Points: Reaven described the insulin resistance syndrome in 1988, and suggested some of the components shown on this slide.12 Insulin resistance has been described as a subnormal biologic response to a given concentration of insulin.13 The key point is that these conditions often occur in the same patient, and they all contribute to coronary artery disease.

Relating atherosclerosis and insulin resistance Content Points: This slide adds several other factors implicated in the insulin resistance syndrome and its relationships to coronary atherosclerosis. Other factors include hypertriglyceridemia; small, dense LDL-C; low HDL-C; and hypercoagulability.

Dyslipidemia in diabetics (Framingham Heart Study) Content Points: Hypertriglyceridemia is the most common lipid abnormality seen in patients with type 2 diabetes. Higher serum triglycerides are associated with very low-density lipoprotein (VLDL), a factor which may result from increased levels of serum free fatty acids (FFA) and glucose. Overproduction of VLDL often results partly from added body weight as well as from insulin resistance. Compared with nondiabetic individuals of both sexes, twice as many adults with type 2 diabetes have elevated plasma triglycerides.14 The data on HDL-C from the Framingham Heart Study is also interesting, in that more type 2 patients than normals have lower levels of HDL-C, with the difference more predominant in women.

Hyperinsulinemia and CHD mortality Content Points: The Paris Prospective Study also supports the hypothesis that a constellation of metabolic abnormalities may play a deleterious role in risk of coronary heart disease.15 The Paris Prospective Study is a long-term study of CHD risk factors in a sample of 7,028 men. The mean follow-up (reported in 1991) was 11 years. The major independent predictors of CHD death were blood pressure, smoking, cholesterol level, and fasting and 2-hour postload plasma insulin level.15 In a sample of 943 patients with impaired glucose tolerance (IGT) or diabetes, 26 died of CHD. When the sample was analyzed by quintiles of fasting plasma insulin, those in the highest quintile had the highest rate of CHD mortality. The strongest independent predictor of subsequent CHD death in this quintile was plasma triglyceride concentration, adding to the growing body of evidence that hyperinsulinemia and hypertriglyceridemia are related.

Hypertriglyceridemia, CHD risk, and hyperinsulinemia Content Points: Despres et al recently reported that the risk for CHD related to hyperinsulinemia was largely independent of the concomitant dyslipidemic state, although hyperinsulinemia tends to increase the atherogenicity of other risk factors, such as high levels of apolipoprotein B (apo B).16 While both insulin levels and apo B levels are independently predictive of CHD, there appears to be a synergistic effect. The synergism between hyperinsulinemia and small, dense LDL-C suggests that much of the atherogenicity of the insulin resistance syndrome might be attributable to the dyslipidemia associated with insulin resistance.

Fasting triglyceride and risk of death from CHD (Paris Prospective Study) Content Points: Triglycerides were implicated again in the Paris Prospective Study.17 Fasting plasma triglyceride concentration was the only significant predictor of CHD death rate on multivariate analysis in 943 middle-aged men with diabetes or impaired glucose tolerance followed up for 11 years. Variables in the analysis were fasting plasma cholesterol, fasting plasma triglyceride, age, systolic blood pressure, smoking, body mass index, and insulin and glucose concentrations. HDL-C concentrations were not measured. The mean annual CHD mortality rate was approximately three times higher in men who had triglyceride levels above the median (123 mg/dL, 1.39 mmol/L) and total cholesterol above the median (220 mg/dL, 5.7 mmol/L) than in men with values below the medians. Triglyceride concentrations ≤ 123 mg/dL seemed to obliterate the harmful effects of hypercholesterolemia; but with triglyceride concentrations > 123 mg/dL, harmful effects became noticeably worse, not only for those with elevated plasma cholesterol, but also for those with a normal cholesterol concentration.

Relation between total cholesterol and CHD death rate in 361,662 men screened for MRFIT Content Points: The Multiple Risk Factor Intervention Trial (MRFIT)18,19 was a randomized, multicenter, clinical study that included 12,866 middle-aged men without evidence of CHD who were nonetheless at high risk for CHD because they had multiple risk factors for CHD (hypertension, cigarette smoking, or elevated cholesterol levels). Volunteers were randomly assigned to a special group in which CHD risk factors were aggressively managed (blood pressure controlled, smoking counseling, and dietary therapy for elevated lipid levels) or to a usual-care control group (who received routine care by their own physicians). MRFIT follow-up showed a strong, linear, continuous relation between total cholesterol levels and 10-year CHD mortality for cholesterol levels beginning at about 180 to 240 mg/dL. In this study, average risk is 1.0; numbers above 1.0 indicate increased risk.