The Scandinavian Simvastatin Survival Study (4S) subgroup analysis of diabetic subjects: implications for the prevention of coronary heart disease.

NIDDM is associated with a marked increase in coronary heart disease (CHD) (1). Reasons for the increased CHD risk in NIDDM are clearly multifactorial (2,3)In this commentary, I will focus on lipoproteins and their treatment in NIDDM. Subjects with NIDDM have increased triglyceride levels and decreased HDL cholesterol levels relative to those in nondiabetic subjects (4). Increased triglyceride and decreased HDL cholesterol levels are also found before the onset of clinical diabetes (5), suggesting that these abnormalities are related to insulin resistance as well as to hyperglycemia. Although the absolute concentration of LDL cholesterol is similar in NIDDM and normoglycemic subjects (4), those with NIDDM have more smalldense LDL than nondiabetic subjects (6). To summarize observational studies, while few data are available for HDL cholesterol, it may be a powerful predictor of CHD in NIDDM subjects (7). Both total cholesterol (8,9) and triglyceride (8,10) levels are significant predictors of CHD in NIDDM subjects. Total triglyceride may be a more powerful predictor of CHD than total cholesterol in NIDDM subjects (7,10); however, observational studies may not be reliable guides to clinical practice, since associations may not predict the effectiveness of interventions. In particular, triglyceride level is much more strongly associated with insulin resistance (11) than is total cholesterol, and in turn, insulin resistance is correlated with other risk factors such as PAI-1 (plasminogen activator inhibitor 1) and perhaps hypertension. Thus, it is possible that hypertriglyceridemia is a better predictor because it is a better marker of risk. Clinical trials are necessary to resolve this issue. Improvement of glycemic control with insulin markedly reduces hypertriglyceridemia in NIDDM subjects (12), but it may have only modest effects on HDL and LDL levels. Improved glycemic control is the treatment of first choice for elevated triglyceride levels in diabetic subjects. In general, hydroxymethylglutaryl coenzyme A (HMGCoA) reductase inhibitors have been preferred to reduce LDL cholesterol levels and fibric acids to markedly reduce hypertriglyceridemia in diabetic subjects (13). Of particular note is that lovastatin at a dose of 40 mg reduced triglyceride levels by 30% (14) in NIDDM subjects with elevated triglyceride levels (~300 mg/dl at baseline), suggesting that HMG-CoA reductase inhibitors may be the drugs of first choice to treat combined hyperlipidemia (elevation of both VLDL and LDL) in subjects with moderate hypertriglyceridemia (after achievement of good glycemic control).