The roles of insulin resistance, hyperinsulinemia, and thiazolidinediones in cardiovascular disease.

Although it is difficult to distinguish between the relative effects of insulin resistance and hyperinsulinemia, insulin resistance is clearly associated with significantly increased cardiovascular and cerebrovascular risk. This effect is consistent across the spectrum of worsening glycemic control, from the onset of impaired glucose tolerance to the development of clinical diabetes. It is more difficult to discriminate between the roles of elevated circulating insulin and proinsulin levels; the association between insulin levels and cardiovascular risk is weak. The thiazolidinediones (TZDs) significantly improve insulin sensitivity and exert numerous effects on the vascular bed, including improved endothelial function, decreased vascular inflammation, decreased plasma free fatty acid levels, improved dyslipidemic profiles, and inhibition of vascular smooth muscle proliferation. These findings provide increasing evidence to suggest that the TZDs may have a beneficial effect on atherosclerosis and may reduce the incidence and severity of adverse cardiovascular outcomes. These effects remain to be substantiated by the results of large outcomes studies to evaluate the impact of glycemic control and reversal of insulin resistance on cardiovascular events.