Drugs of the thiazolidinedione (TZD) class have recently been introduced for treatment of type 2 diabetes. The first drug in the class, troglitazone, caused liver failure on rare occasions and has been removed from clinical use. Two other

TZDs, pioglitazone and rosiglitazone, appear to be safer and are currently mar- £

keted in the United States. As a class, the drugs bind to the nuclear receptor

PPAR-y and alter the transcription of a number of genes. Their effects on carbo- <

hydrate metabolism are manifested as an increase in the sensitivity of skeletal muscle and adipose tissue to insulin in vivo. The available thiazolidinediones are approximately equally potent to sulfonylureas and metformin in lowering glucose

& u concentrations in patients with type 2 diabetes. Their glucose-lowering effects rely on the presence of insulin in the bloodstream, so they are not effective by themselves in patients with type 1 diabetes. Since TZDs have their primary effect on muscle and adipose tissue, their glucose-lowering effects are additive to the effects of metformin, sulfonylurea drugs, and exogenous insulin.

In addition to their effects on glycemia, TZDs have several actions that make them particularly attractive for use in people who have atherosclerosis or are at increased risk for that disease. They ameliorate hyperinsulinemia, which has been associated with an increased risk of atherosclerosis in epidemiological and animal studies. They also have potentially beneficial effects on circulating lipids, although these effects differ between the available TZDs. Pioglitazone lowers triglycerides and raises HDL and LDL cholesterol levels. Rosiglitazone raises LDL and HDL cholesterol but has no consistent impact on triglyceride levels. TZDs have also been reported to shift the pattern of LDL particle size from small and dense to larger and less atherogenic. Finally, TZDs inhibit the growth-promoting effects of some endogenous growth factors on vascular smooth muscle and endothelial cells. In animal models and in one human study, TZDs reduced the endothelial hypertrophy that follows experimental endothelial injury or coronary angioplasty, respectively. These extraglycemic effects suggest that TZDs may have specific antiatherogenic properties. However, they have not yet been rigorously tested for their effects on atherosclerosis or related clinical events in patients with type 2 diabetes. It is of note that our group has observed a 30% reduction in the rate of thickening of carotid intima and media layers in insulin-resistant, nondiabetic women treated with troglitazone. Whether the effect was due to reversal of insulin resistance, which did occur, or to direct vascular effects of the drug is unknown. Nonetheless, this finding raises the possibility that insulin resistance may become a target for clinical intervention in nondiabetic but insulin-resistant individuals in the future.

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