to the editor: I enjoyed the review article¹ on impaired glucose tolerance in the April 15, 2004, issue of American Family Physician. I felt that the section summarizing lifestyle and pharmacologic interventions to prevent the development of diabetes was especially important for practicing physicians.

Of particular importance, the authors cited the TRIPOD (TRoglitazone In the Prevention Of Diabetes) study,^2,3 a double-blind, placebo-controlled study that showed a 55 percent relative risk reduction in the progression to diabetes in 236 Hispanic women with a history of gestational diabetes. However, the authors did not point out the most startling aspect of this study that may have profound implications for the prevention of diabetes in patients at risk.

Although the TRIPOD study ended when the U.S. Food and Drug Administration withdrew troglitazone from the market, the investigators continued to track the progression to diabetes in all women in the study who had received placebo and those who had received troglitazone. Annual incidence rates of progression to diabetes were 21.2 percent in the group who had been taking placebo but were only 3.1 percent in the group who had been taking the thiazolidinedione agent, troglitazone (P = 0.03). This persistent protection from progression to diabetes suggested that the drug had fundamentally altered the underlying metabolic natural history that leads to diabetes rather than simply masking the deterioration by lowering glucose levels acutely.

In 2003, the journal Science published an article that helped explain the physiology behind this persistent therapeutic preventive benefit.⁴ It explained that peroxisome proliferator-activated receptors (PPARs) were a family of nuclear receptors that were specifically targeted by thiazolidinediones (as well as statins and fibrates). When activated, PPARs mediate persistent reductions in insulin resistance and cardiovascular inflammation. The author hypothesized that PPARs may be not only the central metabolic mediator of the clinical overlap in atherosclerotic disease and insulin resistance but also the singular therapeutic target for medicines to reduce, reverse, and prevent the deleterious metabolic changes that lead to diabetes and atherosclerotic disease.

The prevention of diabetes as shown in the TRIPOD follow-up study may have helped to unearth the central mediator of insulin resistance and atherosclerotic vascular disease: PPARs. Further patient-oriented outcome research may move this discovery into the hands of physicians and provide us with the ability to prevent the development of the primary diseases that end the lives of the majority of our patients.