Chronic Therapy in PCOS with Insulin Sensitizers

Both metformin and the thiazolidinediones have been shown to reduce blood pressure and inflammatory markers. Obese women on metformin also tend to lose weight while on metformin in a dose-dependent manner (63). Although the insulin sensitizers' effects on cardiovascular risk factors are favorable, currently there are no prospective randomized outcome trials examining the use of insulin sensitizers in the prevention of diabetes or cardiovascular events in women with PCOS.

2.3.2.1. Insulin Sensitizers in Preventing Type 2 Diabetes Mellitus

Although not specifically conducted in women with PCOS, there are several outcome studies indicating that interventions to improve insulin sensitivity may decrease the incidence of diabetes in individuals at high risk. The Diabetes Prevention Project was a prospective study sponsored by the National Institutes of Health (64). The study included 3234 patients at high risk of diabetes (history of gestational diabetes or presence of impaired glucose tolerance and a first-degree relative with diabetes). Subjects were randomized to standard management, intensive lifestyle intervention, or metformin. During the average follow-up period of 3 years, intensive lifestyle intervention reduced the incidence of newly developed diabetes by 58%. Subjects treated with metformin had a 31% reduction in the risk of developing diabetes. These results indicate that improvement in insulin sensitivity, through either intensive lifestyle modification or metformin, reduces the risk of developing diabetes in high-risk individuals.

The insulin sensitizer troglitazone has also been studied in the prevention of diabetes. Buchanan et al. studied 235 Hispanic women with gestational diabetes who were randomized to troglitazone or placebo (65). During a median follow-up of 30 months, compared with the placebo group, subjects taking troglitazone reduced their rate of progression to diabetes by 56%. This protective effect persisted for 8 months even after troglitazone was discontinued. Protection from diabetes in the troglitazone group was also associated with preservation of pancreatic P-cell function. In the Diabetes Prevention Project, troglitazone was one of the initial arms of the study, but was later discontinued after a mean duration of treatment of 0.9 year following reports of hepatotoxicity (66). During the active treatment period, the diabetes incidence rate was 3.0 cases/100 person-years in the troglitazone arm as compared with 12.0, 6.7, and 5.1 cases/100 person-years in the placebo, metformin, and intensive lifestyle-style groups, respectively. The difference in the reduction in risk was significant between troglitazone and placebo and between troglitazone and metformin. However, this protective effect against progression to diabetes did not persist after the discontinuation of troglitazone (66).

2.3.2.2. Insulin Sensitizers in Preventing Cardiovascular Events

The available evidence suggesting that insulin sensitizers may be cardioprotective is circumstantial, but nonetheless encouraging. In another insulin-resistant state, type 2 diabetes, the United Kingdom Prospective Diabetes Study showed that metformin may be cardioprotective (67). In this large prospective trial in obese diabetic patients, metformin significantly decreased all-cause mortality and stroke endpoints.

The thiazolidinediones have been studied using surrogate cardiovascular endpoints. Specifically in PCOS, troglitazone has been shown to improve endothelial function in obese women with PCOS (68). In another study involving women at high risk of developing diabetes, 266 nondiabetic Hispanic women with gestational diabetes were randomized to placebo or troglitazone. Carotid intima media thickness progression was 31% lower in troglitazone group (p = 0.048), and this reduction was independent of obesity, baseline lipids, and serum levels of glucose or insulin. This beneficial effect was present only in subjects who had an increase in insulin sensitivity on troglitazone during the first 3 months of study. This finding suggests that improving insulin sensitivity using a thiazolidinedione may reduce the progression of subclinical atherosclerosis (69).

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