Effects On Diabetes Prevention

Given the substantial morbidity and excess mortality associated with diabetes, the prevention of type 2 diabetes is a major public-health issue (43). It is well known that subjects with IGT (those with a plasma glucose between 140 and 199 mg/dL 2 hours after a 75 g oral glucose load) are insulin resistant and at high risk to progress on to type 2 diabetes (44). As potent insulin sensitizers, the thiazolidinediones have the potential to prevent type 2 diabetes in high-risk individuals. In the first study to demonstrate this effect (TRIPOD study) (41), Buchanan et al. observed that treatment with troglitazone 400 mg daily for up to 5 years delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women with a history of gestational diabetes by about 50%. This protective effect was associated with the preservation of pancreatic p-cell function and persisted for 8 months after study medications were stopped (41). Women who completed the TRIPOD study were offered participation in the PIPOD study and in these women, 3 years of pioglitazone treatment was associated with stable pancreatic p-cell function and the same diabetes prevention effect seen in the TRIPOD study (42).

The diabetes-prevention effect of the thiazolidinediones was confirmed in the landmark Diabetes Prevention Program, in which more than 4000 subjects with IGT and high FPG were randomized to either intensive lifestyle intervention, metformin 850 mg b.i.d., troglitazone 400 mg daily or placebo (44). In this study, troglitazone was discontinued early due to reports of idiosyncratic hepatotoxicity associated with its use. However, in the subjects who received troglitazone for a mean of 0.9 years, there was a robust 75% reduction in the incidence of diabetes compared to the placebo group. In the same period, there was a 57% reduction in the intensive lifestyle group and a 44% reduction in the metformin group (45). An interesting aspect of this study was that after troglitazone withdrawal, the diabetes incidence rate increased to that of the placebo group, thereby indicating that the protective effect did not persist after the drug was stopped. This is in contrast to the findings from the study conducted by Buchanan et al. in Hispanic women with GDM, in whom the effects of troglitazone persisted for up to 8 months after discontinuation (41).

The DREAM trial (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) is the largest completed diabetes prevention trial and was designed to assess whether rosiglitazone reduces the frequency of diabetes in individuals with IGT or IFG, or both (33). A total of 5269 adults aged 30 years or more with IGT/IFG, or both, and no previous cardiovascular disease were randomly assigned to receive rosiglitazone 8 mg daily or placebo (in this study, ramipril was also studied in a 2 x 2 factorial design). After a median of 3 years, rosiglitazone substantially reduced incident type 2 diabetes by 62% and increased the likelihood of regression to normoglycemia. Cardiovascular event rates were much the same in both groups, although 0.5% of participants in the rosiglitazone group and 0.1% in the placebo group developed heart failure (P = 0.01). Of note, in this study, ramipril failed to reduce the progression to type 2 diabetes. The DREAM trial confirms the results of the earlier studies and strongly suggests that diabetes progression can be altered with thiazolidinedione therapy in high-risk individuals with IGT/IFG. Early treatment with a thiazolidinedione may represent a useful treatment option to effectively prevent or delay the progression of diabetes and its complications. However, the greater benefits in high-risk individuals will have to be balanced against the increased risk of heart failure. Nevertheless, treatment with a thiazolidinedione may be an option in people at high risk of diabetes in whom lifestyle intervention (diet and exercise) and metformin therapy has failed or is not indicated.

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