Type 2 diabetes can be prevented with early pharmacological intervention

Abstract

In the U.S., ∼ 21 × 10(6) individuals have type 2 diabetes, and twice as many have impaired glucose tolerance (IGT). Approximately 40-50% of individuals with IGT will progress to type 2 diabetes over their lifetime. Therefore, treatment of high-risk individuals with IGT to prevent type 2 diabetes has important medical, economic, social, and human implications. Weight loss, although effective in reducing the conversion of IGT to type 2 diabetes, is difficult to achieve and maintain. Moreover, 40-50% of IGT subjects progress to type 2 diabetes despite successful weight reduction. In contrast, pharmacological treatment of IGT with oral antidiabetic agents that improve insulin sensitivity and preserve β-cell function--the characteristic pathophysiological abnormalities present in IGT and type 2 diabetes--uniformly have been shown to prevent progression of IGT to type 2 diabetes. The most consistent results have been observed with the thiazolidinediones (Troglitazone in the Prevention of Diabetes [TRIPOD], Pioglitazone in the Prevention of Diabetes [PIPOD], Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication [DREAM], and Actos Now for the Prevention of Diabetes [ACT NOW]), with a 50-70% reduction in IGT conversion to diabetes. Metformin in the U.S. Diabetes Prevention Program (DPP) reduced the development of type 2 diabetes by 31% and has been recommended by the American Diabetes Association (ADA) for treating high-risk individuals with IGT. The glucagon-like peptide-1 analogs, which augment insulin secretion, preserve β-cell function, and promote weight loss, also would be expected to be efficacious in preventing the progression of IGT to type 2 diabetes. Because individuals in the upper tertile of IGT are maximally/near-maximally insulin resistant, have lost 70-80% of their β-cell function, and have an ∼ 10% incidence of diabetic retinopathy, pharmacological intervention, in combination with diet plus exercise, should be instituted.

Figures

Figure 1

A: Change in body weight during the DPP, during the overlap period, and during the DPP Outcomes Study (DPPOS) (reproduced from Eriksson and Lindgärde [33]). B: Effect of sibutramine versus placebo on weight regain after weight loss (reproduced from James et al. [122a]). C: Rimonabant (Rimo) versus placebo on weight regain after weight loss (reproduced from Pi-Sunyer et al. [123a]).

Figure 2

A: Lack of effect of metformin and sulfonylureas to cause a durable reduction in HbA1c because of a lack of effect on preservation on β-cell function in the UK Prospective Diabetes Study. Reproduced from the UK Prospective Diabetes Study Group (4) and Turner et al. (8). B: Effect of rosiglitazone to decrease the conversion of IGT to type 2 diabetes in the DREAM study. Reproduced from Gerstein et al. (20). C: Effect of lifestyle intervention, metformin, and troglitazone to decrease the conversion of IGT to type 2 diabetes (T2DM) in the DPP (drawn from the data of Knowler et al. [18,43]). D: Effect of lifestyle intervention, metformin, and troglitazone on the conversion rate of IGT to type 2 diabetes in the first 1.5 years of the DPP (i.e., before the discontinuation of troglitazone from the DPP) (drawn from the data of Knowler et al. [18,43]). LS, lifestyle; MET, metformin; TROG, troglitazone.