Preventing Conversion to Diabetes from Impaired Glucose Tolerance

Twenty-one million Americans are affected by type 2 diabetes mellitus, and the prevalence of the disease is increasing. Type 2 diabetes begins with a genetic predisposition and progresses from normal glucose tolerance with insulin resistance to impaired glucose tolerance and eventually type 2 diabetes mellitus with the superimposition of beta-cell failure. Diabetes often leads to microvascular and macrovascular complications, both of which are related to the severity and duration of hyperglycemia. Utilizing interventions that prevent or delay hyperglycemia may, in turn, prevent or delay these long-term complications. Previous studies have shown that changes in lifestyle; use of metformin, thiazolidinediones, or acarbose; and bariatric surgery reduce the rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus. Weight loss, use of thiazolidinediones, and surgery have yielded the greatest reductions in conversion rates. Use of rosiglitazone therapy reduced the risk of diabetes in adults by 62%; however, concerns about cardiovascular safety caused the US Food and Drug Administration to restrict rosiglitazone therapy to patients whose hyperglycemia cannot be controlled with other medications and who cannot take pioglitazone. Researchers recently conducted a randomized, double-blind, placebo-controlled study to examine the effect of pioglitazone on diabetes risk and cardiovascular risk factors in adults with impaired glucose tolerance. They reported study results in the New England Journal of Medicine [2011;364(12):1104-1115]. Male and female patients ≥18 years of age with impaired glucose tolerance and a body mass index of ≥25 were recruited for the study. Inclusion criteria included fasting plasma glucose level between 95 and 125 mg/dL and at least 1 other risk factor of diabetes. In light of the high risk of diabetes in patients with a fasting plasma glucose level between 90 and 125 mg/dL whose 2-hour plasma glucose level during the oral glucose tolerance test was between 170 and 199 mg/dL, the inclusion criteria were modified during the recruitment phase of the study to include those patients. By March 2006, 602 patients had been enrolled; they were followed until they reached the primary end point of diabetes, withdrew from the study, were lost to follow-up, or completed the end of the study. Median follow-up was 2.4 years. The patients were randomized to receive pioglitazone (n=303) or placebo (n=299). Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. During the median follow-up of 2.4 years, diabetes developed in 5.0% (n=15) of those in the pioglitazone group, compared with 16.7% (n=50) of those in the placebo group. The annual average incidence of diabetes, calculated on the basis of person-years, was 7.6% in the placebo group and 2.1% in the pioglitazone group (P<.001). In the pioglitazone group, annual incidence rates for type 2 diabetes mellitus were 2.1%, compared with 7.6% in the placebo group. The hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16-0.49; P<.001). Among the patients who completed the study, 48% (n=103) of those in the pioglitazone group had normal glucose tolerance compared with 28% (n=65) of those in the placebo group (P<.001). Participants in the pioglitazone group achieved greater reduction in fasting and 2-hour glucose levels compared with those in the placebo group (P<.001), with a between-group difference of 3.5 mg/dL and 14 mg/dL, respectively, at the end of the study. Throughout the study, levels of hemoglobin A1c differed between the 2 groups (P<.001), increasing by 0.2% in the placebo group. In the placebo group, body weight, body mass index, and body fat increased from 96.7 to 97.3 kg, 34.5 to 34.7 kg, and 39.0 to 39.3 kg, respectively. The comparable increases in the pioglitazone group were 94.9 to 98.7 kg, 34.1 to 35.5 kg, and 40.0 to 41.9 kg, respectively. The increments were greater with pioglitazone (P<.001 for all comparisons). The researchers noted that, “pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema.”