Pioglitazone reduced the progression from impaired glucose tolerance to type 2 diabetes by 72% in a multicenter study reported in the March 24 issue of the New England Journal of Medicine.
Among 602 adults with impaired glucose tolerance and other risk factors for diabetes, the rate of progressing to diabetes during 2 years of follow-up was 5% in those who took daily oral pioglitazone, compared with 17% in those who took placebo, said Dr. Ralph A. DeFronzo and Dr. Devjit Tripathy of the Texas Diabetes Institute, University of Texas Health Science Center at San Antonio, and their associates.
However, pioglitazone was associated with significant weight gain and edema, which prompted many subjects to discontinue the drug and drop out of the study, the investigators noted.
They assessed the effect of pioglitazone in men and women (mean age, 52 years) who showed impaired glucose tolerance on an oral glucose-tolerance test, had a body mass index of 25 kg/m2 or more, and had at least one other risk factor for diabetes. A total of 407 of the subjects also had elevated fasting glucose levels.
The patients were randomly assigned to receive either oral pioglitazone (303 subjects) or placebo (299 subjects) daily and were followed for a mean of 2.4 years.
Diabetes developed in 50 subjects in the placebo group (17%), compared with only 15 in the pioglitazone group (5%). "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," Dr. DeFronzo and his colleagues wrote (N. Engl. J. Med. 2011;364:1104-15).
"The number of people who would need to be treated to prevent one case of diabetes was 8 for 2.2 years of the trial and 18 for 1 year," they added.
At the conclusion of the trial, 48% of the pioglitazone group showed normal glucose tolerance, compared with only 28% of the placebo group.
A total of 161 patients did not complete the trial, including 90 taking pioglitazone and 71 taking placebo. The main reasons for discontinuing were edema and weight gain; edema was more prevalent with the active drug than with placebo.
Pioglitazone’s protective effect was consistent across subgroups of patients regardless of sex, age, weight, race, and fasting glucose level.
Hemoglobin A1c levels remained unchanged in the pioglitazone group throughout the study, but increased in the placebo group. Similarly, diastolic blood pressure was consistently lower in the pioglitazone group.
Body weight, BMI, and body fat increased in both groups, but the gains were greater in the placebo group. Pioglitazone reduced levels of alanine aminotransferase and aspartate aminotransferase. It also increased HDL cholesterol and decreased triglycerides to a greater degree than did placebo.
Previously, concerns have been raised regarding adverse cardiovascular effects in related drugs such as rosiglitazone. In this study, carotid intima-media thickening, a marker of cardiovascular risk, progressed more slowly with pioglitazone than with placebo. This finding, together with lower diastolic blood pressure and higher levels of HDL cholesterol in the pioglitazone group, suggests that the drug "may provide some protection against the development of atherosclerotic cardiovascular disease," the investigators said.
The rates of cardiovascular events were similar, with 26 in the pioglitazone group and 23 in the placebo group. There was one case of heart failure in each group.
Previous studies have reported an increased incidence of fractures with this class of drug. In this study, there were nine fractures in the pioglitazone group and eight in the placebo group, and all the fractures were associated with trauma. The extent to which these benefits affect the long-term complications of diabetes "remains to be determined," the investigators said.
This study was funded by Takeda Pharmaceuticals Inc. Additional support was provided by the General Clinical Research Centers at the University of Tennessee, Knoxville, and the University of Southern California, Los Angeles, and by the Veterans Affairs centers in Phoenix and San Diego. The investigators reported ties to numerous industry sources.