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Pioglitazone benefits decrease after discontinuing therapy
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The protective effect of pioglitazone on type 2 diabetes prevention observed in adults with impaired glucose tolerance diminishes in the months after discontinuing therapy, with participants randomly assigned the drug progressing to diabetes at a rate similar to those assigned placebo, according to an analysis of the ACT NOW study.
However, researchers also found that the cumulative incidence of diabetes from randomization to end of follow-up remained lower in the pioglitazone group, and more participants in the pioglitazone group reverted to normal glucose tolerance.
“These findings demonstrate that following discontinuation of pioglitazone, disease progression in high-risk IGT individuals can be slowed, although ultimately, the rate of development of diabetes in the pioglitazone-treated group becomes similar to that in the placebo-treated group,” Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at University of Texas Health Science Center, and colleagues wrote.
Researchers analyzed data from 290 adults with IGT at baseline participating in the Actos Now for the Prevention of Diabetes (ACT NOW) study, a randomized, double blind, placebo-controlled trial designed to determine whether pioglitazone therapy (n = 152; 74 men; mean age, 54 years) can prevent or delay progression to diabetes vs. placebo (n = 138; 59 men; mean age, 52 years). Researchers followed the cohort for a mean of 11.4 months after study medication was discontinued and measured incidence of diabetes and IGT.
In both the pioglitazone and placebo groups, 17 participants each developed diabetes during follow-up; however, the cumulative incidence of diabetes from randomization to the end of follow-up remained lower in the pioglitazone group (10.7%) vs. placebo (22.3%; HR = 0.436; 95% CI, 0.285-0.668).
At the end of follow-up, 35 participants in the pioglitazone group remained at normal glucose tolerance (23%) vs. 19 in the placebo group (13.8%; P = .04); cumulative incidence of normal glucose tolerance (at least once during follow-up) was higher in the pioglitazone group vs. placebo (P < .05).
Participants with IGT who progressed to type 2 diabetes during follow-up had a significantly lower insulin secretion/insulin sensitivity index vs. participants who remained at either IGT or normal glucose tolerance. The decline in beta-cell function (IS/IR index) was similar in IGT participants who developed diabetes in both groups, according to researchers.
“In the ACT NOW study, pioglitazone decreased the conversion of IGT (prediabetes) to diabetes by an impressive 72%,” DeFronzo told Endocrine Today. “Not surprisingly, since diabetes has a strong genetic etiology and one cannot choose their parents again, the beneficial effects of pioglitazone on insulin sensitivity and beta-cell function gradually waned over the 12 months following cessation of therapy, and, at the end of 1 year off medications, individuals with IGT were converting to diabetes at the same rate as the placebo-treated group. The good news is that low-dose pioglitazone, which has few side effects, works to prevent the development of diabetes and in the PROactive and IRIS studies was shown to lower risk for [myocardial infarction] and nonfatal stroke. Since pioglitazone has gone generic, it also has become affordable by most patients with type 2 diabetes.” – by Regina Schaffer
For more information:
Ralph A. DeFronzo, MD, can be reached at the University of Texas Health Science Center, 7703 Floyd Curl Drive, MSC7886, San Antonio, TX 78229; email: albarado@uthscsa.edu.
Disclosure: DeFronzo reports receiving grants or speaking fees from or serving on advisory boards for Amylin, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Lexicon, Novo Nordisk and Takeda. DeFronzo’s salary is supported in part by the South Texas Veteran’s Health Care System. Please see the full study for the other authors’ relevant financial disclosures.
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