Inzucchi and colleagues analyzed data from 3,876 patients participating in the Insulin Resistance Intervention after Stroke (IRIS) trial, a study conducted at 179 sites in seven countries. Participants were aged at least 40 years with a qualifying ischemic stroke or TIA within 6 months prior to randomization, no history of diabetes and a fasting plasma glucose of 126 mg/dL or less (mean age, 64 years; 65% men; mean BMI, 30 kg/m²; mean fasting glucose, 98 mg/dL; mean HbA1c, 5.8%). Researchers randomly assigned patients to either daily pioglitazone therapy (Actos, Takeda; n = 1,939; increasing from 15 mg daily to 45 mg daily), or placebo (n = 1,937) for 5 years. Participants provided blood samples at baseline and yearly and agreed to periodic interviews.
At 1 year, participants in the pioglitazone group saw mean homeostatic model assessment of insulin resistance (HOMA-IR) decrease by 24%, from 5.4 to 4.1; FPG decreased from 98.2 mg/dL to 95.1 mg/dL. Participants in the placebo group saw a 7% increase in HOMA-IR, from 5.3 to 5.7, and an increase in FPG from 98.2 mg/dL to 99.7 mg/dL (P < .0001 for all).
During a median of 4.8 years of follow-up, fewer patients went on to develop type 2 diabetes in the pioglitazone group vs. placebo group (3.8% vs. 7.7%) for an HR of 0.48 (95% CI, 0.33-0.69). Those with IFG or an elevated HbA1c drove the effect, according to researchers.
The researchers noted that the mechanism by which pioglitazone improved CV outcomes in IRIS remains uncertain.
“Our findings to date cannot easily elucidate the extent to which insulin sensitization may have mediated the observed CV benefits,” the researchers wrote. “However, it seems unlikely that glucose lowering in this range or diabetes prevention per se can be directly credited, based on prior studies involving the therapy of early diabetes in patients at high CV risk.” – by Regina Schaffer
Disclosure: Inzucchi reports consulting for or serving on research steering committees for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Lexicon, Merck, Poxel and Sanofi, and on data monitoring committees for Novo Nordisk and Intarcia. Please see the full study for the other authors’ relevant financial disclosures.
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