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Pioglitazone increases absolute fracture risk in prediabetes treatment
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Adults with prediabetes and cerebrovascular disease assigned pioglitazone therapy were more likely to sustain a fracture at any site vs. those assigned a placebo, according to a secondary analysis of the IRIS trial.
“The association of [thiazolidinediones] with an increased risk for fracture has been reported previously in clinical trials involving patients with diabetes, while mechanistic studies have provided additional evidence linking this drug class to adverse bone effects,” Catherine M. Viscoli, PhD, a research scientist in medicine at Yale School of Medicine, and colleagues wrote. “The current study was conducted to provide detailed information on the incidence, severity, mechanism, skeletal location and timing of fractures observed in the IRIS trial of patients with insulin resistance but without diabetes.”
Viscoli and colleagues analyzed data from 3,876 adults with prediabetes participating in the IRIS study, who were randomly assigned to pioglitazone (Actos, Takeda) therapy or placebo after an ischemic stroke or transient ischemic attack between February 2005 and January 2013 (mean age, 63 years; 65% men). The cohort was followed for a mean of 4.8 years; fractures were identified through quarterly interviews.
Within the cohort, 376 fractures occurred in 218 patients assigned to pioglitazone; 225 fractures occurred in 145 patients assigned to placebo; 5-year risk for first fracture was 13.6% for pioglitazone vs. 8.8% for placebo (HR = 1.53; 95% CI, 1.24-1.89). The risk for high-energy fractures was low in both treatment groups. For low-energy, non-pathologic fractures requiring surgery or hospitalization, the risk difference between groups was 1.6% (HR = 1.45; 95% CI, 1.03-2.09). Among patients assigned pioglitazone, researchers observed an increased risk for any fracture in both men (HR = 1.83; 95% CI, 1.36-2.48) and women (HR = 1.32; 95% CI, 0.98-1.78) vs. placebo.
Pioglitazone was not shown to have a selective effect on any specific bone or skeletal area, according to researchers; HRs ranged from 1.28 (95% CI, 0.9-1.82) for upper limb fractures to 2.07 (95% CI, 1.18-3.63) for the spine.
The researchers noted that adherence rates in both treatment groups differed by sex; 64% of women reported taking at least 30 mg per day of pioglitazone during year 1 vs. 76% of men; adherence rates were 77% and 88%, respectively, for women and men assigned placebo.
“The net benefit of pioglitazone after an ischemic stroke or TIA is a function of the drug’s
competing effects on preventing vascular disease and causing bone fracture,” the researchers wrote. “It is conceivable that fracture risk mitigation, including fall prevention, and screening and treatment of osteoporosis, would further and favorably affect the benefit/harm ratio for pioglitazone therapy. – by Regina Schaffer
Disclosure: Takeda provided pioglitazone and matching placebo tablets for the trial, but had no role in data collection or analysis. Viscoli reports consulting for Takeda Pharmaceuticals regarding prostate cancer events in the IRIS trial. Please see the full study for the other authors’ relevant financial disclosures.
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