Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease

Abstract

Objective: The Insulin Resistance Intervention after Stroke (IRIS) trial recently found that pioglitazone reduced risk for stroke and myocardial infarction in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack (TIA). This report provides detailed results on the metabolic effects of pioglitazone and the trial's prespecified secondary aim of diabetes prevention.

Research design and methods: A total of 3,876 patients with recent ischemic stroke or TIA, no history of diabetes, fasting plasma glucose (FPG) <126 mg/dL, and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) score >3.0 were randomly assigned to pioglitazone or placebo. Surveillance for diabetes onset during the trial was accomplished by periodic interviews and annual FPG testing.

Results: At baseline, the mean FPG, HbA1c, insulin, and HOMA-IR were 98.2 mg/dL (5.46 mmol/L), 5.8% (40 mmol/mol), 22.4 μIU/mL, and 5.4, respectively. After 1 year, mean HOMA-IR and FPG decreased to 4.1 and 95.1 mg/dL (5.28 mmol/L) in the pioglitazone group and rose to 5.7 and 99.7 mg/dL (5.54 mmol/L), in the placebo group (all P < 0.0001). Over a median follow-up of 4.8 years, diabetes developed in 73 (3.8%) participants assigned to pioglitazone compared with 149 (7.7%) assigned to placebo (hazard ratio [HR] 0.48 [95% CI 0.33-0.69]; P < 0.0001). This effect was predominately driven by those with initial impaired fasting glucose (FPG >100 mg/dL [5.6 mmol/L]; HR 0.41 [95% CI 0.30-0.57]) or elevated HbA1c (>5.7% [39 mmol/mol]; HR 0.46 [0.34-0.62]).

Conclusions: Among patients with insulin resistance but without diabetes who had had a recent ischemic stroke or TIA, pioglitazone decreased the risk of diabetes while also reducing the risk of subsequent ischemic events. Pioglitazone is the first medication shown to prevent both progression to diabetes and major cardiovascular events as prespecified outcomes in a single trial.

Trial registration: ClinicalTrials.gov NCT00091949.

Figure 1

Time to diabetes onset: overall and by metabolic subgroups. A shows the overall onset of diabetes by treatment group. B–D show similar data, with treatment groups further subdivided by baseline metabolic category. B: With or without IFG using ADA criteria. C: HbA_1c above or below the ADA prediabetes cut point of 5.7%. D: Those above versus below the median HOMA-IR value of 4.6, with the former denoting greater insulin resistance. (Blue lines depict the pioglitazone group and red lines the placebo group. Except for A, solid lines indicate the subgroup below the cut point for the variable, whereas dashed lines indicate the subgroup above the cut point.)

Figure 2

Subgroup analysis. Treatment effect for progression to diabetes is displayed between the two randomized categories (pioglitazone vs. placebo) by important subgroups. No heterogeneity of effect is demonstrated, with the exception of a significant interaction with degree of study drug adherence.