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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 ?IU/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.

SUBMITTER: Inzucchi SE

PROVIDER: S-EPMC5033078 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease.

Inzucchi Silvio E SE Viscoli Catherine M CM Young Lawrence H LH Furie Karen L KL Gorman Mark M Lovejoy Anne M AM Dagogo-Jack Samuel S Ismail-Beigi Faramarz F Korytkowski Mary T MT Pratley Richard E RE Schwartz Gregory G GG Kernan Walter N WN

Diabetes care 20160727 10

<h4>Objective</h4>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.<h4>Research design and methods</h4>A total of 3,876 patients ...[more]

PMID: 27465265

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Project description:BACKGROUND:Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone decreased the composite risk for fatal or nonfatal stroke and MI in patients with insulin resistance without diabetes mellitus, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population and the impact of pioglitazone on these events have not been described. METHODS:We performed a secondary analysis of the effects of pioglitazone, in comparison with placebo, on acute coronary syndromes (MI and unstable angina) among IRIS participants. All potential acute coronary syndrome episodes were adjudicated in a blinded fashion by an independent clinical events committee. RESULTS:The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 acute coronary syndrome events, including 141 MIs and 84 episodes of unstable angina. The MIs included 28 (19%) with ST-segment elevation. The majority of MIs were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10× to 100× upper limit of normal in 49 (35%) and >100× upper limit of normal in 39 (28%). Pioglitazone reduced the risk of acute coronary syndrome (hazard ratio, 0.71; 95% confidence interval, 0.54-0.94; P=0.02). Pioglitazone also reduced the risk of type 1 MI (hazard ratio, 0.62; 95% confidence interval, 0.40-0.96; log-rank P=0.03), but not type 2 MI (hazard ratio, 1.05; 95% confidence interval, 0.58-1.91; P=0.87). Similarly, pioglitazone reduced the risk of large MIs with serum troponin >100× upper limit of normal (hazard ratio, 0.44; 95% confidence interval, 0.22-0.87; P=0.02), but not smaller MIs. CONCLUSIONS:Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event. Pioglitazone appeared to have its most prominent effect in preventing spontaneous type 1 MIs. CLINICAL TRIAL REGISTRATION:URL: http://clinicaltrials.gov. Unique identifier: NCT00091949.

Project description:BACKGROUND:The IRIS trial (Insulin Resistance Intervention After Stroke) demonstrated that pioglitazone reduced the risk for both cardiovascular events and diabetes mellitus in insulin-resistant patients. However, concern remains that pioglitazone may increase the risk for heart failure (HF) in susceptible individuals. METHODS:In IRIS, patients with insulin resistance but without diabetes mellitus were randomized to pioglitazone or placebo (1:1) within 180 days of an ischemic stroke or transient ischemic attack and followed for ?5 years. To identify patients at higher HF risk with pioglitazone, we performed a secondary analysis of IRIS participants without HF history at entry. HF episodes were adjudicated by an external review, and treatment effects were analyzed using time-to-event methods. A baseline HF risk score was constructed from a Cox model estimated using stepwise selection. Baseline patient features (individually and summarized in risk score) and postrandomization events were examined as possible modifiers of the effect of pioglitazone. Net cardiovascular benefit was estimated for the composite of stroke, myocardial infarction, and hospitalized HF. RESULTS:Among 3851 patients, the mean age was 63 years, and 65% were male. The 5-year HF risk did not differ by treatment (4.1% pioglitazone, 4.2% placebo). Risk for hospitalized HF was low and not significantly greater in pioglitazone compared with placebo groups (2.9% versus 2.3%, P=0.36). Older age, atrial fibrillation, hypertension, obesity, edema, high C-reactive protein, and smoking were risk factors for HF. However, the effect of pioglitazone did not differ across levels of baseline HF risk (hazard ratio [95% CI] for pioglitazone versus placebo for patients at low, moderate, and high risk: 1.03 [0.61-1.73], 1.10 [0.56-2.15], and 1.08 [0.58-2.01]; interaction P value=0.98). HF risk was increased in patients with versus those without incident myocardial infarction in both groups (pioglitazone: 31.4% versus 2.7%; placebo: 25.7% versus 2.4%; P<0.0001). Edema, dyspnea, and weight gain in the trial did not predict HF hospitalization but led to more study drug dose reduction with a lower mean dose of pioglitazone versus placebo (29±17 mg versus 33±15 mg, P<0.0001). Pioglitazone reduced the composite outcome of stroke, myocardial infarction, or hospitalized HF (hazard ratio, 0.78; P=0.007). CONCLUSIONS:In IRIS, with surveillance and dose adjustments, pioglitazone did not increase the risk of HF and conferred net cardiovascular benefit in patients with insulin resistance and cerebrovascular disease. The risk of HF with pioglitazone was not modified by baseline HF risk. The IRIS experience may be instructive for maximizing the net benefit of this therapy. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT00091949.

Dataset Information

Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease.

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Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease.

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