Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial.

Importance: In the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, pioglitazone, an insulin-sensitizing agent, reduced the risk for recurrent stroke or myocardial infarction (MI) among patients with insulin resistance. However, insulin resistance is not commonly measured in clinical practice. Objective: To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial. Design, Setting, and Participants: The IRIS trial was a randomized multicenter clinical trial in patients with prior stroke or transient ischemic attack as well as insulin resistance but not diabetes. Patients were enrolled from February 2005 to January 2013, and the median follow-up was 4.8 years. The post hoc analyses reported here were performed from June to September 2018. Per American Diabetes Association criteria, prediabetes was defined as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL (to convert to mmol/L, multiply by 0.0555). Good adherence was defined as taking 80% or more of the protocol dose. Fasting glucose and hemoglobin A1c, used to define prediabetes, and adherence of 80% or higher, stipulated in the protocol as defining good adherence, were prespecified subgroups in the analysis plan. Interventions: Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo. Main Outcomes and Measures: The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes. Results: Among 3876 participants analyzed in the IRIS trial, 2885 were included in this analysis (1456 in the pioglitazone cohort and 1429 in the placebo cohort). The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) of patients were men in the pioglitazone and placebo cohort, respectively. In the prediabetic population with good adherence (644 of 1456 individuals [44.2%] in the pioglitazone group and 810 of 1429 [56.7%] in the placebo group), the hazard ratios (95% CI) were 0.57 (0.39-0.84) for stroke/MI, 0.64 (0.42-0.99) for stroke, 0.47 (0.26-0.85) for acute coronary syndrome, 0.61 (0.42-0.88) for stroke/MI/hospitalization for heart failure, and 0.18 (0.10-0.33) for progression to diabetes. There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema. Intention-to-treat results also showed significant reduction of events but to a lesser degree. Hazard ratios (95% CI) were 0.70 (0.56-0.88) for stroke/MI, 0.72 (0.56-0.92) for stroke, 0.72 (0.52-1.00) for acute coronary syndrome, 0.78 (0.63-0.96), for stroke/MI/hospitalization for heart failure, and 0.46 (0.35 to 0.61) for progression to diabetes. Conclusions and Relevance: Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence. Trial Registration: ClinicalTrials.gov identifier: NCT00091949.

Heart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With Pioglitazone.

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.

Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial.

INTRODUCTION: Patients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function. METHODS: In the Insulin Resistance Intervention after Stroke (IRIS) trial, patients with a recent ischaemic stroke or transient ischaemic attack (TIA) were randomised to pioglitazone (target 45 mg daily) or placebo. All patients were insulin resistant based on a Homeostasis Model Assessment-Insulin Resistance score >3.0. For this preplanned analysis of cognitive function, we examined the Modified Mini-Mental State Examination (3MS) score (maximum score, 100) during follow-up. Patients were tested at baseline and annually for up to 5 years. Longitudinal mixed model methods were used to compare changes in the 3MS over time. RESULTS: Of the 3876 IRIS participants, 3398 had a 3MS score at baseline and at least once during follow-up and were included in the analysis. Median 3MS score at baseline was 97 (IQR 93-99). The average overall least squared mean 3MS score increased by 0.27 in the pioglitazone group and by 0.29 in the placebo group (mean difference between treatment groups -0.02; 95% CI -0.33 to 0.28, p=0.88). CONCLUSIONS: Among insulin-resistant patients with a recent ischaemic stroke or TIA, pioglitazone did not affect cognitive function, as measured by the 3MS, over 5 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT00091949; Results.

Pioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial (Insulin Resistance Intervention After Stroke).

BACKGROUND: The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone reduced the risk for a composite outcome of stroke or myocardial infarction among nondiabetic patients with insulin resistance and a recent stroke or transient ischemic attack. The current planned secondary analysis uses updated 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. METHODS: Participants were randomly assigned to receive pioglitazone (45 mg/d target dose) or placebo within 180 days of a qualifying ischemic stroke or transient ischemic attack and were followed for a maximum of 5 years. An independent committee, blinded to treatment assignments, adjudicated all potential stroke outcomes. Time to first stroke event was compared by treatment group, overall and by type of event (ischemic or hemorrhagic), using survival analyses and Cox proportional hazards models. RESULTS: Among 3876 IRIS participants (mean age, 63 years; 65% male), 377 stroke events were observed in 319 participants over a median follow-up of 4.8 years. Pioglitazone was associated with a reduced risk for any stroke at 5 years (8.0% in comparison with 10.7% for the placebo group; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.94; log-rank P=0.01). Pioglitazone reduced risk for ischemic strokes (HR, 0.72; 95% CI, 0.57-0.91; P=0.005) but had no effect on risk for hemorrhagic events (HR, 1.00; 95% CI, 0.50-2.00; P=1.00). CONCLUSIONS: Pioglitazone was effective for secondary prevention of ischemic stroke in nondiabetic patients with insulin resistance. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00091949.

Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus.

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.

Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial.

Context: Pioglitazone reduces cardiovascular risk in nondiabetic patients after an ischemic stroke or transient ischemic attack (TIA) but is associated with increased risk for bone fracture. Objective: To characterize fractures associated with pioglitazone by location, mechanism, severity, timing, and sex. Design, Setting, and Patients: Patients were 3876 nondiabetic participants in the Insulin Resistance Intervention after Stroke trial randomized to pioglitazone or placebo and followed for a median of 4.8 years. Fractures were identified through quarterly interviews. Results: At 5 years, the increment in fracture risk between pioglitazone and placebo groups was 4.9% [13.6% vs 8.8%; hazard ratio (HR), 1.53; 95% confidence interval (CI), 1.24 to 1.89). In each group, ∼80% of fractures were low energy (i.e., resulted from fall) and 45% were serious (i.e., required surgery or hospitalization). For serious fractures most likely to be related to pioglitazone (low energy, nonpathological), the risk increment was 1.6% (4.7% vs 3.1%; HR, 1.47; 95% CI, 1.03 to 2.09). Increased risk for any fracture was observed in men (9.4% vs 5.2%; HR, 1.83; 95% CI, 1.36 to 2.48) and women (14.9% vs 11.6%; HR, 1.32; 95% CI, 0.98 to 1.78; interaction P = 0.13). Conclusions: Fractures affected 8.8% of placebo-treated patients within 5 years after an ischemic stroke or TIA. Pioglitazone increased the absolute fracture risk by 1.6% to 4.9% and the relative risk by 47% to 60%, depending on fracture classification. Our analysis suggests that treatments to improve bone health and prevent falls may help optimize the risk/benefit ratio for pioglitazone.

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

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.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). CONCLUSIONS: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial.

BACKGROUND: Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack (TIA). The IRIS Trial is evaluating an approach to secondary prevention based on the established association between insulin resistance and increased risk for ischemic vascular events. Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA. DESIGN: Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment-Insulin Resistance > 3.0 without meeting criteria for diabetes. Within 6 months of the index stroke or TIA, patients were randomly assigned to pioglitazone (titrated from 15 to 45 mg/d) or matching placebo and followed for up to 5 years. The primary outcome is time to stroke or MI. Secondary outcomes include time to stroke alone, acute coronary syndrome, diabetes, cognitive decline, and all-cause mortality. Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013. Participant follow-up will continue until July 2015. SUMMARY: The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic, insulin-resistant patients with stroke or TIA. Results are expected in early 2016.