Pioglitazone for Secondary Stroke Prevention

Lee, Meng; Saver, Jeffrey L.; Liao, Hung-Wei; Lin, Chun-Ching; Ovbiagele, Bruce

doi:10.1161/strokeaha.116.013977

Cited by 122 publications

(49 citation statements)

References 34 publications

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“…12 In a meta-analysis of studies in patients with stroke and insulin resistance, prediabetes, and diabetes mellitus, pioglitazone was associated with a 42% lower risk of recurrent stroke. 13 Adverse events that were more common in individuals using pioglitazone in the IRIS trial included weight gain, edema, and bone fractures.…”

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confidence: 99%

Pioglitazone Therapy in Patients With Stroke and Prediabetes

et al. 2019

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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 A 1c 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 A 1c , 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 s...

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Pioglitazone Therapy in Patients With Stroke and Prediabetes

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“…In the Diabetes Prevention Program, metformin significantly reduced the myocardial infarction events in prediabetic patients and this effect persisted for a 10-year follow-up [ 19 , 66 ]. Furthermore, the IRIS trial found that patients with insulin resistance receiving pioglitazone had a reduced risk of stroke or myocardial infarction [ 67 ]. Recent studies suggested that metformin has a direct anti-inflammatory action independent of improvement of metabolic parameters (hyperglycemia and insulin resistance) [ 23 ].…”

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confidence: 99%

Cardiac Autonomic Neuropathy as a Result of Mild Hypercaloric Challenge in Absence of Signs of Diabetes: Modulation by Antidiabetic Drugs

Al-Assi

Ghali

Mroueh

et al. 2018

Oxidative Medicine and Cellular Longevity

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Cardiac autonomic neuropathy (CAN) is an early cardiovascular complication of diabetes occurring before metabolic derangement is evident. The cause of CAN remains elusive and cannot be directly linked to hyperglycemia. Recent clinical data report cardioprotective effects of some antidiabetic drugs independent of their hypoglycemic action. Here, we used a rat model receiving limited daily increase in calories from fat (HC diet) to assess whether mild metabolic challenge led to CAN in absence of interfering effects of hyperglycemia, glucose intolerance, or obesity. Rats receiving HC diet for 12 weeks showed reduction in baroreceptor sensitivity and heart rate variability despite lack of change in baseline hemodynamic and cardiovascular structural parameters. Impairment of cardiac autonomic control was accompanied with perivascular adipose inflammation observed as an increased inflammatory cytokine expression, together with increased cardiac oxidative stress, and signaling derangement characteristic of diabetic cardiomyopathy. Two-week treatment with metformin or pioglitazone rectified the autonomic derangement and corrected the molecular changes. Switching rats to normal chow but not to isocaloric amounts of HC for two weeks reversed CAN. As such, we conclude that adipose inflammation due to increased fat intake might underlie development of CAN and, hence, the beneficial effects of metformin and pioglitazone.

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“…The results of three other meta-analyses on the effects of pioglitazone on CVD in randomized–controlled trials (RCTs), are supportive to our results in their conclusion that pioglitazone has protective effects on CVD. However the effects of pioglitazone on HF were inconsistent among the studies, which may in part be explained by differences in the study populations [ 37 – 39 ]. In contrast to these previous meta-analyses, we studied the effects of pioglitazone on cardiovascular events in a specific population of patients with a history of CVD, thereby not restricting our study to patients with insulin resistance, pre-diabetes or diabetes mellitus type 2 (T2DM).…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials

Jong

Worp

Graaf

et al. 2017

Cardiovasc Diabetol

103

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Background and aimsPioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to assess the effects of pioglitazone treatment on the secondary prevention of CVD.MethodsRandomized-controlled trials of pioglitazone in patients with CVD were identified through PubMed, Embase, Cochrane and CINAHL, in a search up to May 2016. Studies were included if pioglitazone was compared with any control (usual care, placebo or active comparator) and if patients were previously diagnosed with CVD. The outcomes of interest included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, all-cause mortality and heart failure (HF). All outcomes were compared by pooled risk ratios (RR) with a 95% confidence interval (CI). Pooled estimates were calculated using a random-effects model.ResultsTen studies reported the effects of pioglitazone on any of the outcomes of interest. Pioglitazone reduced recurrent MACE (RR 0.74, 95% 0.60–0.92; I2 = 35), MI (RR 0.77, 95% CI 0.64–0.93; I2 = 0%), or stroke (RR 0.81, 95% CI 0.68–0.96; I2 = 0%). Pioglitazone did not reduce all-cause mortality (RR 0.94, 95% CI 0.81–1.08; I2 = 0%), whereas pioglitazone treatment was associated with an increased risk of HF (RR 1.33, 95% CI 1.14–1.54).ConclusionsPioglitazone lowers the risk of recurrent MACE, stroke, or MI in patients with clinical manifest vascular disease. Pioglitazone does not lower the risk for all-cause mortality, and increases the risk for the development of HF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0617-4) contains supplementary material, which is available to authorized users.

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Pioglitazone for Secondary Stroke Prevention

Cited by 122 publications

References 34 publications

Pioglitazone Therapy in Patients With Stroke and Prediabetes

Pioglitazone Therapy in Patients With Stroke and Prediabetes

Cardiac Autonomic Neuropathy as a Result of Mild Hypercaloric Challenge in Absence of Signs of Diabetes: Modulation by Antidiabetic Drugs

Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials

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