Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., S.E.I., J.P.C., E.S., A.L., D.L.J., S.E.P., W.N.K.).
VA Medical Center and University of Colorado School of Medicine, Denver (G.G.S.).
Circulation. 2018 Sep 18;138(12):1210-1220. doi: 10.1161/CIRCULATIONAHA.118.034763.
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.
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.
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).
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.
URL: https://www.clinicaltrials.gov . Unique identifier: NCT00091949.
IRIS 试验（中风后胰岛素抵抗干预）表明，吡格列酮可降低胰岛素抵抗患者发生心血管事件和糖尿病的风险。然而，人们仍然担心吡格列酮可能会增加易感个体发生心力衰竭（HF）的风险。
在 IRIS 试验中，在缺血性中风或短暂性脑缺血发作后 180 天内，将有胰岛素抵抗但无糖尿病的患者随机分配至吡格列酮或安慰剂组（1:1），并随访 ≤5 年。为了确定使用吡格列酮治疗时 HF 风险较高的患者，我们对无 HF 病史的 IRIS 参与者进行了二次分析。HF 发作由外部审查进行裁决，使用时间事件方法分析治疗效果。使用逐步选择估计的 Cox 模型构建基线 HF 风险评分。基线患者特征（单独和汇总在风险评分中）和随机后事件被视为吡格列酮作用的可能修饰剂。对中风、心肌梗死和住院 HF 的复合终点进行了心血管净获益估计。
在 3851 名患者中，平均年龄为 63 岁，65%为男性。治疗组 5 年 HF 风险无差异（吡格列酮组 4.1%，安慰剂组 4.2%）。与安慰剂组相比，吡格列酮组因 HF 住院的风险较低且无显著差异（2.9%对 2.3%，P=0.36）。年龄较大、房颤、高血压、肥胖、水肿、高 C 反应蛋白和吸烟是 HF 的危险因素。然而，吡格列酮的作用在不同基线 HF 风险水平上没有差异（低、中、高危患者吡格列酮与安慰剂的危险比[95%CI]：1.03[0.61-1.73]、1.10[0.56-2.15]和 1.08[0.58-2.01]；交互 P 值=0.98）。两组中发生心肌梗死的患者 HF 风险高于未发生心肌梗死的患者（吡格列酮组：31.4%对 2.7%；安慰剂组：25.7%对 2.4%；P<0.0001）。试验中的水肿、呼吸困难和体重增加并不能预测 HF 住院，但导致研究药物剂量减少，吡格列酮的平均剂量低于安慰剂（29±17 mg 对 33±15 mg，P<0.0001）。吡格列酮降低了中风、心肌梗死或住院 HF 的复合终点（危险比，0.78；P=0.007）。
在 IRIS 中，通过监测和剂量调整，吡格列酮并未增加 HF 风险，并为伴有胰岛素抵抗和脑血管疾病的患者带来了心血管净获益。吡格列酮的 HF 风险不受基线 HF 风险的影响。IRIS 的经验可能为最大限度地提高这种治疗的净获益提供指导。
