Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada.
Department of Medicine, Yale School of Medicine, New Haven, Connecticut.
JAMA Neurol. 2019 May 1;76(5):526-535. doi: 10.1001/jamaneurol.2019.0079.
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.
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.
Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo.
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.
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.
Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence.
ClinicalTrials.gov identifier: NCT00091949.
重要性：在胰岛素抵抗干预后的中风（IRIS）随机临床试验中，吡格列酮，一种胰岛素增敏剂，降低了胰岛素抵抗患者再次中风或心肌梗死（MI）的风险。然而，胰岛素抵抗在临床实践中并不常用。
目的：分析 IRIS 试验中依从性好的患者使用吡格列酮的效果，以及糖尿病前期患者使用吡格列酮的意向治疗效果。
设计、地点和参与者：IRIS 试验是一项针对既往中风或短暂性脑缺血发作以及胰岛素抵抗但无糖尿病患者的随机多中心临床试验。患者于 2005 年 2 月至 2013 年 1 月入组，中位随访时间为 4.8 年。本报告的事后分析于 2018 年 6 月至 9 月进行。根据美国糖尿病协会的标准，糖尿病前期定义为糖化血红蛋白水平为 5.7%至 6.4%或空腹血糖水平为 100 mg/dL 至 125 mg/dL（转换为 mmol/L，乘以 0.0555）。良好的依从性定义为服用 80%或更多的方案剂量。空腹血糖和糖化血红蛋白用于定义糖尿病前期，以及协议规定的 80%或更高的依从性，是分析计划中的预先指定亚组。
干预措施：参与者被随机分配到 15 mg 吡格列酮，剂量可滴定至每日 45 mg 的目标剂量，或匹配安慰剂。
主要结果和测量：主要结果是再次中风或 MI。次要结果包括中风、急性冠状动脉综合征、中风/MI/心力衰竭住院治疗以及进展为糖尿病。
结果：在 3876 名接受 IRIS 试验分析的参与者中，2885 名纳入本分析（吡格列酮组 1456 名，安慰剂组 1429 名）。患者的平均（SD）年龄为 64（11）岁，吡格列酮组和安慰剂组分别有 974 名（66.9%）和 908 名（63.5%）患者为男性。在依从性良好的糖尿病前期人群（吡格列酮组 1456 人中的 644 人[44.2%]和安慰剂组 1429 人中的 810 人[56.7%]）中，风险比（95%CI）为中风/MI 的 0.57（0.39-0.84）、中风的 0.64（0.42-0.99）、急性冠状动脉综合征的 0.47（0.26-0.85）、中风/MI/心力衰竭住院的 0.61（0.42-0.88）和糖尿病进展的 0.18（0.10-0.33）。总死亡率、癌症和住院治疗略有下降，严重骨折略有增加，体重增加和水肿增加。意向治疗结果也显示出显著的事件减少，但程度较小。风险比（95%CI）为中风/MI 的 0.70（0.56-0.88）、中风的 0.72（0.56-0.92）、急性冠状动脉综合征的 0.72（0.52-1.00）、中风/MI/心力衰竭住院的 0.78（0.63-0.96）和糖尿病进展的 0.46（0.35 至 0.61）。
结论和相关性：吡格列酮可能对中风/短暂性脑缺血发作患者和糖尿病前期患者的二级预防有效，尤其是依从性好的患者。
试验注册：ClinicalTrials.gov 标识符：NCT00091949。
