BACKGROUND:Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).METHODS:A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups.RESULTS:We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54–0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55–0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28–0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13–2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24–2.48]).CONCLUSIONS:This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

中文翻译：

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GRADE 中的心血管结果（2 型糖尿病的降血糖方法：比较有效性研究）

背景：心血管疾病是2型糖尿病患者发病和死亡的主要原因。降糖药物对心血管风险较低的 2 型糖尿病患者心血管结局的影响尚不清楚。我们按 GRADE（2 型糖尿病的血糖降低方法：比较有效性研究）研究随机分配至甘精胰岛素、格列美脲、利拉鲁肽或西他列汀联合基线二甲双胍治疗组的参与者的心血管结局。方法：总共 5047 名参与者平均±标准差年龄为 57.2±10.0 岁、2 型糖尿病病程为 4.0±2.7 年、心血管疾病基线患病率较低（心肌梗塞，5.1%；脑血管意外，2.0%）的参与者的随访中位数为 5年。预设结局包括 MACE-3（主要不良心血管事件的复合：心血管死亡、心肌梗死和中风）、MACE-4（MACE-3+需要住院或血运重建的不稳定心绞痛）的组间首次事件时间分析、MACE-5（MACE-4+冠状动脉血运重建）、MACE-6（MACE-5+心力衰竭住院）以及各个组成部分。使用 Cox 比例风险模型将利拉鲁肽治疗组的 MACE 结局和心力衰竭住院情况与其他组进行比较。还使用比例率模型将 MACE-6 作为复发事件进行分析，以比较所有治疗组。 结果：我们观察到首次 MACE-3、MACE-4、MACE-5 或 MACE-6 的累积发生率没有统计学显着差异或其各个组成部分，按随机化治疗组。然而，与其他治疗组相比，利拉鲁肽治疗组的 MACE-5 风险显着降低（调整后风险比，0.70 [95% CI，0.54–0.91]；P = 0.021）、MACE-6（调整后的风险比，0.70 [95% CI，0.55-0.90]；P = 0.021），以及因心力衰竭住院（调整后的风险比，0.49 [95% CI，0.28-0.86]；P = 0.022）。与利拉鲁肽组相比，格列美脲（率比，1.61 [95% CI，1.13-2.29]）或西他列汀（率比 1.75；[95% CI，1.24] 治疗组的 MACE-6 事件复发率显着更高–2.48]）。结论：这项对当代 2 型糖尿病成人队列（基本上没有确定的心血管疾病）的比较有效性研究表明，与其他常用药物相比，利拉鲁肽治疗可以降低风险相对较低的患者发生心血管事件的风险降血糖药物。注册：URL：https://www.clinicaltrials.gov；唯一标识符：NCT01794143。