Background:Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes.Methods:Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor–by–treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term.Results:The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58–0.94] and 0.70 [0.37–1.30], respectively), expanded MACEs (0.77 [0.62–0.96] and 0.87 [0.51–1.48]), renal composite (0.70 [0.59–0.83] and 0.52 [0.33–0.83]), and MACEs or death (0.74 [0.59–0.93] and 0.65 [0.36–1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use.Conclusions:The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes.Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298.

中文翻译：

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Efpeglenatide 和临床结果伴有和不伴有钠-葡萄糖协同转运蛋白 2 抑制作用在 2 型糖尿病中的应用：AMPLITUDE-O 试验的探索性分析

背景：钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂和胰高血糖素样肽-1 受体激动剂均可减少 2 型糖尿病患者的心血管事件。然而，还没有心血管结局试验评估过它们联合使用的长期效果。AMPLITUDE-O 试验（Efpeglenatide 对心血管结果的影响）报告说，每周注射一次胰高血糖素样肽-1 受体激动剂 efpeglenatide（与安慰剂相比）可减少主要不良心血管事件（MACE）；MACE、冠状动脉血运重建或不稳定型心绞痛住院（扩大 MACE）；肾脏综合结局；2 型糖尿病和心血管或肾脏疾病患者的 MACE 或死亡。该试验根据基线或预期使用 SGLT2 抑制剂进行了独特的随机分层，包括迄今为止在胰高血糖素样肽-1 受体激动剂心血管结局试验中基线时 SGLT2 抑制剂使用率最高的（N=618，15.2%）。对其结果进行分析，以估计 SGLT2 抑制剂和依培格那肽对临床结果的综合影响。方法：使用针对地区、SGLT2 抑制剂随机分层和 SGLT2 抑制剂与治疗相互作用调整的 Cox 比例风险模型分析心血管和肾脏结果。使用重复测量的混合效应模型分析连续变量，其中还包括交互作用项。结果：在不存在和存在基线 SGLT2 抑制剂的情况下，efpeglenatide 与安慰剂相比对 MACE 的影响（风险比 [95% CI]）（0 .所有相互作用的P >0.2)。efpeglenatide 对血压、体重、低密度脂蛋白胆固醇和尿白蛋白与肌酐比值的降低似乎也与同时使用 SGLT2 抑制剂无关（所有相互作用 P ≥ 0.08 ）。最后，不良事件与基线 SGLT2 抑制剂使用没有差异。结论：efpeglenatide 的疗效和安全性似乎与同时使用 SGLT2 抑制剂无关。这些数据支持 SGLT2 抑制剂和胰高血糖素样肽-1 受体激动剂联合治疗 2 型糖尿病。注册：URL：https://www.clinicaltrials.gov。唯一标识符：NCT03496298。