BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. METHODS In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. RESULTS In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m2/year). CONCLUSIONS This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

中文翻译：

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艾塞那肽和开放标签的SGLT2抑制剂治疗（平行或相继给予）对2型糖尿病的死亡率以及心血管和肾脏结局的影响：来自EXSCEL试验的见解。

背景技术钠葡萄糖共转运蛋白2抑制剂（SGLT2i）和胰高血糖素样肽1受体激动剂（GLP-1 RA）通过不同的机制改善2型糖尿病患者的心血管和肾脏预后。但是，缺乏有关同时接受GLP-1 RA和SGLT2i治疗的患者的临床结局的证据。我们旨在提供与每周一次或每周一次的GLP-1 RA艾塞那肽（EQW）并行使用或不久后使用开放标签SGLT2i对心肾预后的影响的见解。方法在EXSCEL心血管预后试验EQW组中，8.7％的参与者发生了SGLT2i下降。这些EQW + SGLT2i用户倾向匹配：（1）不服用SGLT2i的安慰剂组参与者（每组n = 572）；（2）根据他们在SGLT2i启动之前的最新测量特征，不参加SGLT2i的EQW臂参与者（n = 575），并在比较组中进行等效的研究访问。使用Cox回归分析比较了首次出现重大不良心血管事件（MACE）的时间和全因死亡率（ACM）。使用混合模型重复测量分析对eGFR斜率进行定量。结果在调整后的分析中，与单独使用安慰剂（调整后的危险比0.68，95％CI 0.39-1.17）和单独使用EQW相比，使用EQW + SGLT2i组合进行MACE的风险在数值上较低（0.85，0.48-1.49）。与安慰剂（0.38，0.16-0.90）和EQW（0.41，0.17-0.95）相比，ACM的风险名义上显着降低。与安慰剂组（+ 1.94，95％CI 0.94-2.94 mL / min / 1.73 m2 /年）和单独的EQW（+ 2.38，1.40-3.35 mL / min / 1.73 m2）相比，EQW + SGLT2i的组合使用也名义上显着改善了估计eGFR斜率/年）。结论这项事后分析支持以下假设，即联合EQW和SGLT2i治疗可能对心血管结局和死亡率产生益处。试用注册Clinicaltrials.gov，标识号：NCT01144338，注册日期：2010年6月15日。