背景:钠-葡萄糖协同转运蛋白2抑制剂(SGLT2is)和胰高血糖素样肽-1受体激动剂(GLP-1RA)可降低2型糖尿病(T2DM)患者发生主要不良心血管事件(MACE)的风险。然而,它们相对于彼此和其他二线降糖药的有效性是未知的,没有任何重大的正面交锋的临床试验。
目的:本研究的目的是比较SGLT2is的心血管有效性,GLP-1RA,二肽基肽酶-4抑制剂(DPP4is),和临床磺脲类药物(SUs)作为2型糖尿病的二线抗高血糖药。
方法:跨LEGEND-T2DM(跨2型糖尿病数据库网络的大规模证据生成和评估)网络,包括10个联邦国际数据源,从1992年到2021年。总的来说,1,492,855名接受二甲双胍单药治疗的T2DM和心血管疾病(CVD)患者被确定为启动了4种二线药物中的1种(SGLT2is,GLP-1RA,DPP4is,或SU)。使用大规模倾向评分模型进行主动比较器目标试验仿真,以进行成对比较。在评估了经验均衡和种群普适性之后,治疗中Cox比例风险模型适合3点MACE(心肌梗死,中风,和死亡)和4点MACE(3点MACE加心力衰竭住院)风险和HR估计值使用随机效应荟萃分析进行组合。
结果:超过520万患者年的随访时间和4.89亿患者天的风险时间,患者经历了25,982个3点MACE和41,447个4点MACE.SGLT2is和GLP-1RA的3点MACE风险低于DPP4is(HR:0.89[95%CI:0.79-1.00]和0.83[95%CI:0.70-0.98])和SU(HR:0.76[95%CI:0.65-0.89]和0.72[95%CI:0.58-0.88])。DPP4与低于SUs的3点MACE风险相关(HR:0.87;95%CI:0.79-0.95)。对于4点MACE结果也观察到3点MACE的模式。对于3点或4点MACE,SGLT2is和GLP-1RA之间没有显着差异(HR:1.06[95%CI:0.96-1.17]和1.05[95%CI:0.97-1.13])。
结论:在T2DM和CVD患者中,发现SGLT2is和GLP-1RA可降低心血管风险,两种药物都比DPP4更有效,这反过来又比SUs更有效。这些研究结果表明,SGLT2is和GLP-1RAs的使用应优先作为二线药物在那些已建立的CVD。
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials.
OBJECTIVE: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM.
METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis.
RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]).
CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.