Josey Kevin, Liu Wenhui, Warsavage Theodore, Medici Morten, Kvist Kajsa, Derington Catherine G, Reusch Jane E B, Ghosh Debashis, Raghavan Sridharan
US Department of Veterans Affairs Eastern Colorado Health Care System, Aurora, CO.
Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO.
medRxiv. 2025 May 30:2025.05.12.25327466. doi: 10.1101/2025.05.12.25327466.
To evaluate generalizability of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) randomized clinical trial (RCT) - a cardiovascular outcomes study of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide - to US Veterans Affairs Healthcare System (VA) patients with diabetes, a population at high cardiovascular disease risk lacking direct RCT evidence of GLP-1RA efficacy.
Transportability analysis that integrates real-world and RCT data to estimate the average treatment effect of liraglutide versus placebo had LEADER enrolled VA diabetes patients.
Multi-national RCT and US VA.
9,336 LEADER participants and 357,075 VA users with diabetes from 2015-2023.
Liraglutide versus placebo.
Risk differences (RD) in survival probabilities and hazard ratios (HR) of trial-adjudicated major adverse cardiovascular events (MACE) (composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular mortality) and all-cause mortality, estimated with augmented inverse probability weighting after balancing baseline characteristics between LEADER participants and trial-eligible veterans using approximate balancing weights. Sensitivity analyses varied VA cohort composition and balancing variables.
Transported effects of liraglutide compared to placebo on MACE and all-cause mortality in veterans ("VA-weighted LEADER") consistently overlapped the treatment effects observed in LEADER: RD of 3-year MACE of 2.0% [95% CI 0.8, 3.2] in VA-weighted LEADER versus 1.6% [0.3, 2.9] in LEADER; MACE HR 0.74 [0.61, 0.90] in VA-weighted LEADER versus 0.87 [0.78, 0.97] in LEADER; RD of 3-year all-cause mortality of 1.5% [0.6, 2.4] in VA-weighted LEADER versus 0.9% [-0.09, 1.9] in LEADER; all-cause mortality HR 0.71 [0.57, 0.89] in VA-weighted LEADER versus 0.85 [0.74, 0.97] in LEADER. Results were robust to all sensitivity analyses.
The benefits of liraglutide observed in LEADER generalized to veterans with diabetes - real-world evidence that can guide diabetes treatment decisions for a high-risk population underrepresented in RCTs and inform formulary policies for an integrated healthcare system.
评估利拉鲁肽在糖尿病中的作用及心血管结局研究（LEADER）随机临床试验（RCT）——一项关于胰高血糖素样肽-1受体激动剂（GLP-1RA）利拉鲁肽的心血管结局研究——对美国退伍军人事务医疗系统（VA）糖尿病患者的可推广性，这是一个心血管疾病风险高但缺乏GLP-1RA疗效直接RCT证据的人群。
整合真实世界和RCT数据以估计利拉鲁肽与安慰剂平均治疗效果的可移植性分析，LEADER纳入了VA糖尿病患者。
多国RCT和美国VA。
9336名LEADER参与者以及2015年至2023年期间357075名患有糖尿病的VA使用者。
利拉鲁肽与安慰剂。
通过在使用近似平衡权重平衡LEADER参与者和符合试验条件的退伍军人的基线特征后，采用增强逆概率加权法估计试验判定的主要不良心血管事件（MACE，非致命性心肌梗死、非致命性中风和心血管死亡的复合事件）和全因死亡率的生存概率风险差异（RD）和风险比（HR）。敏感性分析改变了VA队列组成和平衡变量。
与安慰剂相比，利拉鲁肽在退伍军人中对MACE和全因死亡率的移植效应（“VA加权LEADER”）始终与LEADER中观察到的治疗效果重叠：VA加权LEADER中三年MACE的RD为2.0%[95%CI 0.8, 3.2]，而LEADER中为1.6%[0.3, 2.9]；VA加权LEADER中MACE HR为0.74[0.61, 0.90]，而LEADER中为0.87[0.78, 0.97]；VA加权LEADER中三年全因死亡率的RD为1.5%[0.6, 2.4]，而LEADER中为0.9%[-0.09, 1.9]；VA加权LEADER中全因死亡率HR为0.71[0.57, 0.89]，而LEADER中为0.85[0.74, 0.97]。所有敏感性分析结果均稳健。
在LEADER中观察到的利拉鲁肽的益处可推广到患有糖尿病的退伍军人——这一真实世界证据可指导针对RCT中代表性不足的高危人群的糖尿病治疗决策，并为综合医疗系统的处方政策提供参考。
