Why the study?
US Veterans Affairs patients with diabetes are at high cardiovascular disease risk and lack direct randomized clinical trial evidence of GLP-1RA efficacy.
Does liraglutide reduce MACE and all-cause mortality in US VA patients with diabetes?
Does liraglutide reduce MACE and all-cause mortality in US VA patients with diabetes?
The cardiovascular benefits of liraglutide observed in the LEADER trial generalize to the high-risk US VA diabetes population, supporting its use in this group.
Liraglutide's MACE and mortality benefits generalize to VA diabetes patients; extends LEADER evidence to high-risk group underrepresented in RCTs.
Objective: 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. Design: 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. Setting: Multi-national RCT and US VA. Participants: 9,336 LEADER participants and 357,075 VA users with diabetes from 2015-2023. Interventions: Liraglutide versus placebo. Main Outcomes and Measures: 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. Results: 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. Conclusions: 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.
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Josey et al. (2025) studied this question.
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