Importance Whether randomized clinical trial (RCT) results pertain to populations not included in trials remains a question of substantial interest.

Objective To evaluate generalizability of the cardiovascular benefits of liraglutide - a glucagon-like peptide-1 receptor agonist (GLP-1RA) - observed in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial in US Veterans Affairs Healthcare System (VA) patients with diabetes, a population at high cardiovascular disease risk and underrepresented in LEADER.

Design We used transportability methods to integrate real-world and RCT data and estimate the average treatment effect of liraglutide versus placebo had LEADER enrolled VA diabetes patients. We balanced baseline characteristics between LEADER participants and trial-eligible veterans using approximate balancing weights and estimated transported treatment effects with doubly-robust augmented inverse probability weighting. Sensitivity analyses varied VA cohort composition and balancing variables.

Setting Multi-national RCT and US VA

Participants LEADER participants and VA diabetes patients 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.

Results Data from 9,336 LEADER participants were transported onto 357,075 trial-eligible VA diabetes patients. 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, including in veterans currently ineligible for GLP-1RA treatment in the VA.

Conclusions and Relevance The benefits of liraglutide observed in LEADER generalized to veterans with diabetes - real-world evidence that can guide diabetes treatment for a high-risk population underrepresented in RCTs and inform formulary decisions for an integrated healthcare system.

Question Are the benefits of liraglutide observed in the LEADER randomized trial externally valid to US veterans with diabetes - a high-risk population underrepresented in the trial?

Findings When the LEADER study results were weighted to provide treatment effect estimates relevant to trial-eligible veterans, the effects of liraglutide on cardiovascular events and all-cause mortality were similar to that observed in the LEADER trial.

Meaning The cardiovascular and mortality benefits of liraglutide generalized to a population of US adults under-studied in trials of glucagon-like peptide-1 receptor agonists - evidence with implications for treatment access policies in the Veterans Affairs Healthcare System.

M.M. and K.K. are employees of Novo Nordisk and provided data access and assistance with reproducing analyses of the original LEADER study. They provided critical feedback on the manuscript but did not shape or modify the reported results, interpretation, or conclusions. The remaining authors report no conflicts of interest.

The funders had no role in the conduct of the study. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. S.R. was supported by VA award IK2-CX001907 and VA award I01-BX006417. J.E.B.R was supported by 1P30DK116073.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The VA Eastern Colorado Health Care System Research & Development Committee and the Colorado Multiple Institutional Review Board provided human subjects review and approval of the study.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Code for all statistical analysis is available upon request. A deidentified, anonymized limited data set derived from the datasets used for the analysis can be made available upon reasonable request from researchers with necessary human subjects research oversight and in accordance with VA data sharing policies.