Real-world cardiovascular effects of liraglutide: transportability analysis of the LEADER trial

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.

What is already known on this topic

• The LEADER trial demonstrated that liraglutide, a GLP-1 receptor agonist, reduces cardiovascular events in patients with type 2 diabetes, but the trial enrolled few US veterans who have higher cardiovascular risk than the general diabetes population.

• While GLP-1 receptor agonists have proven cardiovascular benefits in clinical trials, their effectiveness in real-world populations with different characteristics than trial participants are unclear, particularly for healthcare systems with patients who are underrepresented in clinical trials.

What this study adds

• ur analysis shows that liraglutide’s cardiovascular benefits observed in LEADER generalize to US veterans with type 2 diabetes, with potentially greater absolute risk reductions for major cardiovascular events and mortality in this high-risk population.

• demonstrate how to extend trial results to a real-world population that may be underrepresented in the trial sample using methods that preserve randomization benefits while accounting for population differences.

• suggest that current VA formulary restrictions based on trial inclusion criteria (prior cardiovascular disease, elevated HbA1c) may unnecessarily limit access to beneficial therapy, as cardiovascular benefits were consistent across a more broadly defined veteran population.