Real-world cardiovascular effectiveness of sustained glucagon-like peptide 1 GLP-1 receptor agonist usage in type 2 diabetes.

Background: Cardiovascular outcome trials have shown that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce cardiovascular event rates more effectively than placebo and in patients with type 2 diabetes at increased cardiovascular risk. However, the generalizability of these findings to real-world settings remains uncertain.

Aim: This study aimed to evaluate the real-world cardiovascular effectiveness of sustained GLP1-RA use compared to dipeptidyl peptidase 4 inhibitor (DPP-4i) over 3.5 years.

Methods: Using Danish nationwide registries, we emulated a target trial to assess the real-world effectiveness of GLP1-RAs in a population of individuals with type 2 diabetes mirroring the inclusion and exclusion criteria from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. The study period was 2012-2022. Outcomes included the composite of myocardial infarction, stroke, and cardiovascular mortality (3P-MACE), as well as each component individually, alongside all-cause mortality, heart failure, angina pectoris, and revascularization. Longitudinal Targeted Minimum Loss-based Estimation, a method that adjusts for both baseline and time-varying confounding, was used to estimate absolute risks of cardiovascular outcomes under sustained use of GLP1-RA and DPP 4i (active comparator), adjusting for baseline and time-varying confounding.

Results: We included 6,681 people initiating GLP1-RA and 19,072 initiating DPP-4i. Accounting for baseline and time-varying confounding, sustained GLP1-RA use showed a 2.5% (95% CI 0.8-4.1%) risk reduction of 3P-MACEover 3.5 years. Risk reductions for cardiovascular mortality, all-cause mortality, heart failure, and unstable angina pectoris were 2.3% (95% CI 1.4-3.1%), 2.5% (95% CI 0.7-4.3%), 0.9% (95% CI 0.01-1.8%), and 0.7% (95% CI 0.01-1.3%), respectively. No significant differences were observed for myocardial infarction, stroke, or revascularization with risk differences of 0.1% (95% CI -1.0 to 0.8%), 0.8% (95% CI -0.2 to 1.7%), and 0.2% (95% CI -0.7-1.1%), respectively.

Conclusions: This real-world study confirms the cardiovascular benefits of GLP1-RAs over DPP-4is, particularly for reducing cardiovascular and all-cause mortality under continuous treatment exposure in patients with type 2 diabetes at increased cardiovascular risk.