Glucagon-like Peptide-1 Receptor Agonists and Risk of Major Adverse Cardiovascular Events in Patients With CKD

Abstract

Rationale & objective: There are limited real-world data describing the cardiovascular benefits of glucagon-like-peptide-1 receptor agonists (GLP1RAs) across the spectrum of chronic kidney disease (CKD) severity. The objective of this study was to evaluate the association of GLP1RAs with major adverse cardiovascular events in comparison to dipeptidyl peptidase-4 (DPP-4) inhibitors in the setting of CKD.

Study design: Retrospective observational cohort study.

Setting & participants: 24,576 new users of GLP1RA and 44,367 new users of DPP-4 inhibitors with estimated glomerular filtration rate (eGFR) <90ml/min/1.73m² in Ontario, Canada.

Exposure: New use of GLP1RAs versus DPP-4 inhibitors.

Outcomes: The primary outcome was major adverse cardiovascular events, comprising non-fatal myocardial infarction, unstable angina, non-fatal ischemic stroke or transient ischemic attack, coronary revascularization, and cardiovascular death. Secondary outcomes included individual components of the composite outcome, hospitalization or emergency department visits for congestive heart failure, peripheral vascular disease revascularization, lower limb amputation, and all-cause mortality.

Analytic approach: Inverse probability of treatment weighting using propensity scores was used to minimize confounding. Multivariable Fine-Gray subdistribution hazard models stratified by eGFR subgroup were fit to evaluate the primary outcome.

Findings: Mean age of study participants was 69 years, 50% were female, 92% had type 2 diabetes mellitus, 40% were taking a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and 41% had CKD stages 3-5. MACE occurred among 1296 (31.6 per 1000 person-years) GLP1RA users vs. 1374 (36.5 per 1000 person-years) DPP-4 inhibitor users (sHR 0.88, 95% CI 0.80 to 0.97). The lower rate of MACE among GLP1RA users was largely related to a lower rate of cardiovascular death (sHR 0.72, 95% CI 0.62 to 0.85). In subgroup analyses, there was no effect modification between the association of GLP1RA initiation and lower rates of MACE by CKD stages, degree of albuminuria, or concomitant use of SGLT2 inhibitors.

Limitations: Retrospective design. A substantial amount of missing information on albuminuria.

Conclusions: In a population-based study of individuals across the spectrum of kidney disease, GLP1RA initiation was associated with a lower rate of MACE than initiation of DPP-4 inhibitors.