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 (GLP1-RAs) across the spectrum of chronic kidney disease (CKD) severity. This study evaluated the association of GLP1-RAs with major adverse cardiovascular events (MACE) in comparison with dipeptidyl peptidase-4 (DPP-4) inhibitors in the setting of CKD.

Study design: Retrospective observational cohort study.

Setting & participants: 24,576 new users of GLP1-RA and 44,367 new users of DPP-4 inhibitors with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m² in Ontario, Canada.

Exposure: New use of GLP1-RAs versus DPP-4 inhibitors.

Outcome: The primary outcome was MACE, comprising nonfatal myocardial infarction, unstable angina, nonfatal 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.

Analytical 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 cotransporter 2 (SGLT2) inhibitor, and 41% had CKD stages 3-5. MACE occurred among 1,296 (31.6 per 1,000 person-years) GLP1-RA users versus 1,374 (36.5 per 1,000 person-years) DPP-4 inhibitor users (subdistribution hazard ratio [SHR], 0.88 [95% CI, 0.80-0.97]). The lower rate of MACE among GLP1-RA users was largely related to a lower rate of cardiovascular death (SHR, 0.72 [95% CI, 0.62-0.85]). In subgroup analyses, there was no effect modification between the association of GLP1-RA 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, GLP1-RA initiation was associated with a lower rate of MACE than initiation of DPP-4 inhibitors.

Plain-language summary: A class of medications called glucagon-like peptide-1 receptor agonists (GLP1-RA) is now used for the treatment of diabetes. This study explored the association of GLP1-RA administration with cardiac health in people with kidney disease compared with another common class of diabetes medication, dipeptidyl peptidase-4 (DPP-4) inhibitors. In this study of nearly 69,000 individuals in Ontario, Canada, with a wide range of kidney function, people taking GLP1-RA experienced a lower rate of heart disease than those taking DPP-4 inhibitors. The lower rate was mainly related to fewer deaths from heart disease. Differences were consistent across different levels of kidney disease and regardless of whether people were also taking other medications that protect the heart.

Keywords: Cardiovascular disease; diabetes mellitus; epidemiologic studies; glucagon-like peptide-1 receptor agonist; heart disease; kidney disease.