Cardiovascular, Kidney and Safety Outcomes with GLP-1 Receptor Agonists Alone and in Combination with SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors both improve cardiovascular and kidney outcomes in persons with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. Methods: We searched MEDLINE and Embase databases from inception until July 12, 2024 for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events ([MACE] nonfatal myocardial infarction, stroke or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50 % reduction in estimated glomerular filtration rate (eGFR ), kidney failure or death due to kidney failure, and annualized rate of decline in eGFR (eGFR slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on PROSPERO (CRD42024565765). Results: We identified three trials with 1,743/17,072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of MACE by 21% (HR 0.79, 95% CI 0.71-0.87), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR 0.77, 95% CI 0.54-1.09 and HR 0.79, 95% CI 0.71-0.87, respectively; P-heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR 0.58, 95% CI 0.36-0.93 and HR 0.73, 95% CI 0.63-0.85; P-heterogeneity=0.26). Effects on the composite kidney outcome (RR 0.79, 95% CI 0.66-0.95 ) and eGFR slope (0.78 mL/min/1.73m₂/year, 95% CI 0.57-0.98) also did not vary according to SGLT2 inhibitor use (P-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P-heterogeneity=0.29 and 0.50, respectively). Conclusions: In persons with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.