Combined use of SGLT2 inhibitor and GLP-1 receptor agonist versus either monotherapy for cardiorenal Outcomes: an exploratory network meta-analysis of 16 randomized trials.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) each provide cardiorenal protection in trials of selected populations, but their combined effect has not been tested in dedicated head-to-head randomized trials. We performed an exploratory network meta-analysis (NMA) that integrated subgroup data from existing randomized controlled trials (RCTs) to compare SGLT2i, GLP-1RA, and concomitant SGLT2i + GLP-1RA use against placebo on cardiorenal outcomes. We ran a frequentist random-effects NMA. Major databases were searched for RCTs or post-hoc analyses (> 1 year follow-up) that reported subgroup outcomes by background SGLT2i or GLP-1RA use. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were hospitalisation for heart failure (HHF), composite renal outcomes, and total estimated glomerular filtration rate (eGFR) slope. Surface Under the Cumulative Ranking Curve (SUCRA) values are reported as supportive ranking summaries. Sixteen RCTs were pooled. Compared with placebo (without background SGLT2i or GLP-1RA), all active strategies reduced MACE and HHF (all p < 0.05). For composite renal events, combined use (RR 0.63, 95% CI 0.41-0.97) and SGLT2i (RR 0.70, 95% CI 0.61-0.79) significantly reduced risk. Combined use ranked first across outcomes (SUCRA 0.928 to 1.000). In head-to-head pooled comparisons, combined use was associated with lower MACE (RR 0.83, 95% CI 0.72-0.96) and HHF (RR 0.73, 95% CI 0.56-0.94) than SGLT2i alone, and with a better total eGFR slope than GLP-1RA alone (MD + 2.29 mL/min/1.73 m2/year, 95% CI 0.14-4.44). A subgroup NMA showed attenuated MACE ranking for combined use in ASCVD or high-ASCVD-risk trials, although the HHF ranking was preserved. In this exploratory synthesis, concomitant SGLT2i and GLP-1RA use appeared to be associated with more favourable cardiorenal effects than either agent alone. Because the combined-use comparison rests largely on non-randomized within-trial subgroups, these findings are hypothesis-generating and require confirmation in dedicated head-to-head randomized trials of combination therapy.