One or two? Comparison of the cardiorenal effects between combination therapy and monotherapy with SGLT2i or GLP1RA

Objective: This study aimed to evaluate the cardiorenal effect of combining sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) when compared with monotherapy of either agent in patients with type 2 diabetes (T2D). Methods: PubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov were systematically searched from inception to June 2024. Eligible studies included randomised controlled trials and observational studies assessing that compared with SGLT2i or GLP-1RA monotherapy, the risk of cardiorenal outcomes in patients with T2D who treated with combination therapy. Pooled relative risk (RR) and 95% confidence intervals (CIs) were computed in random-effects model. Results: In all, five RCTs, 10 post hoc analyses and one observational study were included. The reduced risk of the composite cardiovascular outcome was observed in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.57, 95% CI 0.38–0.86, p = 0.008) or GLP-1RA monotherapy (RR = 0.77, 95% CI 0.65–0.91, p = 0.002). Likewise, the composite renal adverse events were less frequent in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.69, 95% CI 0.59–0.82, p < 0.001) or GLP-1RA monotherapy (RR = 0.66, 95% CI 0.53–0.83, p < 0.001). Compared with GLP-1RA monotherapy, the combination therapy of SGLT2i and GLP-1RA was associated with lower risks of heart failure–related outcomes (RR = 0.63, 95% CI 0.51–0.77, p < 0.001) and all-cause mortality (RR = 0.66, 95% CI 0.50–0.88, p = 0.004) in patients with T2D. Conclusion: The cardiorenal benefits might be magnified with the combination therapy of SGLT2i and GLP-1RA when compared with monotherapy of either agent. Further investigations are needed to validate the findings.