Safety, Efficacy, and Cardiovascular Benefits of Combination Therapy With Sglt-2 Inhibitors and Glp-1 Receptor Agonists in Patients With Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Publisher



Mousavi A^{1, 2} ; Shojaei S^{1, 2} ; Soleimani H^{1, 2} ; Semiraninezhad D³ ; Ebrahimi P^{1, 2} ; Zafari A⁴ ; Ebrahimi R⁴ ; Roozbehi K³ ; Harrison A⁵ ; Syed MA⁶ ; Kuno T⁷ ; Askari MK⁸ ; Almandoz JP⁹ ; Jun J¹⁰ Show All Authors
Source: Diabetology and Metabolic Syndrome Published:2025

Abstract

Background: The potential benefits and risks of combination therapy with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus monotherapy remain a subject of debate to optimize metabolic and cardiovascular outcomes in patients with type 2 diabetes mellitus. This study aims to systematically review and meta-analyze the available evidence from randomized controlled trials. Methods: A comprehensive search identified relevant randomized controlled trials comparing combination therapy with SGLT-2i and GLP-1RA to monotherapy or treatment as usual (TAU). The main outcome was the incidence of hospitalization for heart failure. Other outcomes included major adverse cardiovascular events (MACE) (cardiovascular mortality, all-cause mortality, stroke, and myocardial infarction), changes in metabolic parameters, and adverse events. Random-effects meta-analysis estimated risk ratios (RRs), mean difference (MD), and 95% confidence intervals (CIs). We assessed the risk of bias in included studies using the Cochrane ROB 2.0 tool. Results: The meta-analysis included 10 randomized controlled trials with 42,651 participants, of which 2,820 were on combination therapy and the rest on SGLT-2i (37.1%), GLP-1RA (20.1%) monotherapies or TAU (42.8%). Combination therapy had a lower risk of hospitalization for heart failure versus GLP-1RA monotherapy (RR = 0.37, 95% CI 0.22; 0.65), SGLT-2i monotherapy (RR = 0.37, 95% CI 0.19; 0.75), and TAU (RR = 0.43, 95% CI 0.24; 0.75), respectively. Combination therapy also had a significantly lower risk of MACE versus TAU (RR = 0.73, 95% CI 0.61; 0.88). Combination therapy showed greater weight loss and hemoglobin A1c reduction versus SGLT-2i monotherapy (MD = -2.20, 95% CI −3.09; −1.31 and MD = −0.74, 95% CI −1.21; −0.27), respectively, while no difference was noted versus GLP-1RA monotherapy. The incidence of nausea and diarrhea was higher with combination therapy versus SGLT-2i monotherapy (MD = 3.34, 95% CI 1.74; 6.43 and MD = 1.75, 95% CI 1.10; 2.77), respectively. Conclusion: Combination therapy with SGLT-2i and GLP-1RA may provide superior cardiovascular, weight, and Hemoglobin A1c outcomes versus monotherapy despite higher gastrointestinal adverse events. These results may impact the management of patients with metabolic and cardiovascular diseases and highlight the need for further research on combination therapy to optimize outcomes. © The Author(s) 2025.