Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) independently improve cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM). We conducted a systematic review and meta-analysis to evaluate whether combination SGLT2i and GLP-1RA therapy provides additional cardiorenal benefit compared with either SGLT2i or GLP-1RA monotherapy.

This systematic review followed PRISMA guidelines and was registered with PROSPERO (CRD420251053689). MEDLINE, Embase, Emcare, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, and Global Health databases were searched from inception to 12 January 2026. Randomised controlled trials (RCTs), cohort studies with prospective or retrospective data collection comparing combination therapy with monotherapy in adults with T2DM were included. Primary outcomes were major adverse cardiovascular events (MACE) and major adverse kidney events (MAKE). Secondary outcomes were heart failure hospitalisation (HHF), all-cause mortality, estimated glomerular filtration rate (eGFR) and albuminuria. Hazard ratios (HRs) were pooled using random-effects meta-analysis, while eGFR and albuminuria were synthesised descriptively due to heterogeneous reporting.

Thirty-one studies (8 RCTs, 3 prospective and 20 cohort studies with retrospective data collection) were included. In RCTs, the average pooled effects of combination therapy were: HR=0.85, 0.71-1.01 (MACE), HR=0.65, 0.33-1.31 (MAKE) and HR=0.89, 0.72-1.10 (all-cause mortality), with significant reduction in HHF (HR=0.26, 0.12-0.56). Cohort studies with retrospective data collection demonstrated similar findings for MACE (HR=0.87, 0.73-1.04) and significant reductions in HHF (HR=0.62, 0.58-0.66), MAKE (HR=0.59, 0.46-0.75), and all-cause mortality (HR=0.57, 0.52-0.63). Descriptive synthesis demonstrated inconsistent outcomes of combination therapy on eGFR and albuminuria across studies.

Combination SGLT2i and GLP-1RA therapy significantly reduced HHF compared with monotherapy. Although reductions in MACE, MAKE and all-cause mortality in RCTs were not statistically significant, the direction of effect favoured combination therapy. Further prospective studies with standardised renal outcome reporting are needed to better define the cardiorenal effects of combination therapy.