Combined SGLT2i and GLP-1RA therapy cuts heart failure hospitalizations but not major CV/kidney events in T2DM

Patients with Type 2 Diabetes Mellitus (T2DM) face elevated risks of cardiovascular and renal complications. While both sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have independently demonstrated significant benefits in reducing these risks, the incremental efficacy of combining these two powerful drug classes remained uncertain. Current guidelines often recommend sequential addition, but a clear understanding of whether dual therapy offers superior outcomes for major cardiovascular events (MACE) or major adverse kidney events (MAKE) compared to monotherapy is crucial for optimizing treatment strategies and improving patient prognosis.

This network meta-analysis systematically reviewed and compared cardiovascular and kidney outcomes of combined SGLT2i and GLP-1RA therapy versus monotherapy. Researchers identified 12 randomized controlled trials (RCTs) involving 99,683 participants with type 2 diabetes mellitus through comprehensive searches of MEDLINE, Embase, and the Cochrane Library up to August 15, 2025. The study compared patients receiving SGLT2i alone, GLP-1RA alone, both SGLT2i and GLP-1RA, or neither medication. Primary outcomes included major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke) and major adverse kidney events (decline in eGFR, kidney failure, kidney-related death). Secondary outcomes assessed were heart failure-related hospital admissions, serious adverse events, and hypoglycemia.

The network meta-analysis of 99,683 participants revealed that combined SGLT2i and GLP-1RA therapy did not significantly alter the risk of major adverse cardiovascular events (MACE) compared to SGLT2i monotherapy (risk ratio [RR] 0.86, 95% CI 0.74 to 1.01; very low certainty) or GLP-1RA monotherapy (RR 0.95, 95% CI 0.81 to 1.12; very low certainty). Similarly, the risk of major adverse kidney events (MAKE) showed no significant difference with combined therapy versus SGLT2i (RR 1.05, 95% CI 0.74 to 1.49; very low certainty) or GLP-1RA (RR 0.86, 95% CI 0.60 to 1.21; very low certainty). However, a notable benefit was observed for heart failure-related hospital admissions:

Combined therapy was associated with a significantly lower risk of heart failure-related hospital admission than SGLT2i monotherapy (RR 0.72, 95% CI 0.52 to 0.99; very low certainty) and GLP-1RA monotherapy (RR 0.62, 95% CI 0.45 to 0.86; very low certainty). Risks of serious adverse events or hypoglycemia did not differ significantly between combined therapy and monotherapies, suggesting a comparable safety profile.