Combination Therapy of GLP-1 RA and SGLT2i in Patients with Established Heart Failure: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND

A combination of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1 RA) and a Sodium-Glucose co-transporter-2 Inhibitor (SGLT2i) has demonstrated complementary benefits. This analysis aimed to compare combination therapy (GLP-1 RA and SGLT2i) with SGLT2i alone, both on top of standard HF care, in patients with baseline HF.

METHODS

Systematic searches (PubMed, ScienceDirect, Scopus) and citation searching were performed on February 17, 2026. Original studies directly compared combination therapy and SGLT2i alone in patients with pre-existing HF diagnosis were included. Primary endpoints were all-cause mortality, all-cause hospitalization, and worsening heart failure (WHF). NOS was used for quality assessment. R (v.4.4.1) was used for random-effect meta-analysis. Certainty of evidence was evaluated using the GRADE framework.

RESULTS

Eight cohorts (n = 75,833 patients) were included. Combination therapy resulted in a lower risk of all-cause mortality [RR: 0.62; 95% CI: 0.47-0.83; p = 0.0014], all-cause hospitalization [RR: 0.89; 95% CI: 0.84-0.96; p = 0.0012], and WHF [RR: 0.74; 95% CI: 0.64-0.87; p = 0.0001] during 1-year follow-up. Combination therapy was associated with significantly improved LVEF [MD: 3.83%; 95% CI: 0.44-7.22; p = 0.0397] and reduced acute kidney injury risk [HR: 0.70; 95% CI: 0.65-0.74] without any significant increase in adverse events (including hypoglycemia, gastrointestinal side effects, pancreatitis, and urinary tract infections). GRADE assessment yielded moderate evidence for three primary endpoints.

CONCLUSIONS

In patients with established HF, combination of GLP-1 RA and SGLT2i therapy was associated with significant reductions in mortality, hospitalization, and WHF, without significant adverse events. Further randomized trials are urgently warranted to confirm such outcomes.

REGISTRATION: PROSPERO identifier no. CRD420261320840.