Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure

Heart failure (HF) is a major cardiovascular complication of type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) both improve cardiovascular outcomes, but their comparative roles in HF and the potential value of combination therapy remain uncertain.

SGLT2 inhibitors consistently reduce HF hospitalization and cardiovascular death across the spectrum of ejection fraction, with relative risk reductions of approximately 30-37% (Hazard ratio (HR) 0.63-0.70). In contrast, GLP-1 receptor agonists have a more modest effect on HF hospitalization (approximately 11% risk reduction; HR 0.89) while primarily reducing atherosclerotic cardiovascular events and supporting weight and metabolic control. Mechanistically, SGLT2 inhibitors act predominantly through hemodynamic and cardiorenal pathways, whereas GLP-1 receptor agonists exert metabolic, anti-inflammatory, and anti-atherosclerotic effects, providing a rationale for potential complementarity. Emerging data from meta-analyses, subgroup analyses, and observational studies suggest possible additive benefits of combination therapy; however, most evidence is indirect and not derived from dedicated randomized heart failure trials. Safety data indicate no major excess risk with combination therapy, although gastrointestinal effects and class-specific adverse events remain relevant.

SGLT2 inhibitors are established therapies for reducing HF outcomes, whereas GLP-1 receptor agonists primarily address cardiometabolic risk with uncertain direct HF benefit. Combination therapy is mechanistically plausible but remains insufficiently supported by dedicated randomized evidence in HF populations. Further prospective trials are required to define its clinical role.