Combination of GLP-1 receptor agonists and SGLT2 inhibitors in cardiometabolic disease: synergistic, additive, or non-additive effects? A narrative review.

backgroundGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) are two novel classes of glucose-lowering agents with proven cardiometabolic benefits beyond glycaemic control. Both are now recommended in international guidelines for patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk. As they operate through complementary mechanisms, their combined use may confer additive or synergistic benefits on cardiometabolic outcomes.

aimThis narrative review examines and summarizes the available evidence on the synergistic effects of GLP-1 RAs and SGLT2 inhibitors in cardiometabolic disease, encompassing their effects on glycaemic control, body weight, blood pressure, cardiovascular events, renal outcomes, and mortality.

methodsA narrative review of randomised clinical trials, observational studies, post-hoc analyses, and meta-analyses evaluating the combination of GLP-1 RAs and SGLT2 inhibitors in patients with T2DM was conducted. Individual drug class evidence from landmark cardiovascular and renal outcome trials is also reviewed to contextualise the potential for synergy. Evidence from trials conducted in non-diabetic populations with obesity or heart failure with preserved ejection fraction (HFpEF) is also examined where relevant to the combination therapy rationale.

resultsThe combination of GLP-1 RAs and SGLT2 inhibitors consistently produced greater reductions in HbA1c (- 1.0 to - 1.5%), body weight (- 3 to - 9 kg), and systolic blood pressure (- 4 to - 10 mmHg) compared with either agent alone across multiple randomised trials, including DURATION-8, AWARD-10, SUSTAIN-9, and LIRA-ADD2SGLT2. Observational studies suggest a significant reduction in major adverse cardiovascular events and heart failure hospitalisations with combination therapy versus individual agents taken separately, while both classes also confer cardiovascular and renal benefits in non-diabetic populations at standard doses. However, randomised trial data do not consistently confirm superiority in cardiovascular event rates. Effects on renal outcomes are inconsistent across studies. Combination therapy appears well tolerated, with no significant increase in serious adverse events beyond those expected from each agent individually.

conclusionsThe combination of GLP-1 RAs and SGLT2 inhibitors exerts additive benefits on glycaemic control, body weight, and blood pressure reduction. Evidence for synergistic cardiovascular and renal protection is promising but remains limited, largely derived from observational data and secondary analyses. Larger, dedicated randomised trials are needed to determine whether combination therapy confers superior cardiometabolic outcomes beyond either agent alone.