BACKGROUND: Whether using both sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is more effective than using either alone in type 2 diabetes mellitus remains uncertain. We sought to assess cardiovascular and kidney outcomes of combined SGLT2i and GLP-1RA therapy versus monotherapy using network meta-analysis.
METHODS: We identified randomized controlled trials (RCTs) of SGLT2i or GLP-1RA in patients with type 2 diabetes mellitus through a comprehensive search of MEDLINE, Embase, and the Cochrane Library until Aug. 15, 2025. We compared patients receiving SGLT2i, GLP-1RA, both SGLT2i and GLP-1RA, or neither medication in a systematic review and network meta-analysis. Primary outcomes were major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) and major adverse kidney events (decline in estimated glomerular filtration rate, kidney failure, and death due to kidney failure). Secondary outcomes included heart failure-related hospital admissions, serious adverse events, and hypoglycemia.
RESULTS: We included 12 RCTs with 99 683 participants. The risk of major adverse cardiovascular events did not differ significantly with combined SGLT2i and GLP-1RA therapy compared with SGLT2i (risk ratio [RR] 0.86, 95% confidence interval [CI] 0.74 to 1.01; very low certainty) or GLP-1RA alone (RR 0.95, 95% CI 0.81 to 1.12; very low certainty). Similarly, the risk of major adverse kidney events did not differ significantly with combined therapy from 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, combined therapy was associated with a lower risk of heart failure-related hospital admission than SGLT2i (RR 0.72, 95% CI 0.52 to 0.99; very low certainty) or GLP-1RA (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 monotherapy.
INTERPRETATION: Compared with SGLT2i or GLP-1RA alone, combined therapy did not significantly reduce the risk of major adverse cardiovascular or kidney events but was associated with lower risks of heart failure-related hospital admission. Randomized controlled trials directly comparing combined therapy with monotherapy are needed to clarify the comparative effectiveness of combined therapy in patients with type 2 diabetes mellitus.
PROTOCOL REGISTRATION: PROSPERO - CRD42024605727.
| Discipline Area | Score |
|---|---|
| Internal Medicine |  |
| Endocrine | |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
Useful information as an internist. Many are giving the combination in the hopes of additive benefits. Sobering to know the evidence is not there (yet?).
With a meta-analysis of this size, some direct contrasts for every pairwise comparison (except dual treatment vs placebo), low heterogeneity, and good consistency across the network, the best reflection of the potential effect size is the point estimate 0.86. The fact that the confidence interval barely crosses 1.01 does not mean that there is no effect on major adverse cardiovascular events worth noting. The abstract results falsely treat the p-value as a dichotomous switch (significant/not significant) rather than the nuance that it is a spectrum.
