Background
Evidence on the cardiovascular benefits of combining empagliflozin with glucagon-like peptide-1 receptor agonists (GLP-1RA) is limited, derived primarily from indirect comparisons or subgroup analyses of cardiovascular outcome trials.
Methods
We conducted a cohort study emulating two comparative effectiveness trials using US healthcare databases (2013–2022), including federal Medicare and commercial claims data (Optum Clinformatics and MarketScan). Among adults with type 2 diabetes in routine care, we compared cardiovascular outcomes in patients initiating:
- (i) empagliflozin first, followed by augmentation with either GLP-1RA or dipeptidyl peptidase-4 inhibitors (DPP-4i), and
- (ii) GLP-1RA first, followed by augmentation with either empagliflozin or sulfonylureas.
Primary outcomes were modified major adverse cardiovascular events (MACE; composite of myocardial infarction, stroke, and all-cause mortality) and a composite of hospitalization for heart failure (HHF) or all-cause mortality.
We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years with 95% confidence intervals (CI), adjusting for over 130 baseline covariates using propensity score matching weights.
Results
Compared with empagliflozin-DPP-4i initiators, empagliflozin-GLP-1RA was associated with:
- lower risk of MACE: HR 0.81 (95% CI: 0.67, 0.97); RD -3.7 (-7.1, -0.2)
- lower HHF-mortality: HR 0.61 (0.48, 0.77); RD -6.6 (-9.3, -3.9)
Compared with the GLP-1RA-sulfonylurea combination, the GLP-1RA-empagliflozin combination had:
- lower risk of MACE: HR 0.68 (0.56, 0.81); RD -5.3 (-7.9, -2.6)
- lower HHF-mortality: HR 0.62 (0.51, 0.76); RD -3.7 (-6.1, -1.8)
Conclusions
In US clinical practice, adding GLP-1RA to empagliflozin was associated with lower risks of MACE and HHF-mortality compared with adding DPP-4i. Among GLP-1RA initiators, adding empagliflozin was associated with lower cardiovascular risk than adding sulfonylureas, supporting potential additive cardiovascular benefits of GLP-1RA-empagliflozin combination therapy.
Keywords: Cardiovascular disease; Empagliflozin; Glucagon-like peptide-1 receptor agonist; Heart failure; Sodium-glucose cotransporter-2 inhibitor; Type 2 diabetes mellitus.
© 2026. The Author(s).
