Risk of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Addition of SGLT2 Inhibitors Versus Sulfonylureas to Baseline GLP-1RA Therapy

Background: Several glucagon-like peptide receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents, and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits.

Methods: Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 US claims datasets (2013-2018) and were 1:1 propensity score-matched, adjusting for >95 baseline covariates. The primary outcomes were a composite cardiovascular end point (comprising myocardial infarction, stroke, and all-cause mortality) and heart failure hospitalization. Adjusted hazard ratios (HRs) and 95% CIs were estimated in each dataset and pooled through fixed-effects meta-analysis.

Results: Among 12 584 propensity score-matched pairs (mean [SD] age, 58.3 [10.9] years; 48.2% male) across the 3 datasets, there were 107 composite cardiovascular end point events (incidence rate per 1000 person-years, 9.9 [95% CI, 8.1-11.9]) among SGLT2i initiators compared with 129 events (incidence rate, 13.0 [95% CI, 10.9-15.3]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.76 (95% CI, 0.59-0.98); this decrease in composite cardiovascular end point was driven by numeric decreases in the risk of myocardial infarction (HR, 0.71 [95% CI, 0.51-1.003]) and all-cause mortality (HR, 0.68 [95% CI, 0.40-1.14]) but not stroke (HR, 1.05 [95% CI, 0.62-1.79]). For the outcome of heart failure hospitalization, there were 141 events (incidence rate, 13.0 [95% CI, 11.0-15.2]) among SGLT2i initiators versus 206 events (incidence rate, 20.8 [95% CI, 18.1-23.8]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.65 (95% CI, 0.50-0.82).

Conclusions: Risk of residual confounding cannot be fully excluded. Individual therapeutic agents within each class may have different magnitudes of effect. In this large real-world cohort of patients with diabetes already on GLP-1RA, addition of SGLT2i conferred greater cardiovascular benefit compared with addition of sulfonylurea. The magnitude of the cardiovascular risk reduction was comparable with the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo, where baseline GLP-1RA use was minimal.