Risk of Cardiovascular Outcomes in Type 2 Diabetes Patients Following Addition of SGLT2 Inhibitors Versus Sulfonylureas to Baseline GLP-IRA Therapy.

Background: Several glucagon-like peptide agonists (GLP-1RA) and sodium-glucose co-transporter 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 (PSM) adjusting for >95 baseline covariates. The primary outcomes were 1) composite cardiovascular endpoint (CCE; comprised of myocardial infarction, stroke, and all-cause mortality) and 2) heart failure hospitalization. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated in each dataset and pooled via fixed-effects meta-analysis. Results: Among 12,584 propensity-score matched pairs (mean [SD] age 58.3 [10.9] year; male (48.2%)) across the 3 datasets, there were 107 CCE events [incidence rate per 1,000 person-years (IR) = 9.9; 95% CI: 8.1, 11.9] among SGLT2i initiators compared to 129 events [IR = 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 CCE was driven by numerical decreases in the risk of MI (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 [IR = 13.0; 95% CI: 11.0, 15.2] among SGLT2i initiators versus 206 [IR = 20.8; 95% CI: 18.1, 23.8] events 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 diabetic patients already on GLP-1RA, addition of SGLT2i - compared to addition of sulfonylurea - conferred greater cardiovascular benefit. The magnitude of the cardiovascular risk reduction was comparable to the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo where baseline GLP-1RA use was minimal.