Sodium-Glucose Co-Transporter 2 inhibitors and cardiovascular outcomes: a trial-similar population vs. a broad population

Abstract Background The ‘Empagliflozin Cardiovascular Outcome Event Trial’ (EMPA-REG) reported a survival benefit of Sodium glucose co-transporters 2 inhibitor (SGLT2i) in high risk patients with type 2 diabetes (T2D). We aimed to emulate two target trials: one in a high-risk population resembling the EMPA-REG population and one in a broader real-world population, using causal inference methods. Methods We identified a trial-similar population with T2D using Danish nationwide registries, applying key EMPA-REG inclusion criteria: HbA1c >7.0% and established cardiovascular disease. In parallel, we defined a broader population of SGLT2i users where the main inclusion criterion was the presense of an Hba1c within 1 year of baseline and being over 18 years of age. Baseline confounders included sex, age, education, income, diabetes duration, HbA1c, renal disease, cardiovascular disease, diabetes medications, and cardiovascular medications. Time-varying confounders included additional diabetes medications and comorbidities. The primary outcome was time to the first major adverse cardiovascular event (MACE: cardiovascular death, myocardial infarction, or stroke). We applied longitudinal targeted minimum loss-based estimation (LTMLE) to estimate the continuous on-treatment effect of SGLT2i versus the cardiovascular-neutral DPP4i, accounting for both baseline and time-varying confounders. Outcomes were evaluated at 3 years. Results A total of 116,140 individuals initiating SGLT2i or DPP4i were identified. After applying EMPA-REG criteria, 14,090 individuals were eligible (SGLT2i: 6,133; DPP4i: 7,957). In the broad population, 107,494 individuals were included (SGLT2i: 52,596; DPP4i: 54,898). In the trial-similar population, the 3-year absolute risk of MACE was 11.5% (95% CI 10.0-12.9) for SGLT2i users and 14.2% (95% CI 13.1-15.4) for DPP4i users, yielding an absolute risk difference of 2.8 percentage-points (95% CI 1.1-4.4). In the broad population, the 3-year absolute risk of MACE was 6.7% (95% CI 6.2 - 7.2) for SGLT2i users and 8.0% (95% CI 7.8 - 8.3) for DPP4i users, yielding an absolute risk difference of 1.3 percentage-points (95% CI 0.8-1.8). Conclusion SGLT2i reduced the absolute risk of MACE compared to DPP4i in both a high-risk and a broader population. However, the absolute benefit is greater in high-risk individuals, highlighting the importance of baseline cardiovascular risk when considering treatment strategies.