Type 2 diabetes, sodium-glucose cotransporter-2 inhibitors and cardiovascular outcomes: real world evidence versus a randomised clinical trial.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefits in randomised controlled trials (RCT). However, the controlled nature of RCTs and the selected trial populations limit their generalizability to real-world practice. Substantial methodological advances now enable robust estimation of absolute risks, risk differences, and continuous on-treatment effects, providing more clinically interpretable measures of SGLT2i effectiveness than previously possible with traditional models reliant on hazard ratios. METHODS: We conducted a target trial emulation using nationwide Danish registries to evaluate the real-world effectiveness of SGLT2i versus dipeptidyl peptidase-4 inhibitors (DPP4i) in individuals with type 2 diabetes (T2D) and cardiovascular disease (CVD). Outcomes included major adverse cardiovascular events (MACE), heart failure hospitalizations, and all-cause mortality. Absolute risks and risk differences for three years of continuous treatment were estimated using longitudinal targeted minimum loss-based estimation, adjusting for baseline and time-varying confounders. RESULTS: Among 116,823 patients who redeemed SGLT2i or DPP4i for the first time, 13,524 met inclusion and exclusion criteria (SGLT2i: 6,025; DPP4i: 7,499). At three years, the risk of MACE was 11.5% for SGLT2i users versus 14.2% for DPP4i users (risk-difference: 2.8 percentage-points, 95% CI: 1.1-4.4%). Heart failure hospitalizations were lower by 5.1 percentage-points (95% CI: 4.3-6.0%), and all-cause mortality by 3.1 percentage-points (95% CI: 1.5-4.7%), all favoring SGLT2i. Notably, we also observed a risk reduction in stroke by 2.4 percentage-points (95% CI: 1.7-3.1%). CONCLUSIONS: This study demonstrates the real-world effectiveness of continuous SGLT2i treatment in reducing cardiovascular events in patients with T2D and CVD. The absolute benefit of SGLT2i was larger in a real world population than in the intention to treat estimate in clinical trials.