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

Puriya Daniel Würtz Yazdanfard; Kathrine Kold Sørensen; Bochra Zareini; Ulrik Pedersen‐Bjergaard; Johan Sebastian Ohlendorff; Anders Munch; Mikkel Porsborg Andersen; Rasmus Bo Hasselbalch; Henrik Imberg; Viktor Tasseleus; Marcus Lind; Jonathan Valabhji; Pratik Choudhary; Stefanie Schmid; Stefanie Lanzinger; Julia K. Mader; Thomas Alexander Gerds; Christian Torp‐Pedersen

doi:10.1186/s12933-025-02924-0

Why the study?

The controlled nature and selected populations of RCTs limit the generalizability of SGLT2i cardiovascular benefits to real-world practice.

Does continuous SGLT2i treatment reduce major adverse cardiovascular events compared to DPP4i in patients with type 2 diabetes and cardiovascular disease?

Structured PICO

Does continuous SGLT2i treatment reduce major adverse cardiovascular events compared to DPP4i in patients with type 2 diabetes and cardiovascular disease?

P

Population

13,524 individuals with type 2 diabetes (T2D) and cardiovascular disease (CVD)

I

Intervention

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) for three years of continuous treatment

C

Comparator

Dipeptidyl peptidase-4 inhibitors (DPP4i)

O

Outcome

Major adverse cardiovascular events (MACE)composite

Real-world target trial emulation confirms that SGLT2i treatment significantly reduces MACE, heart failure hospitalizations, and mortality compared to DPP4i in patients with T2D and CVD, with absolute benefits exceeding those seen in clinical trials.

Implication

Real-world data may support SGLT2i use beyond trial populations; leaves open causal effects and broader applicability.

Abstract

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.