Effects of SGLT2 Inhibitors on Cardiovascular and Lower Limb Events in Patients with Type 2 Diabetes: A Nationwide Population-Based Study

Abstract

Purpose: The cardiovascular (CV) benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) are well established, but their effects on lower limb events (LLEs) remain inconclusive, with conflicting findings from clinical trials and real-world studies. This study aimed to assess the risks of CV and LLEs associated with SGLT2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with type 2 diabetes.

Patients and methods: The study included patients with type 2 diabetes who were newly prescribed SGLT2i or DPP-4i using data from the National Health Insurance Service in South Korea. A 1:1 propensity score matching method was used to assign 97,584 patients to the SGLT2i and DPP-4i groups. The study endpoints included all-cause mortality, CV events, and LLEs-a composite outcome encompassing diabetic foot or ulcer, amputation, debridement, graft transplantation or flap operation, and revascularization.

Results: Over a median follow-up of 2.74 years, the SGLT2i group had a lower incidence of all-cause mortality (hazard ratio [HR] 0.63, 95% CI 0.51-0.78), heart failure (HR 0.85, 95% CI 0.78-0.93), ischemic stroke (HR 0.77, 95% CI 0.67-0.88), and peripheral artery disease (HR 0.66, 95% CI 0.63-0.69) than the DPP-4i group. However, no significant difference was observed in the incidence of myocardial infarction (HR 1.06, 95% CI 0.87-1.28) or LLEs (HR 1.05, 95% CI 0.80-1.38) between the two groups.

Conclusion: In this nationwide, real-world study, SGLT2i use demonstrated a neutral effect on LLEs compared to DPP-4i in patients with type 2 diabetes. However, SGLT2i was associated with a lower risk of all-cause mortality, heart failure, ischemic stroke, and peripheral artery disease. These findings contribute to the ongoing debate on the safety of SGLT2i regarding LLEs and highlight their broader CV benefits, warranting further investigation into their long-term effects on lower limb complications.

Keywords: amputation; cardiovascular diseases; diabetic foot; lower extremity; peripheral arterial disease; sodium-glucose transporter 2 inhibitors; surgical.

Figure 1

Flow chart of the study cohort.

Figure 2

Kaplan-Meier curves of endpoints in new users of SGLT2 inhibitors vs DPP-4 inhibitors. (A) Cumulative incidence for the all-cause death. (B) Cumulative incidence for the heart failure. (C) Cumulative incidence for the myocardial infarction. (D) Cumulative incidence for the percutaneous coronary intervention. (E) Cumulative incidence for the ischemic stroke. (F) Cumulative incidence for the peripheral artery disease. (G) Cumulative incidence for the lower limb events.

Figure 3

Subgroup analyses of lower limb events: SGLT2 inhibitor vs DPP-4 inhibitor.