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

Min Jin Lee,1,2,* Ji Hyun Bae,1,2,* Ah Reum Khang,1,2 Yang Ho Kang,1,2 Joo Yeon Kim,1,2 Su Hyun Kim,1,2 Soo Yong Lee,2,3 Seung Hun Woo,2,4 Minae Park,5 Sojeong Park,5 Dong Hee Kim,2 Dasol Kang,2 Sujin Park,2 Dongwon Yi1,3 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea; 2Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea; 3Division of Cardiology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea; 4Department of Orthopedic Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea; 5Department of Data Science, Hanmi Pharm. Co., Ltd, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Dongwon Yi, Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea, Email [email protected]: 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: sodium-glucose transporter 2 inhibitors, cardiovascular diseases, lower extremity, peripheral arterial disease, diabetic foot, amputation, surgical