Effectiveness of Sodium–Glucose Cotransporter-2 Inhibitors Versus Glucagon-like Peptide-1 Receptor Agonists on Diabetic Foot Disease

BACKGROUND: The effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on diabetic foot disease have been mixed in prior trials of SGLT-2is compared with placebo. The comparative risk for diabetic foot disease with SGLT-2is compared with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is unknown. OBJECTIVE: To compare risks for foot disease in new users of SGLT-2is and GLP-1RAs. DESIGN: Cohort study using target trial emulation. SETTING: Danish population-based study. PARTICIPANTS: Patients with type 2 diabetes initiating SGLT-2i or GLP-1RA treatment, identified using national health care registry data from 2013 to 2023, and a convenience sample enrolled in a research cohort study with additional behavioral and clinical assessments. MEASUREMENTS: Incident diagnosis of foot disease outcomes (peripheral neuropathy, peripheral artery disease, foot ulcers, or lower-limb amputation) as defined by the International Working Group on the Diabetic Foot. Inverse probability of treatment-weighted risk ratios (RRs) were estimated, with adjustment for 45 demographic, clinical, and other factors. RESULTS: The registry cohort included 53 769 new users of SGLT-2is and 30 380 of GLP-1RAs. During 6 years of follow-up, any foot disease occurred in 10.8% of SGLT-2i users and 12.0% of GLP-1RA users, corresponding to an RR of 0.90 (95% CI, 0.84 to 0.97) in an intention-to-treat analysis; differences did not emerge until after year 3, when 40% of SGLT-2i users and 32% of GLP-1RA users had discontinued initial treatment. The modest reduction in risk among SGLT-2i users was driven by lower risk for neuropathy (RR, 0.78 CI, 0.68 to 0.87). Users of SGLT-2is and GLP-1RAs had similar risks for peripheral artery disease, foot ulcers, amputations, and all-cause mortality. LIMITATION: Residual confounding; exposure and outcome misclassification. CONCLUSION: New SGLT-2i users had a modestly lower risk for foot disease largely driven by a lower risk for neuropathy than GLP-1RA users. PRIMARY FUNDING SOURCE: Aarhus University and Center for Population Medicine.