Lower Extremity Complications in Adults With Type 2 Diabetes Treated With Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter 2 Inhibitors, Dipeptidyl Peptidase-4 Inhibitors, and Sulfonylureas: An Emulated Target Trial.
Publication Title
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
Document Type
Article
Publication Date
2-2-2026
Keywords
SGLT2 inhibitor; amputation; comparative effectiveness; lower extremity complications; trial emulation; type 2 diabetes.; washington; spokane; pmrc
Abstract
OBJECTIVE: Lower extremity complications significantly impact morbidity and health care costs among people with type 2 diabetes (T2D). Evidence regarding the impact of different glucose-lowering medications on these outcomes remains inconclusive.
METHODS: We emulated a target trial using 2 linked national claims databases (Optum Labs Data Warehouse, Medicare fee-for-service). We included adults with T2D at moderate cardiovascular risk who initiated glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), or sulfonylurea between 2014 and 2021, and used propensity score inverse probability of treatment weighted Cox proportional hazards models to compare the incidence rates of the primary composite outcome of incident foot ulcer/abscess, osteomyelitis, Charcot arthropathy, or amputation across the 4 medication classes under the intention-to-treat framework.
RESULTS: The weighted study cohort included 81,998 DPP-4i initiators, 43,734 GLP-1RA initiators, 57,399 SGLT2i initiators, and 206,374 sulfonylurea initiators; they were well balanced on all examined baseline characteristics. Sulfonylurea use was associated with a higher risk of the composite lower extremity complications outcome compared with DPP-4i (hazard ratio [HR] 1.15; 95% CI 1.11-1.19), GLP-1RA (HR 1.20; 95% CI 1.13-1.28), and SGLT2i (HR 1.08; 95% CI 1.02-1.14). SGLT2i use was also associated with a higher risk compared with GLP-1RA (HR 1.11; 95% CI 1.03-1.21). Amputation events were rare in all treatment groups.
CONCLUSION: We observed greater relative risks of lower extremity complications with sulfonylurea use compared with DPP-4i, GLP-1RA, and SGLT2i use, and with SGLT2i use compared with GLP-1RA use. Reassuringly, the absolute event rate differences between the medication classes were < 1%. Diabetes management teams may consider these medication-associated risks when selecting glucose-lowering therapies for individuals without high cardiovascular risk, especially those predisposed to lower extremity morbidity.
Area of Special Interest
Kidney & Diabetes
Area of Special Interest
Orthopedics & Sports Medicine
Specialty/Research Institute
Endocrinology
Specialty/Research Institute
Orthopedics
Specialty/Research Institute
Surgery
DOI
10.1016/j.eprac.2026.01.012
