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
Authors' 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.
Study context
- Population
- Adults with T2D at moderate cardiovascular risk initiating GLP-1 RA, SGLT2i, DPP-4i or SU, 2014–2021 (Optum Labs Data Warehouse, Medicare fee-for-service)weighted cohort
- Participants
- 81,998 / 43,734 / 57,399 / 206,374
- Comparison
- GLP-1 RA vs SGLT2i vs DPP-4i vs SU
- DPP-4in = 81,998
- GLP-1RAn = 43,734
- SGLT2in = 57,399
- Sulfonylurean = 206,374
- Outcome
- Composite of:
- Incident foot ulcer/abscess
- Osteomyelitis
- Charcot arthropathy
- Amputation
Methodological details2 linked national claims databases, propensity score inverse probability of treatment weighted, intention-to-treat
- 2 linked national claims databases
- Propensity score inverse probability of treatment weighted
- Intention-to-treat
Main finding
As reported in the abstract
Composite lower extremity complications
Hazard ratio (95% CI)
Sulfonylureavs DPP-4i
1.15(1.11–1.19)
Sulfonylureavs GLP-1RA
1.20(1.13–1.28)
Sulfonylureavs SGLT2i
1.08(1.02–1.14)
SGLT2ivs GLP-1RA
1.11(1.03–1.21)
Further findings
- Amputation events were rare in all treatment groups
Original publication
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. Endocr Pract. Published 2 February 2026. doi:10.
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