AIM: To examine whether sodium-glucose co-transporter-2 (SGLT2) inhibitors are associated with a higher risk of lower-extremity amputation than dipeptidyl-peptidase-4 (DPP-4) inhibitors and sulphonylureas. METHODS: We conducted a retrospective cohort study, using the MarketScan Commercial Claims and Encounters Database (2013-2015), to compare the incidence of lower-extremity amputation (LEA) between initiators of SGLT2 inhibitors and initiators of two second-line drugs, DPP-4 inhibitors and sulphonylureas (SUs). We estimated crude incidence rates (IRs) and adjusted hazard ratios (aHR), with 95% confidence intervals (CIs), before and after propensity-score weighting. We additionally conducted sensitivity analyses using a comparator group of all non-metformin, non-SGLT2 inhibitor glucose-lowering drugs, as previous studies used this approach. RESULTS: In a cohort of 328 150 individuals aged 18 to 64 years, the IR of LEA ranged from 1.5 to 2.4 per 1000 person-years. In as-treated analysis, the estimated hazard of LEA was increased among SGLT2 inhibitor initiators compared to DPP-4 inhibitor initiators (aHR 1.69, 95% CI 1.20-2.38), but not compared to SU initiators (aHR 1.02, 95% CI 0.67-1.55) or non-metformin, non-SGLT2 inhibitor initiators (aHR 1.02, 95% CI 0.54-1.93). Results were consistent in intention-to-treat analysis and across a number of sensitivity analyses. CONCLUSIONS: Among commercially insured patients in the United States, our results suggest that initiation of SGLT2 inhibitors may increase the risk of LEA compared to initiation of DPP-4 inhibitors. Contrasting results when comparing SGLT2 inhibitor initiators to DPP-4 inhibitor and SU initiators highlight the importance of choosing appropriate comparator drugs when addressing comparative effectiveness and safety questions that can inform clinical decision-making.