Society of Diabetic Nephropathy Prevention Journal of Preventive Epidemiology 2476-3934 10 1 2025 01 01 Limb amputation following sodium-glucose cotransporter type 2 inhibitor therapy e38251 e38251 10.34172/jpe.2025.38251 EN Meysam Alipour https://orcid.org/0009-0006-2730-6001 Jalal Rezaei https://orcid.org/0009-0000-9601-9803 Venus Shahabi Rabori https://orcid.org/0000-0002-2589-5360 Meysam Arbuzia https://orcid.org/0000-0002-4643-7748 Amin Norouzbeygi https://orcid.org/0000-0001-9728-5740 Sara Rasta https://orcid.org/0009-0002-5081-7935 Hossein Mardanparvar https://orcid.org/0000-0001-7455-5373 Mobin Forghan https://orcid.org/0009-0002-9100-9854 Journal Article 10.34172/jpe.2025.38251 2024 07 13 2024 09 02 This review article examines the association between sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and the risk of limb amputation, particularly in patients with type 2 diabetes mellitus. This review aims to provide a comprehensive understanding of the risks associated with SGLT2i therapy and to inform future research directions in this area. While SGLT2i medications, such as canagliflozin, are recognized for their cardiovascular and renal benefits, emerging evidence suggests a potential increase in the risk of lower limb amputations (LLAs) among users compared to non-users of SGLT2i. This review synthesizes findings from various studies that report a slightly elevated risk of amputation linked to SGLT2i therapy, with mechanisms proposed including diuretic-induced hypovolemia and the partial inhibition of sodium-glucose cotransporter 1. Factors such as pre-existing peripheral artery disease (PAD), sensory neuropathy, and poor foot health are identified as significant risk enhancers for lower limb amputations in this patient population. In conclusion, patients with these conditions are at increased risk of limb ischemia and subsequent amputation, and the administration of SGLT2 inhibitors may potentially further increase this risk.