Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT2i) & Lower Limb Amputation

Following an approximately 2-fold increased risk of lower limb amputations associated with canagliflozin use observed in the CANagliflozin cardioVascular Assessment Study (CANVAS) trial and the CANVAS-Renal trial (a.k.a., CANVAS program), two randomized, placebo-controlled trials, the U.S. Food and Drug Administration (FDA) initiated this study to assess the feasibility of the Sentinel System to investigate the relationship between sodium-glucose co-transporter-2 inhibitor (SGLT2i) use and risk of lower limb amputations in real-world practice across products in the class of SGLT2i. 

This feasibility analysis was conducted to assess the overall numbers and person time of new use of SGLT2i (canagliflozin, dapagliflozin, and empagliflozin) and dipeptidyl peptidase-4 inhibitors (DPP4i) (sitagliptin, saxagliptin, linagliptin, and alogliptin), and the overall number of lower limb amputations by age group, sex, and year, during the period between January 1, 2013, and May 15, 2016. Results indicated that there were not enough eligible SGLT2i initiators to provide sufficient statistical power for evaluation of the risk of lower limb amputation either as a class or across individual products in the Sentinel Distributed Database, and the Active Risk Identification and Analysis (ARIA) System was found to be insufficient to conduct an inferential study.

Due to the lack of sufficient statistical power to evaluate risk of lower limb amputation in the Sentinel System, FDA initiated a protocol-based assessment using Medicare data to better characterize the safety concern.  Simultaneously clinical trial data became available that led to a 2017 FDA Drug Safety Communication requiring a boxed warning related to this safety concern; however, with more clinical trial data and information from the FDA protocol based assessment using Medicare data and published observational studies that became available, FDA updated the benefit and risk assessment and subsequently removed this Boxed warning in 2020 (2020 FDA Drug Safety Communication).