Sodium–Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study

Sodium–Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study

Diabetes Care Aug 2020, dc200267; DOI: 10.2337/dc20-0267

Oriana Hoi Yun Yu, Sophie Dell’Aniello, Baiju R. Shah, Vanessa C. Brunetti, Jean-Marc Daigle, MichaelFralick, Antonios Douros, Nianping Hu, Silvia Alessi-Severini, Anat Fisher, Shawn C. Bugden, Paul E.Ronksley, Kristian B. Filion, Pierre Ernst, Lisa M. Lix for the Canadian Network for Observational Drug Effect Studies (CNODES) Investigators

OBJECTIVE Reports of amputations associated with sodium–glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS This multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results.

RESULTS The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71–1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule.

CONCLUSIONS In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.

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