American Diabetes Association
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Sodium Glucose Co-transporter-2 Inhibitors and the Risk of Below-knee Amputation: a Multicenter Observational Study

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posted on 2020-08-05, 20:53 authored by Oriana Hoi Yun Yu, Sophie Dell’Aniello, Baiju R. Shah, Vanessa C. Brunetti, Jean-Marc Daigle, Michael Fralick, Antonios Douros, Nianping Hu, Silvia Alessi-Severini, Anat Fisher, Shawn C. Bugden, Paul E. Ronksley, Kristian B. Filion, Pierre Ernst, Lisa M. Lix, the Canadian Network for Observational Drug Effect Studies (CNODES) Investigators
Objective: Reports of amputations associated with sodium glucose co-transporter (SGLT) 2 inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase (DPP)-4 inhibitors among patients with type 2 diabetes.

Research Design and Methods: This is a multicenter observational study using administrative healthcare databases from 7 Canadian provinces and the United Kingdom. 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% confidence intervals (CI) 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 among SGLT2 inhibitor users was 1.3 per 1,000 person-years 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 to 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 to DPP-4 inhibitor use. While these findings provide some reassurance, studies with longer duration of follow-up are needed to assess potential long-term effects.


The Canadian Network for Observational Drug Effect Studies (CNODES), a collaborating centre of the Drug Safety and Effectiveness Network (DSEN), is funded by the Canadian Institutes of Health Research (CIHR; Grant # DSE-146021).


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