Canagliflozin should be prescribed with caution to individuals with type 2 diabetes and high risk of amputation
Around 80% of lower extremity amputations (LEA) in individuals with diabetes are preceded by a diabetic foot ulcer . Diabetic foot ulcers usually occur due to a direct or indirect trauma associated with loss of protective sensation and are frequently accompanied by peripheral artery disease. Several factors increase the risk of LEA in diabetic individuals with or without diabetic foot ulcers, such as male sex, sensory neuropathy, peripheral artery disease, prior history of foot ulcer or amputation, poor glycaemic control, renal dysfunction, non-Asian ethnicity and presence of infection [2, 3, 4, 5, 6, 7, 8]. Recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, in which individuals were randomised to receive intensive therapy (HbA1c <42 mmol/mol [<6%]) or standard glycaemic control (HbA1c 53–63 mmol/mol [7.0–7.9%]), showed that the intensive regimen resulted in a significant decrease in LEA risk and that mean HbA1cstrongly predicted LEA...
KeywordsAdverse drug reactions Canagliflozin Diabetic foot Lower extremity amputation SGLT2
CANagliflozin cardioVascular Assessment Study
CANagliflozin cardioVascular Assessment Study-Renal
Dipeptidyl peptidase 4
Food and Drug Administration
Lower extremity amputations
Sodium–glucose cotransporter 2
All authors made substantial contributions to the conception and design, drafting the article, and giving final approval of the version to be published.
VA Puget Sound Healthcare System provided support for EJB’s participation in writing this commentary. The study sponsor was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.
Duality of interest
EJB received support from Bayer AG for his participation at an expert committee meeting. MM-S and IR-V declare no duality of interest associated with this manuscript.
- 7.van Battum P, Schaper N, Prompers L et al (2011) Differences in minor amputation rate in diabetic foot disease throughout Europe are in part explained by differences in disease severity at presentation. Diabet Med 28(2):199–205. https://doi.org/10.1111/j.1464-5491.2010.03192.x CrossRefPubMedGoogle Scholar
- 10.Matthews DR, Li Q, Perkovic V et al (2019) Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. https://doi.org/10.1007/s00125-019-4839-8
- 12.Neal B, Perkovic V, Matthews DR et al (2017) Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab 19(3):387–393. https://doi.org/10.1111/dom.12829 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Li D, Yang JY, Wang T, Shen S, Tang H (2018) Risks of diabetic foot syndrome and amputation associated with sodium glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes Metab 44(5):410–414. https://doi.org/10.1016/j.diabet.2018.02.001 CrossRefPubMedGoogle Scholar
- 17.Ryan PB, Buse JB, Schuemie MJ et al (2018) Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: a real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab 20(11):2585–2597. https://doi.org/10.1111/dom.13424 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Yuan Z, DeFalco FJ, Ryan PB et al (2018) Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: a retrospective cohort study. Diabetes Obes Metab 20(3):582–589. https://doi.org/10.1111/dom.13115 CrossRefPubMedGoogle Scholar
- 21.Yang JY, Wang T, Pate V et al (2019) Sodium-glucose cotransporter-2 inhibitor use and risk of lower-extremity amputation: evolving questions, evolving answers. Diabetes Obes Metab. https://doi.org/10.1111/dom.13647
- 22.Udell JA, Yuan Z, Rush T, Sicignano NM, Galitz M, Rosenthal N (2018) Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor: results from the EASEL population-based cohort study (evidence for cardiovascular outcomes with sodium glucose cotransporter 2 inhibitors in the real world). Circulation 137(14):1450–1459. https://doi.org/10.1161/CIRCULATIONAHA.117.031227 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Prentice RL, Langer R, Stefanick ML et al (2005) Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women’s Health Initiative clinical trial. Am J Epidemiol 162(5):404–414. https://doi.org/10.1093/aje/kwi223 CrossRefPubMedGoogle Scholar
- 28.Razzaghi R, Pidar F, Momen-Heravi M, Bahmani F, Akbari H, Asemi Z (2018) Magnesium supplementation and the effects on wound healing and metabolic status in patients with diabetic foot ulcer: a randomized, double-blind, placebo-controlled trial. Biol Trace Elem Res 181(2):207–215. https://doi.org/10.1007/s12011-017-1056-5 CrossRefPubMedGoogle Scholar
- 29.Razzaghi R, Pourbagheri H, Momen-Heravi M et al (2017) The effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: a randomized, double-blind, placebo-controlled trial. J Diabetes Complicat 31(4):766–772. https://doi.org/10.1016/j.jdiacomp.2016.06.017 CrossRefPubMedGoogle Scholar
- 32.(2018) Ertugliflozin for type 2 diabetes. JAMA 319(23): 2434–2435. https://doi.org/10.1001/jama.2018.5840