Effects of Sodium-glucose Cotransporter 2 Inhibitors on Amputation, Bone Fracture, and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus Using an Alternative Measure to the Hazard Ratio
- 230 Downloads
Background and Objective
Empagliflozin and canagliflozin decreased the risk of major adverse cardiovascular events (MACE) compared with placebo in randomized clinical trials which were conducted to evaluate their cardiovascular risks. However, canagliflozin increased the risks of amputation and bone fracture, and the reasons for these observed differences remain unclear. The objective of this study was to evaluate the safety risks, specifically the risks of amputation and bone fracture, associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors by using the difference in restricted mean survival time (RMST), an alternative measure to the hazard ratio.
This study included all the randomized clinical trials with cardiovascular events as a primary endpoint, comparing SGLT2 inhibitors with placebo in patients with type 2 diabetes mellitus, the results of which have been published as of 11 September 2018: EMPA-REG OUTCOME (empagliflozin) and CANVAS Program (canagliflozin). We reevaluated these trials by estimating RMSTs based on the reconstructed individual patient data for each time-to-event outcome from publicly available information.
The differences of RMSTs (SGLT2 inhibitors minus placebo: point estimate and 95% confidence interval) for lower-extremity amputations and low-trauma fracture were − 20 days (− 30, − 10) and − 15 days (− 30, 0), respectively, in CANVAS Program (2190 days follow-up). That for lower-limb amputation was 1 day (− 6, 8) in EMPA-REG OUTCOME (1440 days follow-up). Regarding the MACE, both empagliflozin and canagliflozin statistically significantly decreased the risk compared with placebo.
Canagliflozin was shown to increase the risks of amputation and bone fracture compared with placebo when using the difference in RMST.
Compliance with Ethical Standards
Conflict of interest
Masayuki Kaneko and Mamoru Narukawa declare that they have no conflict of interest.
The preparation of this manuscript was not supported by any external funding.
- 1.American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S74.Google Scholar
- 2.US Department of Health and Human Services, Food and Drug Administration; Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071627.pdf. Accessed 11 Sep 2018.
- 14.American Diabetes Association Conference 2017. The results of the CANVAS study. https://www.georgeinstitute.org/sites/default/files/canvas-study-results-ada-2017.pdf. Accessed 11 Sep 2018.
- 17.R Foundation for Statistical Computing. R: a language and environment for statistical computing. https://www.R-project.org. Accessed 11 Sep 2018.
- 18.US Department of Health and Human Services, Food and Drug Administration. Jardiance [prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204629s016lbl.pdf. Accessed 11 Sep 2018.
- 21.Yuan Z, DeFalco FJ, Ryan PB, Schuemie MJ, Stang PE, Berlin JA, et al. 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. 2018;20:582–9.CrossRefGoogle Scholar
- 23.US Department of Health and Human Services, Food and Drug Administration. Invokana [prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204042s026lbl.pdf. Accessed 11 Sep 2018.
- 24.Japan Pharmaceuticals and Medical Devices Agency. Canaglu [package insert]. http://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/400315_3969022F1029_1_11. Accessed 11 Sep 2018.
- 27.US National Library of Medicine, Clinicaltrials.gov. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). https://clinicaltrials.gov/ct2/show/NCT01730534. Accessed 11 Sep 2018.