Advertisement

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

  • Masayuki Kaneko
  • Mamoru Narukawa
Original Research Article
  • 70 Downloads

Abstract

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.

Methods

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.

Results

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.

Conclusions

Canagliflozin was shown to increase the risks of amputation and bone fracture compared with placebo when using the difference in RMST.

Notes

Compliance with Ethical Standards

Conflict of interest

Masayuki Kaneko and Mamoru Narukawa declare that they have no conflict of interest.

Funding

The preparation of this manuscript was not supported by any external funding.

References

  1. 1.
    American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S74.Google Scholar
  2. 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.
  3. 3.
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefGoogle Scholar
  4. 4.
    Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.CrossRefGoogle Scholar
  5. 5.
    Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.CrossRefGoogle Scholar
  6. 6.
    Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al. Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. J Clin Oncol. 2014;32:2380–5.CrossRefGoogle Scholar
  7. 7.
    Uno H, Wittes J, Fu H, Solomon SD, Claggett B, Tian L, et al. Alternatives to hazard ratios for comparing the efficacy or safety of therapies in noninferiority studies. Ann Intern Med. 2015;163:127–34.CrossRefGoogle Scholar
  8. 8.
    Trinquart L, Jacot J, Conner SC, Porcher R. Comparison of treatment effects measured by the hazard ratio and by the ratio of restricted mean survival times in oncology randomized controlled trials. J Clin Oncol. 2016;34:1813–9.CrossRefGoogle Scholar
  9. 9.
    Chappell R, Zhu X. Describing differences in survival curves. JAMA Oncol. 2016;2:906–7.CrossRefGoogle Scholar
  10. 10.
    Zucker DM. Restricted mean life with covariates: modification and extension of a useful survival analysis method. J Am Stat Assoc. 1998;93:702–9.CrossRefGoogle Scholar
  11. 11.
    Royston P, Parmar MK. The use of restricted mean survival time to estimate the treatment effect in randomized clinical trials when the proportional hazards assumption is in doubt. Stat Med. 2011;30:2409–21.CrossRefGoogle Scholar
  12. 12.
    Zhao L, Tian L, Uno H, Solomon SD, Pfeffer MA, Schindler JS, et al. Utilizing the integrated difference of two survival functions to quantify the treatment contrast for designing, monitoring, and analyzing a comparative clinical study. Clin Trials. 2012;9:570–7.CrossRefGoogle Scholar
  13. 13.
    Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol. 2013;13:152.CrossRefGoogle Scholar
  14. 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.
  15. 15.
    Inzucchi SE, Iliev H, Pfarr E, Zinman B. Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41:e4–5.CrossRefGoogle Scholar
  16. 16.
    Guyot P, Ades AE, Ouwens MJ, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12:9.CrossRefGoogle Scholar
  17. 17.
    R Foundation for Statistical Computing. R: a language and environment for statistical computing. https://www.R-project.org. Accessed 11 Sep 2018.
  18. 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.
  19. 19.
    d’Emden M, Amerena J, Deed G, Pollock C, Cooper ME. SGLT2 inhibitors with cardiovascular benefits: transforming clinical care in Type 2 diabetes mellitus. Diabetes Res Clin Pract. 2018;136:23–31.CrossRefGoogle Scholar
  20. 20.
    Fadini GP, Avogaro A. SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System. Lancet Diabetes Endocrinol. 2017;5:680–1.CrossRefGoogle Scholar
  21. 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
  22. 22.
    Fisher M. The CANVAS trial programme raises more questions than answers. Pract Diab. 2017;34:232–3.CrossRefGoogle Scholar
  23. 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. 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.
  25. 25.
    Rastogi A, Bhansali A. SGLT2 inhibitors through the windows of EMPA-REG and CANVAS trials: a review. Diabetes Ther. 2017;8:1245–51.CrossRefGoogle Scholar
  26. 26.
    Khouri C, Cracowski JL, Roustit M. SGLT-2 inhibitors and the risk of lower-limb amputation: is this a class effect? Diabetes Obes Metab. 2018;20:1531–4.CrossRefGoogle Scholar
  27. 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.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical SciencesKitasato UniversityTokyoJapan

Personalised recommendations