Skip to main content
SpringerLink
Log in

Time-Matched Evaluation of Cardiovascular Risks Associated with Drugs for Type 2 Diabetes Mellitus

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and Objective

The results of large placebo-controlled clinical trials to evaluate cardiovascular risks associated with drugs for type 2 diabetes mellitus indicated different cardiovascular effects among these drugs, but the detailed design of each trial was not completely the same. The aim of this study was to perform time-matched evaluation of cardiovascular risks of drugs for type 2 diabetes.

Methods

We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Regarding drugs for type 2 diabetes used currently, this study included all 10 clinical trials in patients with type 2 diabetes at high cardiovascular risk the results of which have been published as of 30 November 2018. Since the shortest study follow-up time was about 672 days in SUSTAIN-6, we chose 672 days as a common time point to estimate the RMSTs regarding each safety event.

Results

The differences of RMSTs (drugs for type 2 diabetes minus placebo: point estimate and 95% confidence interval) for major adverse cardiovascular events (MACE) were 8 days (1, 15) for semaglutide, 5 days (1, 9) for liraglutide, and 7 days (2, 13) for empagliflozin. Those for death from cardiovascular causes were 5 days (2, 8) for empagliflozin and 2 days (1, 4) for canagliflozin. Those for death from any cause were 4 days (1, 8) for empagliflozin.

Conclusions

Through the evaluation up to 672 days, semaglutide, liraglutide, and empagliflozin decreased the risk of MACE. Concerning the risk of each cardiovascular event, risk reduction was seen with empagliflozin and canagliflozin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. 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 13 Mar 2019.

  2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.

    Article  CAS  PubMed  Google Scholar 

  3. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.

    Article  CAS  PubMed  Google Scholar 

  4. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.

    Article  CAS  PubMed  Google Scholar 

  5. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.

    Article  CAS  PubMed  Google Scholar 

  6. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.

    Article  CAS  PubMed  Google Scholar 

  7. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.

    Article  CAS  PubMed  Google Scholar 

  9. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  PubMed  Google Scholar 

  16. Chappell R, Zhu X. Describing differences in survival curves. JAMA Oncol. 2016;2:906–7.

    Article  PubMed  Google Scholar 

  17. Zucker DM. Restricted mean life with covariates: modification and extension of a useful survival analysis method. J Am Stat Assoc. 1998;93:702–9.

    Article  Google Scholar 

  18. 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.

    Article  PubMed  Google Scholar 

  19. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al. Heart failure, saxagliptin and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579–88.

    Article  CAS  PubMed  Google Scholar 

  23. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. April 14, 2015 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. https://wayback.archive-it.org/7993/20170403223910/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm426278.htm. Accessed 13 Mar 2019.

  24. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067–76.

    Article  CAS  PubMed  Google Scholar 

  25. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. 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 13 Mar 2019.

  28. R Foundation for Statistical Computing. R: a language and environment for statistical computing. https://www.R-project.org. Accessed 13 Mar 2019.

  29. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321:69–79.

    Article  CAS  PubMed  Google Scholar 

  30. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. October 24–25, 2018 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm597256.htm. Accessed 13 Mar 2019.

  31. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol. 2018;71:2628–39.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Masayuki Kaneko & Mamoru Narukawa

Authors
  1. Masayuki Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mamoru Narukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masayuki Kaneko.

Ethics declarations

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 311 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaneko, M., Narukawa, M. Time-Matched Evaluation of Cardiovascular Risks Associated with Drugs for Type 2 Diabetes Mellitus. Clin Drug Investig 39, 469–476 (2019). https://doi.org/10.1007/s40261-019-00770-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-019-00770-z

Search

Navigation