Skip to main content

Cardiovascular Safety of New Drugs for Diabetes: Getting the Balance Right?

Pharmaceutical Medicine volume 28, pages 109–117 (2014)Cite this article

Abstract

In 2008, the US Food and Drug Administration (FDA) issued guidance requiring demonstration of cardiovascular safety for all new glucose-lowering agents intended for the treatment of type 2 diabetes. The main driver for this move was the negative experience that the FDA had encountered with rosiglitazone. This widely prescribed thiazolidinedione had come under intense pressure with publication of an analysis suggesting an increased risk of myocardial infarction. The new FDA stringency stipulated the need for randomized controlled trials involving adequate numbers of participants over sufficiently long exposure and follow-up periods with adjudicated cardiovascular endpoints assessed against specific safety limits. It has been argued that these requirements are perhaps overzealous and run the risk of reducing innovation. Aspects of the pharmaceutical industry are perceived as being increasingly risk-averse within an increasingly competitive diabetes market. Set against these concerns is an opportunity to fill much-needed gaps in knowledge about the cardiovascular risks and benefits of glucose-lowering drugs, both old and new. Five years since the issuance of the FDA guidelines, we assess the operation of the current approval processes. We set the agency’s decision making in a broader context of other major regulatory bodies. Using recent data from trials of saxagliptin, alogliptin, and canagliflozin as examples, alongside the recently announced removal of the prescribing and dispensing restrictions for rosiglitazone, we consider whether the guidelines are functioning as intended.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

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

References

  1. Krentz AJ. Rosiglitazone: trials, tribulations and termination. Drugs 2011;71:123–30.

  2. Bourg CA, Phillips BB. Rosiglitazone, myocardial ischemic risk, and recent regulatory actions. Ann Pharmacother. 2012;46:282–9.

    Article  PubMed  Google Scholar 

  3. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring: FDA; 2008.

  4. Adler AI. Drugs and diabetes: understanding the new breed of cardiovascular safety trials. Lancet Diabetes Endocrinol. 2013;1:175–7.

    Article  PubMed  Google Scholar 

  5. EMA guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/02/WC500073570.pdf). Accessed 20 Dec 2013.

  6. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187–215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Scirica BM, Bhatt DL, Braunwald E, 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 

  8. White WB, Cannon CP, Heller SR, 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 

  9. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13:221–8.

    Article  CAS  PubMed  Google Scholar 

  10. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89.

    Article  CAS  PubMed  Google Scholar 

  11. FDA drug safety communication: FDA to review heart failure risk with diabetes drug saxagliptin (marketed as Onglyza and Kombiglyze XR). Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM385315.pdfre.). Accessed 25 Feb 2014.

  12. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs: insights from the rosiglitazone experience. N Engl J Med 2013;369:1285–7.

  13. Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin. 2011;27(Suppl 3):57–64.

    Article  CAS  PubMed  Google Scholar 

  14. Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122:16–27.

    Article  PubMed  Google Scholar 

  15. Krentz AJ, Morrow L, Hompesch M. Developing new drugs for diabetes and cardiometabolic disorders: a changing paradigm. Drugs. 2012;72:1709–11.

    Article  PubMed  Google Scholar 

  16. Hirshberg B, Katz A. Cardiovascular outcome studies with novel antidiabetes agents: scientific and operational considerations. Diabetes Care. 2013;36(Suppl 2):S253–8.

    Article  CAS  PubMed  Google Scholar 

  17. Pelletier EM, Pawaskar M, Smith PJ, Best JH, Chapman RH. Economic outcomes of exenatide vs liraglutide in type 2 diabetes patients in the United States: results from a retrospective claims database analysis. J Med Econ. 2012;15:1039–50.

    Article  PubMed  Google Scholar 

  18. Novo Nordisk reported to police over disclosure delay on ruling. Available from: http://www.ft.com/intl/cms/s/0/6fc97422-6171-11e3-b7f1-00144feabdc0.html?siteedition=uk#axzz30sKwfcop. Accessed 29 Dec 2013.

  19. Gore MO, McGuire DK. Drugs for type 2 diabetes mellitus: the imperative for cardiovascular outcome assessment. Diab Vasc Dis Res 2012;9:85–8.

  20. Kilo C, Miller JP, Williamson JR. The crux of the UGDP. Spurious results and biologically inappropriate data analysis. Diabetologia. 1980;18:179–85.

    Article  CAS  PubMed  Google Scholar 

  21. Wheeler S, Moore K, Forsberg CW, et al. Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy. Diabetologia. Epub 25 Jun 2013.

  22. Krentz AJ, Sinclair AJ. Do sulfonylureas still have a role in type 2 diabetes? Prescriber 2011;22:32–6.

  23. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res. 2013;10:289–301.

    Article  PubMed  Google Scholar 

  24. ClinicalTrials.gov. CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes. Available from: http://clinicaltrials.gov/show/NCT01243424. Accessed 22 Dec 2013.

  25. Home P. Cardiovascular disease and oral agent glucose-lowering therapies in the management of type 2 diabetes. Diabetes Technol Ther. 2012;14(Suppl 1):S33–42.

    CAS  PubMed  Google Scholar 

  26. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006;332:73–8.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;115:114–26.

    Article  PubMed  Google Scholar 

  28. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56:686–95.

    Article  CAS  PubMed  Google Scholar 

  29. Giraldez RR, Clare RM, Lopes RD, et al. Prevalence and clinical outcomes of undiagnosed diabetes mellitus and prediabetes among patients with high-risk non-ST-segment elevation acute coronary syndrome. Am Heart J. 2013;165(918–25):e2.

    PubMed  Google Scholar 

  30. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–53.

  32. Krentz AJ. Sulfonylureas in the prevention of vascular complications: from UKPDS to the ADVANCE study. In: Crepaldi GT, Avogaro A, editors. The metabolic syndrome: diabetes, obesity, hyperlipidemia and hypertension. Amsterdam: Excertpa Medical International Conference Series; 2002:261–77.

  33. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65.

  34. Lyons MR, Peterson LR, McGill JB, et al. Impact of sex on the heart’s metabolic and functional responses to diabetic therapies. Am J Physiol Heart Circ Physiol. 2013;305:H1584–91.

    Article  CAS  PubMed  Google Scholar 

  35. Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011;32:1900–8.

    Article  CAS  PubMed  Google Scholar 

  36. FDA Drug Safety Communication. FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. 2013. Available from: http://www.fda.gov/drugs/drugsafety/ucm376389.htm.). Accessed 23 Dec 2013.

  37. Nissen SE. Rosiglitazone: a case of regulatory hubris. BMJ. 2013;347:f7428.

  38. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294:2581–6.

    Article  CAS  PubMed  Google Scholar 

  39. Lincoff AM, Tardif JC, Neal B, et al. Evaluation of the dual peroxisome proliferator-activated receptor alpha/gamma agonist aleglitazar to reduce cardiovascular events in patients with acute coronary syndrome and type 2 diabetes mellitus: rationale and design of the AleCardio trial. Am Heart J. 2013;166:429–34.

    Article  CAS  PubMed  Google Scholar 

  40. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med. 2008;358:2630–3.

    Article  CAS  PubMed  Google Scholar 

  42. Gerstein HC, Miller ME, Action to Control Cardiovascular Risk in Diabetes Study Group, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  CAS  PubMed  Google Scholar 

  43. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.

    Article  CAS  PubMed  Google Scholar 

  44. Patel A, MacMahon S, Advance Collaborative Group, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.

    Article  CAS  PubMed  Google Scholar 

  45. US FDA. FDA news release. FDA approves Invokana to treat type 2 diabetes. Available from: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm345848.htm. Accessed 3 Jan 2014.

  46. ClinicalTrials.gov. CANVAS: CANagliflozin cardioVascular Assessment Study. Available from: http://clinicaltrials.gov/ct2/show/NCT01032629?term=CANVAS&rank=1. Accessed 3 Jan 2014.

  47. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS): a randomized placebo-controlled trial. Am Heart J. 2013;166(217–23):e11.

    PubMed  Google Scholar 

  48. Novo Nordisk. Novo Nordisk receives Complete Response Letter in the US for Tresiba® and Ryzodeg®. Available from: http://www.novonordisk.com/include/asp/exe_news_attachment.asp?sAttachmentGUID=83700060-0ce3-4577-a35a-f3e57801637d. Accessed 4 Jan 2014.

  49. Insulin degludec and insulin degludec/insulin aspart treatment to improve glycemic control in patients with diabetes mellitus. NDAs 203314 and 203313. Briefing document. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM327017.pdf. Accessed 23 Dec 2013

  50. US FDA. Degludec and degludec/aspart. Endocrinologic and Metabolic Drugs Advisory Committee Meeting, 8 Nov 2012. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM330923.pdf. Accessed 4 Jan 2014.

  51. Monnier L, Hanefeld M, Schnell O, Colette C, Owens D. Insulin and atherosclerosis: how are they related? Diabetes Metab. 2013;39:111–7.

    Article  CAS  PubMed  Google Scholar 

  52. Investigators OT, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.

    Article  Google Scholar 

  53. Rendell M. The path to approval of new drugs for diabetes. Expert Opin Drug Saf. 2013;12:195–207.

    Article  CAS  PubMed  Google Scholar 

  54. White WB, Kupfer S, Cushman WC, Bakris GL, Heller SK, Bergenstal RM, et al. Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. Washington DC: American College of Cardiology 2014 Scientific Sessions; 2104.

  55. Scheen AJ. Cardiovascular effects of gliptins. Nature Rev Cardiol. 2013;10:73–84.

    Article  CAS  Google Scholar 

  56. Mullard A. Outcome results renew debate about diabetes drug development. Lancet Diabetes Endocrinol. 2013. doi:10.1016/S2213-8587(13)70118-9.

  57. Ledford H. Diabetes drugs ride a bumpy road. Nature. 2013;504:198.

  58. Serafino P. Sanofi pulls U.S. file for lixisenatide diabetes drug. Available from: http://www.bloomberg.com/news/2013-09-12/sanofi-pulls-u-s-file-for-lixisenatide-diabetes-drug.html. Accessed 6 Jan 2014.

Download references

Conflict of Interest

No funding was received for writing this article. Profil Institute for Clinical Research Inc. undertakes early-phase clinical studies of new therapies for diabetes and obesity. Professor Krentz and Dr Hompesch have no other potential conflicts of interest. The views expressed are those of the authors.

Author information

Authors and Affiliations

  1. Profil Institute for Clinical Research, 855 3rd Ave, Suite # 4430, Chula Vista, CA, 91911, USA

    Andrew J. Krentz & Marcus Hompesch

Authors
  1. Andrew J. Krentz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus Hompesch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew J. Krentz.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Krentz, A.J., Hompesch, M. Cardiovascular Safety of New Drugs for Diabetes: Getting the Balance Right?. Pharm Med 28, 109–117 (2014). https://doi.org/10.1007/s40290-014-0053-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40290-014-0053-7

Keywords

  • Rosiglitazone
  • Major Adverse Cardiac Event
  • Glimepiride
  • Saxagliptin
  • Linagliptin