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Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus

  • Hylton V. Joffe
  • Mary H. Parks
  • Robert Temple
Article

Abstract

All medications currently approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus are indicated to improve glycemic control. Since 1995, FDA has used HbA1c as the primary basis for approval of these therapies because a reduction in blood glucose lessens the symptoms of hyperglycemia and lowering of HbA1c has been shown to reduce the risk for some of the chronic complications of diabetes. Despite evidence of clinical benefit with therapies that reduce HbA1c, concerns have been raised that some diabetes medications may increase cardiovascular risk in a patient population that is already vulnerable to cardiovascular disease. Therefore, FDA convened a public advisory committee meeting to discuss the role of cardiovascular assessment in the pre-approval and post-approval settings for medications developed for the treatment of type 2 diabetes. After considering the advisory panel’s recommendations and other data, FDA published a guidance document requesting evidence showing that new treatments for type 2 diabetes do not result in an unacceptable increase in cardiovascular risk. This review article begins by summarizing the events leading up to publication of this guidance. Subsequent sections discuss the guidance itself as well as general considerations for implementing the new cardiovascular recommendations. The new approach to developing medications for the treatment of type 2 diabetes will lead to evaluation in patients more representative of those who will use these therapies, if approved, and will help healthcare providers make informed decisions when choosing a medication within the growing treatment armamentarium for type 2 diabetes.

Keywords

Diabetes mellitus Cardiovascular disease Drug development Food and Drug Administration 

Notes

Acknowledgements

The authors thank Ilan Irony, M.D. for his critical review of the manuscript.

References

  1. 1.
    National estimates on diabetes. In: National diabetes statistics, 2007. National Institutes of Health. 2007. http://diabetes.niddk.nih.gov/DM/PUBS/statistics. Accessed 21 Feb 2010.
  2. 2.
    Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365:1333–46.CrossRefPubMedGoogle Scholar
  3. 3.
    Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34.CrossRefPubMedGoogle Scholar
  4. 4.
    Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med. 1991;151:1141–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241:2035–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434–44.CrossRefPubMedGoogle Scholar
  7. 7.
    Goldbourt U, Yaari S, Medalie JH. Factors predictive of long-term coronary heart disease mortality among 10, 059 male Israeli civil servants and municipal employees. A 23-year mortality follow-up in the Israeli Ischemic Heart Disease Study. Cardiology. 1993;82:100–21.CrossRefPubMedGoogle Scholar
  8. 8.
    Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study. Br Med J (Clin Res Ed). 1983;287:867–70.CrossRefGoogle Scholar
  9. 9.
    Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA. 1991;265:627–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Standards of medical care in diabetes-2010. Diabetes Care 2010;33 Suppl 1:S11–-61.Google Scholar
  11. 11.
    Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Peterson CM, et al. Tests of glycemia in diabetes. Diabetes Care. 2004;27:1761–73.CrossRefPubMedGoogle Scholar
  12. 12.
    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977–86.Google Scholar
  13. 13.
    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.Google Scholar
  14. 14.
    Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes. 1970;19:s747–830.Google Scholar
  15. 15.
    Approved repaglinide package insert. In: Drugs@FDA. United States Food and Drug Administration. 2008. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020741s035lbl.pdf. Accessed 21 Feb 2010.
  16. 16.
    Cardiovascular ischemic events with rosiglitazone. In: FDA briefing document for July 30, 2007, joint meeting of the endocrinologic and metabolic drugs advisory committee and the drug safety and risk management advisory committee meeting. United States Food and Drug Administration. 2007. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-02-fda-backgrounder.pdf. Accessed 21 Feb 2010.
  17. 17.
    Rosen CJ. The rosiglitazone story—lessons from an FDA Advisory Committee meeting. N Engl J Med. 2007;357:844–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Joffe HV, Parks MH, Meyer RJ, Jenkins JK, Temple R. Rosiglitazone and the FDA. N Engl J Med. 2007;357:1775–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Role of cardiovascular assessment in the preapproval and postapproval settings for drugs and biologics developed for the treatment of type 2 diabetes mellitus. In: Dockets for July 1–2, 2008, endocrinologic and metabolic drugs advisory commitee meeting. United States Food and Drug Administration. 2008. http://www.fda.gov/ohrms/dockets/ac/cder08.html#EndocrinologicMetabolic. Accessed 21 Feb 2010.
  20. 20.
    Guidance for industry: Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. In: Guidances (drugs). United States Food and Drug Administration. 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed 21 Feb 2010.
  21. 21.
    Guidance for industry: Diabetes mellitus—developing drugs and therapeutic biologics for treatment and prevention (draft). In: Guidances (Drugs). United States Food and Drug Administration. 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf. Accessed 21 Feb 2010.
  22. 22.
    E1: The extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-life-threatening conditions. In: ICH guidelines. International Conference on Harmonisation. 1994. http://www.ich.org/LOB/media/MEDIA435.pdf. Accessed 21 Feb 2010.
  23. 23.
    Full text of FDAAA law. In: public law 110-85. 110th congress. 2007. http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110. Accessed 21 Feb 2010.
  24. 24.
    Becker MC, Wang TH, Wisniewski L, Wolski K, Libby P, Luscher TF, et al. Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis. Am Heart J. 2009;157:606–12.CrossRefPubMedGoogle Scholar
  25. 25.
    Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults with diagnosed diabetes from 1999 to 2004. Diabetes Care. 2008;31:102–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963–72.CrossRefPubMedGoogle Scholar
  27. 27.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–96.CrossRefPubMedGoogle Scholar
  29. 29.
    Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–22.CrossRefPubMedGoogle Scholar
  30. 30.
    Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.CrossRefPubMedGoogle Scholar
  31. 31.
    Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.CrossRefPubMedGoogle Scholar
  32. 32.
    Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.CrossRefPubMedGoogle Scholar

Copyright information

© US Government 2010

Authors and Affiliations

  • Hylton V. Joffe
    • 1
    • 3
  • Mary H. Parks
    • 1
  • Robert Temple
    • 2
  1. 1.Division of Metabolism and Endocrinology ProductsCenter for Drug Evaluation and Research, U.S. Food and Drug AdministrationSilver SpringUSA
  2. 2.Center for Drug Evaluation and Research, U.S. Food and Drug AdministrationSilver SpringUSA
  3. 3.Division of Metabolism and Endocrinology ProductsU.S. Food and Drug AdministrationSilver SpringUSA

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