Skip to main content
SpringerLink
Log in

Cardiovascular disease and type 2 diabetes mellitus: Regulating glucose and regulating drugs

  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Type 2 diabetes mellitus is a major and increasingly prevalent independent risk factor for cardiovascular morbidity and mortality worldwide. Glycemic control is a target of therapy and a principal marker of therapeutic success in diabetes, but whether lowering glucose is accompanied by a commensurate reduction in cardiovascular risk is a matter of ongoing controversy. It has become increasingly apparent from recent large-scale clinical outcome trials that glucose lowering is a poor predictor of cardiovascular outcome, and several instances of unexpectedly increased cardiovascular risk with antihyperglycemic drugs have sounded the alarm with regulatory agencies. This article reviews the critical facts that have led to a recent shift in the regulation of glucose-lowering drugs and makes the case for why new and existing antidiabetic medications should be assessed in clinical trials of cardiovascular outcome.

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 and Recommended Reading

  1. Almdal T, Scharling H, Jensen JS, Vestergaard H: The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 2004, 164:1422–1426.

    Article  PubMed  Google Scholar 

  2. American Diabetes Association: Economic costs of diabetes in the U.S. in 2007. Diabetes Care 2008, 31:596–615.

    Article  Google Scholar 

  3. Fleming A: FDA approach to the regulation of drugs for diabetes. Am Heart J 1999, 138:S338–S345.

    PubMed  CAS  Google Scholar 

  4. 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, 352:837–853.

  5. Holman RR, Paul SK, Bethel MA, et al.: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008, 359:1577–1589.

    Article  PubMed  CAS  Google Scholar 

  6. 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, 294:2581–2586.

    Article  PubMed  CAS  Google Scholar 

  7. Nissen SE, Wolski K: Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007, 356:2457–2471.

    Article  PubMed  CAS  Google Scholar 

  8. Home PD, Pocock SJ, Beck-Nielsen H, et al.: Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 2007, 357:28–38.

    Article  PubMed  CAS  Google Scholar 

  9. The Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al.: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008, 358:2545–2559.

    Article  PubMed  CAS  Google Scholar 

  10. ADVANCE Collaborative Group, Patel A, MacMahon S: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008, 358:2560–2572.

    Article  PubMed  CAS  Google Scholar 

  11. Duckworth W, Abraira C, Moritz T, et al.: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009, 360:129–139.

    Article  PubMed  CAS  Google Scholar 

  12. Merriam-Webster’s Collegiate Dictionary. Springfield, MA: Merriam-Webster; 2003:1258.

  13. Temple R: Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 1999, 282:790–795.

    Article  PubMed  CAS  Google Scholar 

  14. Prentice R: Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 1989, 8:431–440.

    Article  PubMed  CAS  Google Scholar 

  15. Packer M, Carver JR, Rodeheffer RJ, et al.: Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991, 325:1468–1475.

    PubMed  CAS  Google Scholar 

  16. Cohn JN, Goldstein SO, Greenberg BH, et al.: A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med 1998, 339:1810–1816.

    Article  PubMed  CAS  Google Scholar 

  17. O’Connor CM, Gattis WA, Uretsky BF, et al.: Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J 1999, 138:78–86.

    Article  PubMed  Google Scholar 

  18. Cannon CP, McCabe CH, Wilcox RG, et al.: Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000, 102:149–156.

    PubMed  CAS  Google Scholar 

  19. O’sNeill WW, Serruys P, Knudtson M, et al.: Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. EXCITE Trial Investigators. Evaluation of Oral Xemilofiban in Controlling Thrombotic Events. N Engl J Med 2000, 342:1316–1324.

    Article  Google Scholar 

  20. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. The SYMPHONY Investigators. Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-acute Coronary Syndromes. Lancet 2000, 355:337–345.

  21. Second SYMPHONY Investigators: Randomized trial of aspirin, sibrafiban, or both for secondary prevention after acute coronary syndromes. Circulation 2001, 103:1727–1733.

    Google Scholar 

  22. Chew DP, Bhatt DL, Sapp S, Topol EJ: Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a metaanalysis of phase III multicenter randomized trials. Circulation 2001, 103:201–206.

    PubMed  CAS  Google Scholar 

  23. Barter PJ, Caulfield M, Eriksson M, et al.; the ILLUMINATE Investigators: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007, 357:2109–2122.

    Article  PubMed  CAS  Google Scholar 

  24. Ridker PM, Cushman M, Stampfer MJ, et al.: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997, 336:973–979.

    Article  PubMed  CAS  Google Scholar 

  25. Koenig W, Sund M, Frohlich M, et al.: C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999, 99:237–242.

    PubMed  CAS  Google Scholar 

  26. Danesh J, Whincup P, Walker M, et al.: Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000, 321:199–204.

    Article  PubMed  CAS  Google Scholar 

  27. Bresalier RS, Sandler RS, Quan H, et al.: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005, 352:1092–1102.

    Article  PubMed  CAS  Google Scholar 

  28. Gislason GH, Jacobsen S, Rasmussen JN, et al.: Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation 2006, 113:2906–2913.

    Article  PubMed  CAS  Google Scholar 

  29. Baron JA, Sandler RS, Bresalier RS, et al.: Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 2008, 372:1756–1764.

    Article  PubMed  CAS  Google Scholar 

  30. Fosbol EL, Gislason GH, Jacobsen S, et al.: Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009, 85:190–197.

    Article  PubMed  CAS  Google Scholar 

  31. Davi G, Patrono C: Platelet activation and atherothrombosis. N Engl J Med 2007, 357:2482–2494.

    Article  PubMed  CAS  Google Scholar 

  32. Raju NC, Eikelboom JW, Hirsh J: Platelet ADP-receptor antagonists for cardiovascular disease: past, present and future. Nat Clin Pract Cardiovasc Med 2008, 5:766–780.

    Article  PubMed  CAS  Google Scholar 

  33. Watkins PB, Whitcomb RW: Hepatic dysfunction associated with troglitazone. N Engl J Med 1998, 338:916–917.

    Article  PubMed  CAS  Google Scholar 

  34. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998, 97:1440–1445.

  35. Landmesser U, Bahlmann F, Mueller M, et al.: Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005, 111:2356–2363.

    Article  PubMed  CAS  Google Scholar 

  36. 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, 352:854–865.

  37. Klein R: Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 1995, 18:258–268.

    Article  PubMed  CAS  Google Scholar 

  38. Standl E, Balletshofer B, Dahl B, et al.: Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich General Practitioner Project. Diabetologia 1996, 39:1540–1545.

    Article  PubMed  CAS  Google Scholar 

  39. Turner RC, Millns H, Neil HA, et al.: Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998, 316:823–828.

    PubMed  CAS  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, 321:405–412.

    Article  PubMed  CAS  Google Scholar 

  41. Singh S, Loke YK, Furberg CD: Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007, 298:1189–1195.

    Article  PubMed  CAS  Google Scholar 

  42. Dahabreh IJ, Economopoulos K: Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone. Clin Trials 2008, 5:116–120.

    Article  PubMed  Google Scholar 

  43. Friedrich JO, Beyene J, Adhikari NK: Rosiglitazone: can meta-analysis accurately estimate excess cardiovascular risk given the available data? Re-analysis of randomized trials using various methodologic approaches. BMC Res Notes 2009, 2:5.

    Article  PubMed  Google Scholar 

  44. US Food and Drug Administration: Food and Drug Administration Endocrinologic and Metabolic Drugs Advisory Committee Meeting, July 1 and 2, 2008. Available at http://www.fda.gov/ohrms/dockets/ac/cder08.html#EndocrinologicMetabolic. Accessed January 2009.

  45. FDA announces new recommendations on evaluating cardiovascular risk in drugs intended to treat type 2 diabetes [press release]. Silver Spring, MD: US Food and Drug Administration; December 17, 2008. Available at http://www.fda.gov/bbs/topics/NEWS/2008/NEW01928.html. Accessed January 2009.

  46. US Food and Drug Administration: Food and Drug Administration guidance for industry. Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Published December 2008. Available at http://www.fda.gov/Cder/Guidance/8576fnl.pdf. Accessed January 2009.

  47. US Code of Federal Regulations, Vol 5, Title 21, Sec. 314.510: Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. Revised April 1, 2008. Available at http://www.gpoaccess.gov/cfr/retrieve.html. Accessed January 2009.

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5909 Harry Hines Boulevard, Room HA9.133, Dallas, TX, 75235-9047, USA

    Darren K. McGuire

Authors
  1. M. Odette Gore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darren K. McGuire
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Darren K. McGuire.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gore, M.O., McGuire, D.K. Cardiovascular disease and type 2 diabetes mellitus: Regulating glucose and regulating drugs. Curr Cardiol Rep 11, 258–263 (2009). https://doi.org/10.1007/s11886-009-0038-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-009-0038-4

Keywords

Search

Navigation