Current Atherosclerosis Reports

, Volume 7, Issue 1, pp 50–57 | Cite as

The impact of antidiabetic therapies on cardiovascular disease

  • Brandy Panunti
  • Biju Kunhiraman
  • Vivian Fonseca


Cardiovascular disease disproportionately affects people with diabetes and is a leading cause of death. Glycemic control has so far not been conclusively shown to decrease cardiovascular events. The therapeutic agents used in treating glycemia have different effects on cardiovascular risks and, therefore, may have different effects on outcome. Insulin sensitizers impact cardiovascular risk factors, including dyslipidemia and fibrinolysis. Metformin is the only oral antidiabetic medication shown to decrease cardiovascular events independent of glycemic control. Thiazolidinediones improve insulin resistance and lower insulin concentrations, which is beneficial because hyperinsulinemia is an independent predictor of cardiovascular disease. Insulin therapy acutely reduces cardiovascular mortality and morbidity in patients with diabetes and known coronary artery disease and also in patients with hyperglycemia when critically ill, but the long-term effects are unclear. In contrast, insulin secretagogues have very little effect on both cardiovascular risk factors and outcomes.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Feskens EJ, Kromhout D: Glucose tolerance and the risk of cardiovascular disease: the Zutphen Study. J Clin Epidemiol 1992, 45:1327–1334.PubMedCrossRefGoogle Scholar
  2. 2.
    Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001, 285:2486–2497.Google Scholar
  3. 3.
    Haffner SM, Lehto S, Ronnemaa T, et al.: Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998, 339:229–234.PubMedCrossRefGoogle Scholar
  4. 4.
    Gu K, Cowie CC, Harris MI: Diabetes and decline in heart disease mortality in US adults. JAMA 1999, 281:1291–1297.PubMedCrossRefGoogle Scholar
  5. 5.
    Malmberg K, Yusuf S, Gerstein HC, et al.: Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndrome) Registry. Circulation 2000, 102:1014–1019.PubMedGoogle Scholar
  6. 6.
    Stein B, Weintraub WS, Gebhart SP, et al.: Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation 1995, 91:979–989.PubMedGoogle Scholar
  7. 7.
    Stamler J, Vaccaro O, Neaton JD, et al.: Diabetes other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993, 16:434–444.PubMedCrossRefGoogle Scholar
  8. 8.
    Beckman JA, Creager MA, Libby P: Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002, 287:2570–2581.PubMedCrossRefGoogle Scholar
  9. 9.
    Creager MA, Luscher TF, Cosentino F, et al.: Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 2003, 108:1527–1532.PubMedCrossRefGoogle Scholar
  10. 10.
    Zimmerman BR: Sulfonylureas. Endocrinol Metab Clin North Am 1997, 26:511–522.PubMedCrossRefGoogle Scholar
  11. 11.
    Goldner MG, Knatterud GL, Prout TE: Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA 1971, 218:1400–1410.PubMedCrossRefGoogle Scholar
  12. 12.
    Deutsch E, Berger M, Kussmaul WG, et al.: Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features. Circulation 1990, 82:2044–2051.PubMedGoogle Scholar
  13. 13.
    Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986, 74:1124–1136.PubMedGoogle Scholar
  14. 14.
    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.Google Scholar
  15. 15.
    DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999, 131:281–303.PubMedGoogle Scholar
  16. 16.
    Desouza C, Salazar H, Cheong B, et al.: Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. Diabetes Care 2003, 26:1485–1489.PubMedCrossRefGoogle Scholar
  17. 17.
    Paolisso G, Rizzo MR, Barbieri M, et al.: Cardiovascular risk in type 2 diabetics and pharmacological regulation of mealtime glucose excursions. Diabetes Metab 2003, 29(4 Pt 1):335–340.PubMedCrossRefGoogle Scholar
  18. 18.
    Perfetti R, Ahmad A: Novel sulfonylurea and non-sulfonylurea drugs to promote the secretion of insulin. Trends Endocrinol Metab 2000, 11:218–223.PubMedCrossRefGoogle Scholar
  19. 19.
    Davidson MB, Peters AL: An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997, 102:99–110.PubMedCrossRefGoogle Scholar
  20. 20.
    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.Google Scholar
  21. 21.
    Kao J, Tobis J, McClelland RL, et al.: Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol 2004, 93:1347–1350, A5.PubMedCrossRefGoogle Scholar
  22. 22.
    Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996, 19:64–66.PubMedCrossRefGoogle Scholar
  23. 23.
    Despres JP, Lamarche B, Mauriege P, et al.: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996, 334:952–957.PubMedCrossRefGoogle Scholar
  24. 24.
    Chu NV, Kong AP, Kim DD, et al.: Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 2002, 25:542–549.PubMedCrossRefGoogle Scholar
  25. 25.
    Rosenblatt S, Miskin B, Glazer NB, et al.: The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coronary Artery Dis 2001, 12:413–423.CrossRefGoogle Scholar
  26. 26.
    Raji A, Seely EW, Bekins SA, et al.: Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care 2003, 26:172–178.PubMedCrossRefGoogle Scholar
  27. 27.
    Ghazzi MN, Perez JE, Antonucci TK, et al.: Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 1997, 46:433–439.PubMedCrossRefGoogle Scholar
  28. 28.
    Friedlander Y, Kidron M, Caslake M, et al.: Low density lipoprotein particle size and risk factors of insulin resistance syndrome. Atherosclerosis 2000, 148:141–149.PubMedCrossRefGoogle Scholar
  29. 29.
    Steinberg D, Parthasarathy S, Carew TE, et al.: Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989, 320:915–924.PubMedCrossRefGoogle Scholar
  30. 30.
    Parulkar AA, Pendergrass ML, Granda-Ayala R, et al.: Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001, 134:61–71.PubMedGoogle Scholar
  31. 31.
    Kersten S, Desvergne B, Wahli W: Roles of PPARs in health and disease. Nature 2000, 405:421–424.PubMedCrossRefGoogle Scholar
  32. 32.
    Simonson DC: Etiology and prevalence of hypertension in diabetic patients. Diabetes Care 1988, 11:821–827.PubMedCrossRefGoogle Scholar
  33. 33.
    Ogihara T, Rakugi H, Ikegami H, et al.: Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hypertens 1995, 8:316–320.PubMedCrossRefGoogle Scholar
  34. 34.
    Fullert S, Schneider F, Haak E, et al.: Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 2002, 87:5503–5506.PubMedCrossRefGoogle Scholar
  35. 35.
    St John SM, Rendell M, Dandona P, et al.: A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 2002, 25:2058–2064.CrossRefGoogle Scholar
  36. 36.
    Sung BH, Izzo JL Jr, Dandona P, et al.: Vasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. Hypertension 1999, 34:83–88.PubMedGoogle Scholar
  37. 37.
    Fukunaga Y, Itoh H, Doi K, et al.: Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 2001, 158:113–119.PubMedCrossRefGoogle Scholar
  38. 38.
    Tooke J: The association between insulin resistance and endotheliopathy. Diabetes Obes Metab 1999, 1(Suppl 1):S17-S22.PubMedCrossRefGoogle Scholar
  39. 39.
    Avena R, Curry KM, Sidawy AN, et al.: The effect of occult diabetic status and oral glucose intake on brachial artery vasoactivity in patients with peripheral vascular disease. Cardiovasc Surg 1998, 6:584–589.PubMedCrossRefGoogle Scholar
  40. 40.
    Avena R, Mitchell ME, Nylen ES, et al.: Insulin action enhancement normalizes brachial artery vasoactivity in patients with peripheral vascular disease and occult diabetes. J Vasc Surg 1998, 28:1024–1031.PubMedCrossRefGoogle Scholar
  41. 41.
    Murakami T, Mizuno S, Ohsato K, et al.: Effects of troglitazone on frequency of coronary vasospastic-induced angina pectoris in patients with diabetes mellitus. Am J Cardiol 1999, 84:92–94, A8.PubMedCrossRefGoogle Scholar
  42. 42.
    Ghanim H, Aljada A, Mohanty P, et al.: Acute hyperglycemia increases the reactive oxygen species (ROS) generation by mononuclear cells (MNC) and impair the brachial artery reactivity in healthy volunteers. Presented at the American Diabetes Association’s Annual Scientific Sessions, San Francisco, CA, 2002.Google Scholar
  43. 43.
    Mohanty P, Aljada A, Ghanim H, et al.: Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab 2004, 89:2728–2735.PubMedCrossRefGoogle Scholar
  44. 44.
    Garg R, Kumbkarni Y, Aljada A, et al.: Troglitazone reduces reactive oxygen species generation by leukocytes and lipid peroxidation and improves flow-mediated vasodilatation in obese subjects. Hypertension 2000, 36:430–435.PubMedGoogle Scholar
  45. 45.
    Minamikawa J, Tanaka S, Yamauchi M, et al.: Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998, 83:1818–1820.PubMedCrossRefGoogle Scholar
  46. 46.
    Koshiyama H, Shimono D, Kuwamura N, et al.: Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001, 86:3452–3456.PubMedCrossRefGoogle Scholar
  47. 47.
    Desouza CV, Murthy SN, Diez J, et al.: Differential effects of peroxisome proliferator activator receptor-alpha and gamma ligands on intimal hyperplasia after balloon catheter-induced vascular injury in Zucker rats. J Cardiovasc Pharmacol Ther 2003, 8:297–305.PubMedGoogle Scholar
  48. 48.
    American Diabetes Association Position Statement: Nephropathy in diabetes. Diabetes Care 2004, 27:S79-S83.CrossRefGoogle Scholar
  49. 49.
    Bakris G, Viberti G, Weston WM, et al.: Rosiglitazone reduces urinary albumin excretion in type II diabetes. J Hum Hypertens 2003, 17:7–12.PubMedCrossRefGoogle Scholar
  50. 50.
    Marx N, Froehlich J, Siam L, et al.: Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2003, 23:283–288.PubMedCrossRefGoogle Scholar
  51. 51.
    Huber K, Christ G, Wojta et al.: Plasminogen activator inhibitor type-1 in cardiovascular diasese. Status Report 2001. Thromb Res 2001, 103(Suppl 1):S7-S19.PubMedCrossRefGoogle Scholar
  52. 52.
    Fonseca VA, Reynolds T, Hemphill D, et al.: Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 1998, 12:181–186.PubMedCrossRefGoogle Scholar
  53. 53.
    Kato K, Satoh H, Endo Y, et al.: Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: a possible role for PPARgamma in endothelial function. Biochem Biophys Res Commun 1999, 258:431–435.PubMedCrossRefGoogle Scholar
  54. 54.
    Ridker PM, Rifai N, Rose L, et al.: Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002, 347:1557–1565.PubMedCrossRefGoogle Scholar
  55. 55.
    Aljada A, Garg R, Ghanim H, et al.: Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? J Clin Endocrinol Metab 2001, 86:3250–3256.PubMedCrossRefGoogle Scholar
  56. 56.
    Satoh N, Ogawa Y, Usui T, et al.: Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 2003, 26:2493–2499.PubMedCrossRefGoogle Scholar
  57. 57.
    Sidhu JS, Cowan D, Kaski JC: The effects of rosiglitazone, a peroxisome proliferators-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. J Am Coll Cardiol 2003, 42:1757–1763.PubMedCrossRefGoogle Scholar
  58. 58.
    Charbonnel B, Dormandy J, Erdmann E, et al.: The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care 2004, 27:1647–1653.PubMedCrossRefGoogle Scholar
  59. 59.
    Malmberg K, Norhammar A, Wedel H, et al.: Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999, 99:2626–2632.PubMedGoogle Scholar
  60. 60.
    Stefanidis A, Melidonis A, Tournis S, et al.: Intensive insulin treatment reduces transient ischaemic episodes during acute coronary events in diabetic patients. Acta Cardiol 2002, 57:357–364.PubMedCrossRefGoogle Scholar
  61. 61.
    Khoury VK, Haluska B, Prins J, et al.: Effects of glucose insulin-potassium infusion on chronic ischaemic left ventricular dysfunction. Heart 2003, 89:61–65.PubMedCrossRefGoogle Scholar
  62. 62.
    van der Horst, I, Zijlstra F, van’t Hof AW, et al.: Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol 2003, 42:784–791.PubMedCrossRefGoogle Scholar
  63. 63.
    Furnary AP, Gao G, Grunkemeier GL, et al.: Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003, 125:1007–1021.PubMedCrossRefGoogle Scholar
  64. 64.
    Van den Berghe G: Insulin therapy for the critically ill patient. Clin Cornerstone 2003, 5:56–63.PubMedCrossRefGoogle Scholar
  65. 65.
    Melidonis A, Stefanidis A, Tournis S, et al.: The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients. Clin Cardiol 2000, 23:160–164.PubMedCrossRefGoogle Scholar
  66. 66.
    Chaudhuri A, Janicke D, Wilson MF, et al.: Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation 2004, 109:849–854.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • Brandy Panunti
    • 1
  • Biju Kunhiraman
    • 1
  • Vivian Fonseca
    • 1
  1. 1.Department of Medicine, Section of EndocrinologyTulane University Medical CenterNew OrleansUSA

Personalised recommendations