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Antidiabetic agents and cardiovascular risk in type 2 diabetes

Nature Reviews Endocrinology volume 5, pages 500–506 (2009)Cite this article

Abstract

Despite the clear relationship between HbA1c levels and risk of cardiovascular disease in patients with type 2 diabetes mellitus (T2DM) in epidemiologic studies, prospective data on the role of glucose-lowering therapy in reducing cardiovascular events are equivocal. Initial studies of intensive glycemic control suffered from inadequate statistical power to show reductions in cardiovascular events, as well as a lack of durable glycemic control and relatively poor control of associated cardiovascular risk factors. Subsequently, controversy existed over whether rosiglitazone was associated with an increased risk of myocardial ischemic events. Large, prospective, cardiovascular outcome trials that assessed intensive glycemic control versus standard glycemic control have had disappointing results; however, cardiovascular event rates seem to be declining substantially in patients with T2DM managed with aggressive global cardiovascular risk factor modification, which might have masked the benefits of glycemic control. Individuals with T2DM without a history of cardiovascular disease, as well as younger individuals with more modest elevations of HbA1c, may benefit from a more intensive glucose-lowering strategy. A comprehensive and multifactorial intervention strategy that includes aggressive glycemic control, blood-pressure-lowering and lipid-lowering therapy, aspirin use and lifestyle modifications is beneficial in reducing both macrovascular and microvascular events in patients with T2DM.

Key Points

  • Diabetes is the leading cause of morbidity and mortality in the US and prevalence of type 2 diabetes mellitus is expected to double by 2030

  • Results of large, prospective, cardiovascular outcome trials of intensive glycemic control have been disappointing, but aggressive cardiovascular risk factor modification in participants probably influenced the findings

  • A comprehensive, multifactorial, intervention strategy that includes tight as well as durable glycemic control, blood-pressure-lowering and lipid-lowering medications, aspirin use and lifestyle modifications is beneficial

  • Individuals without a history of cardiovascular disease, as well as younger individuals with more modest elevations of HbA1c may benefit from a more intensive glucose lowering strategy

  • Caution is advised with use of thiazolidinediones, owing to concerns over an increased risk of congestive heart failure; however, these agents achieve more durable glycemic control than sulfonylureas and metformin

  • An insulin-sensitizing strategy seems to be warranted in patients with type 2 diabetes mellitus and coronary disease

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References

  1. Stamler, J., Vaccaro, O., Neaton, J. D. & Wentworth, D. Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Invention Trial. Diabetes Care 16, 434–444 (1993).

    Article  CAS  Google Scholar 

  2. Mak, K. H. et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J. Am. Coll. Cardiol. 30, 171–179 (1997).

    Article  CAS  Google Scholar 

  3. Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, 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. 339, 229–234 (1998).

    Article  CAS  Google Scholar 

  4. Wild, S., Roglic, G., Green, A., Sicree, R. & King, H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27, 1047–1053 (2004).

    Article  Google Scholar 

  5. Buse, J. et al. Primary prevention of cardiovascular disease in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 115, 114–126 (2007).

    Article  Google Scholar 

  6. Selvin, E. et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetics. Ann. Intern. Med. 141, 421–431 (2004).

    Article  CAS  Google Scholar 

  7. [No authors listed]. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).

  8. Stratton, I. M. et al. Association of glycaemia with microvascular and macrovascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321, 405–412 (2000).

    Article  CAS  Google Scholar 

  9. Schwartz, T. & Meinhert, C. The UGDP controversy: thirty-four years of contentious ambiguity laid to rest. Perspec. Biol. Med. 47, 564–574 (2004).

    Article  Google Scholar 

  10. [No authors listed]. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854–865 (1998).

  11. Eurich, D., Majumbar, S., McAlister, F., Tsuyuki, R. T. & Johnson, J. A. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 28, 2345–2351 (2005).

    Article  CAS  Google Scholar 

  12. Masoudi, F. et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure. Circulation 111, 583–590 (2005).

    Article  CAS  Google Scholar 

  13. Parulkar, A. A., Pendergrass, M. L., Granda-Ayala, R., Lee, T. R. & Fonseca, V. A. Non-hypoglycemic effects of thiazolidinediones. Ann. Intern. Med. 134, 61–71 (2001).

    Article  CAS  Google Scholar 

  14. Yue, T. et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 104, 2588–2594 (2001).

    Article  CAS  Google Scholar 

  15. Shiomi, T. et al. Pioglitazone, a peroxisome proliferator-activated receptor-agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 106, 3126–3132 (2002).

    Article  Google Scholar 

  16. Sauer, W. H., Berlin, J. A. & Kimmel, S. E. Thiazolidinediones and prevention of myocardial infarction with type 2 diabetes. Circulation 106, 2777 (2002).

    Google Scholar 

  17. Takagi, T. et al. Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study. Am. Heart J. 146, E5 (2003).

    Article  Google Scholar 

  18. Choi, D. et al. Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. Diabetes Care 27, 2654–2660 (2004).

    Article  CAS  Google Scholar 

  19. Langenfeld, M. R. et al. Pioglitazone decreases carotid intima–media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation 111, 2525–2531 (2005).

    Article  CAS  Google Scholar 

  20. Mazzone, T. et al. Effect of pioglitazone compared with glimepiride on carotid intima–media thickness in type 2 diabetes: a randomized trial. JAMA 296, 2572–2581 (2006).

    Article  CAS  Google Scholar 

  21. Sidhu, J. S., Kaposzta, Z., Markus, H. S. & Kaski, J. C. Effect of rosiglitazone on common carotid intima–media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 24, 930–934 (2004).

    Article  CAS  Google Scholar 

  22. Nissen, S. et al. Comparison of pioglitazone vs glimiperide on progression of atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized trial. JAMA 299, 1561–1573 (2008).

    Article  CAS  Google Scholar 

  23. Charbonnel, B. et al. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5,238 patients. Diabetes Care 27, 1647–1653 (2004).

    Article  Google Scholar 

  24. Betteridge, D. J., DeFronzo, R. A. & Chilton, R. J. PROactive: time for a critical appraisal. Eur. Heart J. 29, 969–983 (2008).

    Article  Google Scholar 

  25. Nissen, S. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457–2471 (2007).

    Article  CAS  Google Scholar 

  26. Diamond, G. A., Bax, L. & Kaul, S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann. Intern. Med. 147, 578–581 (2007).

    Article  Google Scholar 

  27. Singh, S., Loke, Y. K. & Furberg, C. D. Long-term risk of cardiovascular events with rosiglitazone. A meta-analysis. JAMA 298, 1189–1195 (2007).

    Article  CAS  Google Scholar 

  28. Lincoff, A. M., Wolski, K., Nicholls, S. J. & Nissen, S. E. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298, 1180–1188 (2007).

    Article  CAS  Google Scholar 

  29. Home, P. D. et al. Rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes (RECORD): study design and protocol. Diabetologia 48, 1726–1735 (2005).

    Article  CAS  Google Scholar 

  30. Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373, 2125–2135 (2009).

    Article  CAS  Google Scholar 

  31. Lago, R. M., Singh, P. P. & Nesto, R. W. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomized clinical trials. Lancet 370, 1129–1136 (2007).

    Article  CAS  Google Scholar 

  32. Duckworth, W. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

    Article  CAS  Google Scholar 

  33. Action to Control Cardiovascular Risk in Diabetes Study Group et al. Effects of intensive blood glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545–2559 (2008).

  34. BARI 2D study group. A randomized trial of therapies for type 2 diabetes and coronary disease. N. Engl. J. Med. 360, 2503–2515 (2009).

  35. Holman, R., Retnakaran, R., Farner, A. & Stevens, R. PROactive study. Lancet 367, 25–26 (2006).

    Article  CAS  Google Scholar 

  36. Eurich, D. T. et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 335, 497 (2007).

    Article  CAS  Google Scholar 

  37. Dargie, H. et al. A randomized placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association functional class I or II heart failure. J. Am. Coll. Cardiol. 49, 1694–1704 (2007).

    Article  Google Scholar 

  38. Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 356, 2427–2443 (2006).

    Article  Google Scholar 

  39. Chaisson, J. L. et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 290, 486–494 (2003).

    Article  Google Scholar 

  40. Bullock, B. P., Heller, R. S. & Habener, J. F. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 137, 2968–2978 (1996).

    Article  CAS  Google Scholar 

  41. Ban, K. et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and independent pathways. Circulation 117, 2340–2350 (2008).

    Article  CAS  Google Scholar 

  42. Dandona, P., Mohanty, P., Chaudhuri, A., Garg, R. & Aljada, A. Insulin infusion in acute illness. J. Clin. Invest. 115, 2069–2072 (2005).

    Article  CAS  Google Scholar 

  43. Anselmino, M. et al. Glucose lowering treatment in patients with coronary artery disease is prognostically important not only in established but also in newly detected diabetes mellitus: a report from the European Heart Survey on Diabetes and the Heart. Eur. Heart J. 29, 177–184 (2008).

    Article  Google Scholar 

  44. Mellvin, L. G. et al. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur. Heart J. 29, 166–176 (2008).

    Article  Google Scholar 

  45. Malmberg, K. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 314, 1512–1515 (1997).

    Article  CAS  Google Scholar 

  46. Nathan, D. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes mellitus. N. Engl. J. Med. 353, 2643–2653 (2005).

    Article  Google Scholar 

  47. ORIGIN Trial Investigators et al. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am. Heart J. 155, 26–32 (2008).

  48. The ADVANCE collaborative group et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 358, 2560–2572 (2008).

  49. Pitale, S. et al. Two years of intensive glycemic control and left ventricular function in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus. Diabetes Care 23, 1316–1320 (2000).

    Article  CAS  Google Scholar 

  50. Holman, R., Paul, S., Bethel, A., Matthews, D. R. & Neil, H. A. 10-year follow up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).

    Article  CAS  Google Scholar 

  51. Gaede, P., Lund-Andersen, H., Parving, H. & Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580–591 (2008).

    Article  CAS  Google Scholar 

  52. Gaede, P. et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med. 348, 383–393 (2003).

    Article  Google Scholar 

  53. Gaede, P. & Pederen, O. Intensive integrated therapy of type 2 diabetes: implications for long term prognosis. Diabetes 53 (Suppl. 3), S39–S47 (2004).

    Article  CAS  Google Scholar 

  54. Howard, B. V. et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes. The SANDS randomized trial. JAMA 299, 1678–1689 (2008).

    Article  CAS  Google Scholar 

  55. Nathan, D. et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32, 193–203 (2009).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Bridgeport Hospital, Bridgeport, CT, USA

    Stuart W. Zarich

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Correspondence to Stuart W. Zarich.

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The author declares associations with the following companies: GlaxoSmithKline (consultant, speakers' bureau), Sanofi-Aventis (consultant).

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Zarich, S. Antidiabetic agents and cardiovascular risk in type 2 diabetes. Nat Rev Endocrinol 5, 500–506 (2009). https://doi.org/10.1038/nrendo.2009.150

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