Skip to main content

Advertisement

SpringerLink
Log in

Is the evidence from clinical trials for cardiovascular risk or harm for glitazones convincing?

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Thiazolidinediones (TZDs), agonists of the nuclear receptor peroxisome proliferator-activated receptor-γ, induce the expression of many genes, including several enzymes and transporters involved in glucose and lipid metabolism. Although the efficacy of TZDs on blood glucose control in type 2 diabetes is not questionable, their cardiovascular effects have been debated, with beneficial or harmful actions suggested by different authors. This article reviews the available clinical evidence on the cardiovascular effects of TZDs, discussing possible mechanisms underlying the observed effects and suggesting some directions for future research.

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. Monami M, Luzzi C, Lamanna C, et al.: Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes Metab Res Rev 2006, 22:477–482.

    Article  PubMed  CAS  Google Scholar 

  2. Monami M, Balzi D, Lamanna C, et al.: Are sulphonylureas all the same? A cohort study on cardiovascular and cancer-related mortality. Diabetes Metab Res Rev 2007, 23:479–484.

    Article  PubMed  CAS  Google Scholar 

  3. Thisted H, Johnsen SP, Rungby J: Sulfonylureas and the risk of myocardial infarction. Metabolism 2006, 55:S16–S19.

    Article  PubMed  CAS  Google Scholar 

  4. Margolis DJ, Hoffstad O, Strom BL: Association between serious ischemic cardiac outcomes and medications used to treat diabetes. Pharmacoepidemiol Drug Saf 2008, 17:753–759.

    Article  PubMed  Google Scholar 

  5. Nathan DM, Buse JB, Davidson MB, 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 2009, 32:193–203.

    Article  PubMed  CAS  Google Scholar 

  6. Home PD, Jones NP, Pocock SJ, et al.: Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med 2007, 24:626–634.

    Article  PubMed  CAS  Google Scholar 

  7. Perfetti R, D’Amico E: Rational drug design and PPAR agonists. Curr Diab Rep 2005, 5:340–345.

    Article  PubMed  CAS  Google Scholar 

  8. 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, 366:1279–1289.

    Article  PubMed  CAS  Google Scholar 

  9. Mannucci E, Monami M, Lamanna C, et al.: Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis 2009 May 7 (Epub ahead of print).

  10. 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 

  11. 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 

  12. 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 

  13. Diamond GA, Kaul S: Rosiglitazone and cardiovascular risk. N Engl J Med 2007, 357:938–939.

    PubMed  CAS  Google Scholar 

  14. Diamond GA, Bax L, Kaul S: Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med 2007, 147:578–581.

    PubMed  Google Scholar 

  15. Gerstein HC, Yusuf S, Bosch J, et al.: Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006, 368:1096–1105.

    Article  PubMed  CAS  Google Scholar 

  16. Khan MA, St Peter JV, Xue JL: A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care 2002, 25:708–711.

    Article  PubMed  CAS  Google Scholar 

  17. Mannucci E, Monami M, Marchionni N: Rosiglitazone and cardiovascular risk. N Engl J Med 2007, 357:938–940.

    PubMed  CAS  Google Scholar 

  18. Mannucci E, Monami M, Di Bari M, et al.: Cardiac safety profile of rosiglitazone. A comprehensive meta-analysis of randomized clinical trials. Int J Cardiol 2009 Mar 26 (Epub ahead of print).

  19. Mannucci E, Monami M, Lamanna C, et al.: Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials. Diabetes Obes Metab 2008, 10:1221–1238.

    Article  PubMed  CAS  Google Scholar 

  20. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE: Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007, 298:1180–1188.

    Article  PubMed  CAS  Google Scholar 

  21. Langenfeld MR, Forst T, Hohberg C, 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 2005, 111:2525–2531.

    Article  PubMed  CAS  Google Scholar 

  22. Mazzone T, Meyer PM, Feinstein SB, et al.: Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006, 296:2572–2581.

    Article  PubMed  CAS  Google Scholar 

  23. Sidhu JS, Kaposzta Z, Markus HS, Kaski JC: Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol 2004, 24:930–934.

    Article  PubMed  CAS  Google Scholar 

  24. Chen L, Tonkin A: A meta-analysis of the effect of thiazolidinediones on in-stent restenosis after coronary stent implantation. Am Heart J 2007, 154:e41.

    Article  PubMed  Google Scholar 

  25. Geng DF, Jin DM, Wu W, et al.: Effect of thiazolidinediones on in-stent restenosis in patients after coronary stenting: a meta-analysis of randomized controlled trials. Atherosclerosis 2009, 202:521–528.

    Article  PubMed  CAS  Google Scholar 

  26. Hedblad B, Zambanini A, Nilsson P, et al.: Rosiglitazone and carotid IMT progression rate in a mixed cohort of patients with type 2 diabetes and the insulin resistance syndrome: main results from the Rosiglitazone Atherosclerosis Study. J Intern Med 2007, 261:293–305.

    Article  PubMed  CAS  Google Scholar 

  27. Nissen SE, Nicholls SJ, Wolski K, et al.: Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008, 299:1561–1573.

    Article  PubMed  CAS  Google Scholar 

  28. Ratner RE, Cannon CP, Gerstein HC, et al.: Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in diabetes patients with Cardiovascular History (APPROACH): study design and baseline characteristics. Am Heart J 2008, 156:1074–1079.

    Article  PubMed  CAS  Google Scholar 

  29. Gilbert J, Raboud J, Zinman B: Meta-analysis of the effect of diabetes on restenosis rates among patients receiving coronary angioplasty stenting. Diabetes Care 2004, 27:990–994.

    Article  PubMed  Google Scholar 

  30. Riche DM, Valderrama R, Henyan NN: Thiazolidinediones and risk of repeat target vessel revascularization following percutaneous coronary intervention: a meta-analysis. Diabetes Care 2007, 30:384–388.

    Article  PubMed  CAS  Google Scholar 

  31. Selvin E, Marinopoulos S, Berkenblit G, et al.: Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004, 141:421–431.

    PubMed  CAS  Google Scholar 

  32. 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 

  33. Kahn SE, Haffner SM, Heise MA, et al.: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006, 355:2427–2443.

    Article  PubMed  CAS  Google Scholar 

  34. 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 [no authors listed]. Lancet 1998, 352:854–865.

  35. Gegick CG, Altheimer MD: Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors. Curr Med Res Opin 2004, 20:919–930.

    Article  PubMed  CAS  Google Scholar 

  36. Aronoff S, Rosenblatt S, Braithwaite S, et al.: Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000, 23:1605–1611.

    Article  PubMed  CAS  Google Scholar 

  37. Bakris GL, Ruilope LM, McMorn SO, et al.: Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria. J Hypertens 2006, 24:2047–2055.

    Article  PubMed  CAS  Google Scholar 

  38. Haffner SM, Greenberg AS, Weston WM, et al.: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002, 106:679–684.

    Article  PubMed  CAS  Google Scholar 

  39. Pischon T, Girman CJ, Hotamisligil GS, et al.: Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004, 291:1730–1737.

    Article  PubMed  CAS  Google Scholar 

  40. Miyazaki Y, Mahankali A, Matsuda M, et al.: Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002, 87:2784–2791.

    Article  PubMed  CAS  Google Scholar 

  41. Lago RM, Singh PP, Nesto RW: Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007, 370:1129–1136.

    Article  PubMed  CAS  Google Scholar 

  42. Monami M, Marchionni N, Mannucci E: Winners and losers at the rosiglitazone gamble. A meta-analytical approach at the definition of the cardiovascular risk profile of rosiglitazone. Diabetes Res Clin Pract 2008, 82:48–57.

    Article  PubMed  CAS  Google Scholar 

  43. Derosa G, Dangelo A, Ragonesi PD, et al.: Effects of rosiglitazone and pioglitazone combined with metformin on the prothrombotic state of patients with type 2 diabetes mellitus and metabolic syndrome. J Int Med Res 2006, 34:545–555.

    PubMed  CAS  Google Scholar 

  44. Derosa G, Cicero AF, D’Angelo A, et al.: Effects of 1 year of treatment with pioglitazone or rosiglitazone added to glimepiride on lipoprotein (a) and homocysteine concentrations in patients with type 2 diabetes mellitus and metabolic syndrome: a multicenter, randomized, double-blind, controlled clinical trial. Clin Ther 2006, 28:679–688.

    Article  PubMed  CAS  Google Scholar 

  45. Derosa G, Cicero AF, Gaddi A, et al.: Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelvemonth, multicenter, double-blind, randomized, controlled, parallel-group trial. Clin Ther 2004, 26:744–754.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Section of Geriatric Cardiology, Azienda Ospedaliero-Universitaria Careggi, Via delle Oblate 4, 50141, Florence, Italy

    Edoardo Mannucci

Authors
  1. Edoardo Mannucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matteo Monami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edoardo Mannucci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mannucci, E., Monami, M. Is the evidence from clinical trials for cardiovascular risk or harm for glitazones convincing?. Curr Diab Rep 9, 342–347 (2009). https://doi.org/10.1007/s11892-009-0054-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-009-0054-1

Keywords

Search

Navigation