Review: Statin plus thiazolidinedione use in patients with diabetes at high cardiovascular risk

Abstract

People with type 2 diabetes carry an excess burden of cardiovascular risk that warrants close attention to risk factors in the majority of patients. Despite multifactorial intervention, often including statin therapy, a substantial residual risk remains, highlighting the need for novel therapies. Thiazolidinediones (TZDs) are activators of the peroxisome proliferator-activated receptor-gamma that have multiple potentially beneficial effects on established and emerging metabolic risk factors. Available evidence suggests that, even in the presence of statin therapy, TZDs can improve risk factor profiles, reduce atherosclerosis and have a beneficial effect on cardiovascular outcomes. This article reviews the evidence supporting the use of therapy combining a TZD with a statin in patients with type 2 diabetes.

Keywords

cardiovascular risk reduction thiazolidinediones type 2 diabetes statins.

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References

Ryden L. , Standl E. , Bartnik M. et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007;28(1):88-136.

IDF Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. Brussels: International Diabetes Federation, 2005.

Gaede P. , Vedel P. , Larsen N. , Jensen GV , Parving HH , Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.

Snow V. , Aronson MD , Hornbake ER , Mottur-Pilson C. , Weiss KB Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2004;140:644-9.

Taskinen MR Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003;46:733-49.

Costa J. , Borges M. , David C. , Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ 2006;332:1115-24.

Vijan S. , Hayward RA Pharmacologic lipid-lowering therapy in type 2 Physicians. Ann Intern Med 2004;140:650-8. diabetes mellitus: background paper for the American College of Physicians. Ann Intern Med 2004:140: 650 8.

Colhoun HM , Betteridge DJ , Durrington PN 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.

Ginsberg HN REVIEW: Efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab 2006 ;91:383-92.

10.

Liao JK , Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89-118.

11.

Yano M. , Matsumura T. , Senokuchi T. et al. Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal- regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ Res 2007;100:1442-51.

12.

Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106-18.

13.

Scheen AJ Thiazolidinediones and liver toxicity. Diabetes Metab 2001;27:305-13.

14.

Patel CB , De Lemos JA , Wyne KL , McGuire DK Thiazolidinediones and risk for atherosclerosis: pleiotropic effects of PPAR gamma agonism. Diabetes Vasc Dis Res 2006;3:65-71.

15.

Paumelle R. , Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res 2007;100:1394-5.

16.

Ye Y. , Lin Y. , Atar S. et al. Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions. Am J Physiol Heart Circ Physiol 2006;291:H1158-H1169.

17.

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;296:2572-81.

18.

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;366:1279-89.

19.

Nissen SE , Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.

20.

Home PD , Pocock SJ , Beck-Nielsen H. et al. Rosiglitazone Evaluated for Cardiovascular Outcomes - An Interim Analysis. N Engl J Med 2007;357(1):28-38.

21.

The DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial . Lancet 2006;368:1096-105.

22.

Kahn SE , Haffner SM , Heise MA et al. for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy . NEJM 2006;355:2427-43.

23.

Meirhaeghe A. , Amouyel P. Impact of genetic variation of PPARgamma in humans. Mol Genet Metab 2004;83(1-2):93-102.

24.

Liu HB , Hu YS , Medcalf RL , Simpson RW , Dear AE Thiazolidinediones inhibit TNFalpha induction of PAI-1 independent of PPARgamma activation. Biochem Biophys Res Commun 2005 ;334(1):30-7.

25.

Sakamoto J. , Kimura H. , Moriyama S. et al. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 2000;278:704-11.

26.

Lehmann JM , Moore LB , Smith-Oliver TA , Wilkison WO , Willson TM , Kliewer SA An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270:12953-6.

27.

Fajas L. , Auboeuf D. , Raspe E. et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem 1997;272:18779-89.

28.

Nissen SE , Nicholls SJ , Sipahi I. et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65.

29.

Murdock DK , Jansen D. , Juza RM , Kersten M. , Olson K. , Hendricks B. Benefit of adding pioglitazone to statin therapy in non-diabetic patients with the metabolic syndrome. WMJ 2006;105:22-5.

30.

Spanheimer R. , Tan M. , Yates J. , Charbonnel B. , Ferrannini E. Effects of long-term treatment with pioglitazone on lipid levels in patients receiving statin therapy at baseline in the PROactive study abstract. Diabetes 2007;56(Suppl 1):A237.

31.

King AB , Armstrong DU Lipid response to pioglitazone in diabetic patients: clinical observations from a retrospective chart review. patients: clinical observations from a retrospective chart review. Diabetes Technol Ther 2002;4:145-51.

32.

Lewin AJ , Kipnes MS , Meneghini LF et al. Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther 2004;26:379-89.

33.

Gaudiani LM , Lewin A. , Meneghini L. et al. Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients. Diabetes Obes Metab 2005;7(1):88-97.

34.

Goldberg RB , Kendall DM , Deeg MA et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547-54.

35.

Yu D. , Murdoch SJ , Parikh SJ et al. Rosiglitazone increases LDL particle size and buoyancy and decreases C-reactive protein in patients with type 2 diabetes on statin therapy. Diabetes Vasc Dis Res 2006;3:189-96.

36.

Freed MI , Ratner R. , Marcovina SM et al. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus. Am J Cardiol 2002;90:947-52.

37.

Chu CS , Lee KT , Lee MY et al. Effects of rosiglitazone alone and in combination with atorvastatin on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Am J Cardiol 2006;97:646-50.

38.

Hanefeld M. , Forst T. , Karagiannis E. et al. Effect of pioglitazone and/or simvastatin on LDL subfractions in patients with cardiovascular disease and insulin resistance . Diabetic Med 2006;23(suppl 4):112.

39.

Llaverias G. , Lacasa D. , Vinals M. et al. Reduction of intracellular cholesterol accumulation in THP-1 macrophages by a combination of rosiglitazone and atorvastatin . Biochem Pharmacol 2004;68:155-63.

40.

Berhanu P. , Kipnes MS , Khan MA et al. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy. Diabetes Vasc Dis Res 2006;3(1):39-44.

41.

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;25:708-11.

42.

Hanefeld M. , Marx N. , Pfutzner A. et al. Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J Am Coll Cardiol 2007;49:290-7.

43.

Yosefy C. , Magen E. , Kiselevich A. et al. Rosiglitazone improves, while Glibenclamide worsens blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic activity. J Cardiovasc Pharmacol 2004;44:215-22.

44.

Chen J. , Mehta JL Angiotensin II mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone. Am J Physiol Heart Circ Physiol 2006;291:H1738-H1145.

45.

Wei J. , Ma C. , Li YM Combined effect of pioglitazone and simvastatin on urinary liver-type fatty acid-binding protein concentration in diabetic patients with microalbuminuria . Diabetologia 2007 [Epub ahead of print].

46.

Shiomi M. , Ito T. , Tsukada T. , Tsujita Y. , Horikoshi H. Combination treatment with troglitazone, an insulin action enhancer, and pravastatin, an inhibitor of HMG-CoA reductase, shows a synergistic effect on atherosclerosis of WHHL rabbits. Atherosclerosis 1999;142:345-53.

47.

Gonon AT , Bulhak A. , Labruto F. , Sjoquist PO , Pernow J. Cardioprotection mediated by rosiglitazone, a peroxisome proliferator-activated receptor gamma ligand, in relation to nitric oxide. Basic Res Cardiol 2007;102(1):80-9.

48.

European Diabetes Policy Group 1998-1999. A Desktop Guide to Type 2 Diabetes Mellitus . http://www.staff.ncl.ac.uk/philip.home/t2dgw97r.doc [Accessed July 2006].

49.

Bennett KE , Williams D. , Feely J. Under-prescribing of cardiovascular therapies for diabetes in primary care . Eur J Clin Pharmacol 2003;58:835-41.

50.

Brown LC , Johnson JA , Majumdar SR , Tsuyuki RT , McAlister FA Evidence of suboptimal management of cardiovascular risk in patients with type 2 diabetes mellitus and symptomatic atherosclerosis. CMAJ 2004;171:1189-92.

51.

Ko DT , Mamdani M. , Alter DA Lipid-lowering therapy with statins in high-risk elderly patients: the treatment-risk paradox. JAMA 2004;291:1864-70.

52.

Emberson JR , Whincup PH , Lawlor DA , Montaner D. , Ebrahim S. Coronary heart disease prevention in clinical practice: are patients with diabetes special? Evidence from two studies of older men and women. Heart 2005;91:451-5.

53.

Leiter LA , Betteridge DJ , Chacra AR et al. AUDIT study: Evidence of global undertreatment of dyslipidaemia in patients with type 2 diabetes mellitus. Br J Diabetes Vasc Dis 2006;6:31-40.

54.

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;111:2525-31.

55.

ClinicalTrials.gov [website]. U.S. National Institutes of Health. [Updated 2006 December 27; cited 2007 Feb 19]. Available from: http://www.clinicaltrials.gov/ct .

56.

Home PD , Pocock SJ , Beck-Nielsen H. et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia 2005;48:1726-35.

57.

Sobel BE , Frye R. , Detre KM Burgeoning dilemmas in the management of diabetes and cardiovascular disease: rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Circulation 2003;107:636-42.