Review: Defining the role of statins in diabetes

Abstract

Diabetes increases cardiovascular risk, and is recognised as a cardiovascular disease equivalent. Effective reduction of cardiovascular risk factors in diabetes patients is therefore vital. Several landmark clinical trials, including the Heart Protection Study, showed that statins reduce cardiovascular risk, even in patients with pretreatment low-density lipoprotein cholesterol (LDL-C) below 3 mmol/L. The Collaborative Atorvastatin Diabetes Study demonstrated that statin therapy significantly reduces LDL-C and major coronary events in patients with type 2 diabetes. Several studies have assessed which statins are most effective at reducing LDL-C. In patients with diabetes, rosuvastatin 10 mg and atorvastatin 10 mg bring 94% and 79% of patients, respectively, to European LDL-C goals. The benefits of more effective lipid lowering using high-dose statin therapy are being investigated in trials such as Treating to New Targets. Furthermore, studies indicate that combining a fibrate or niacin with a statin may offer more comprehensive lipid control in diabetes patients.

Keywords

statins diabetes cardiovascular risk.

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References

Bagust A. , Hopkinson PK , Maslove L. , Currie CJ The projected health care burden of Type 2 diabetes in the UK from 2000 to 2060. Diabet Med 2002;19(suppl 4):1-5.

Narayan KM , Boyle JP , Thompson TJ , Sorensen SW , Williamson DF Lifetime risk for diabetes mellitus in the United States. JAMA 2003;290: 1884-90.

Howard BV , Rodriguez BL , Bennett PH et al. Prevention Conference VI: Diabetes and Cardiovascular disease: Writing Group I: epidemiology. Circulation 2002;105:e132-7.

Stamler J. , Vaccaro O. , Neaton JD , Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44.

Wagenknecht LE , D'Agostino RB Jr , Haffner SM , Savage PJ , Rewers M. Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness: the Insulin Resistance Atherosclerosis Study. Diabetes Care 1998 ;21: 1812-18.

Hsueh WA , Law RE Diabetes is a vascular disease. J Investig Med 1998; 46:387-90.

http://www.publications.doh.gov.uk/nsf/diabetes

Niskanen L. , Turpeinen A. , Penttila I. , Uusitupa MI Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis. Diabetes Care 1998;21:1861-9.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.

10.

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults: 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;285:2486-97.

11.

Grundy SM , Cleeman JI , Bairey Merz CN et al. for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39.

12.

Eckel RH , Wassef M. , Chait A. et al. Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group II: pathogenesis of atherosclerosis in diabetes. Circulation 2002;105:e138-43.

13.

Durrington PN Diabetic dyslipidaemia. Baillieres Best Pract Res Clin Endocrinol Metab 1999;13:265-78.

14.

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;316:823-8.

15.

Jenkins AJ , Lyons TJ , Zheng D. et al.; DCCT/EDIC Research Group. Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy. Kidney Int 2003;64:817-28.

16.

Assmann G. , Schulte H. Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Munster Study. Am J Cardiol 1992;70:10H-13H.

17.

Manninen V. , Tenkanen L.S. Koskinen P. et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation 1992;85:37-45.

18.

Robins SJ , Collins D. , Wittes JT et al.; VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention Trial. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-91.

19.

BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;102:21-7.

20.

De Backer G. , Ambrosioni E. , Borch-Johnsen K. et al.; Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice . Eur Heart J 2003;24:1601-10.

21.

Haffner SM ; American Diabetes Association . Management of dyslipidemia in adults with diabetes . Diabetes Care 2003;26(suppl 1):S83-6.

22.

A desktop guide to Type 2 diabetes mellitus. European Diabetes Policy Group 1999. Diabet Med 1999;16:716-30.

23.

Centers for Disease Control and Prevention (CDC). Self-reported heart disease and stroke among adults with and without diabetes - United States, 1999-2001. MMWR Morb Mortal Wkly Rep 2003;52:1065-70.

24.

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

25.

Keech AC , Field Study Investigators T. The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study ISRCTN64783481. Cardiovasc Diabetol 2004;3:9 [Epub ahead of print].

26.

Downs JR , Clearfield M. , Weis S. et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-22.

27.

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007.

28.

Frick MH , Elo O. , Haapa K. et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-45.

29.

Shepherd J. , Blauw GJ , Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30.

30.

Sever PS , Dahlof B. , Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58. 31. Collins R. , Armitage J. , Parish S. , Sleigh P. , Peto R. ; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16.

31.

Hoogwerf BJ , Waness A. , Cressman M. et al. Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial. Diabetes 1999;48:1289-94.

32.

Pyörälä K. , Pedersen TR , Kjekshus J. , Faergeman O. , Olsson AG , Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997; 20:614-20.

33.

Sacks FM , Pfeffer MA , Moye LA et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-09.

34.

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57.

35.

Serruys PW , de Feyter P. , Macaya C. et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;287:3215-22.

36.

Andersen AR , Christiansen JS , Andersen JK , Kreiner S. , Deckert T. Diabetic nephropathy in Type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983;25:496-501.

37.

Tuomilehto J. , Borch-Johnsen K. , Molarius A. Incidence of cardiovascular disease in type 1 (insulin-dependent) diabetic subjects with and without diabetic nephropathy in Finland. Diabetologia 1998;41:784-90.

38.

Soedamah-Muthu SS , Chaturvedi N. , Toeller M. et al. EURODIAB Prospective Complications Study Group. Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study . Diabetes Care 2004;27:530-7.

39.

Misra A. , Kumar S. , Kishore Vikram N. , Kumar A. The role of lipids in the development of diabetic microvascular complications : implications for therapy. Am J Cardiovasc Drugs 2003;3:325-38.

40.

Sen K. , Misra A. , Kumar A. , Pandey RM Simvastatin retards progression of retinopathy in diabetic patients with hypercholesterolemia . Diabetes Res Clin Pract 2002;56:1-11.

41.

Baghdasarian SB , Jneid H. , Hoogwerf BJ Association of dyslipidemia and effects of statins on nonmacrovascular diseases. Clin Ther 2004;26:33751.

42.

Coulhoun HM , Betteridge DJ , Durrrington PN et al. The Collaborative Atorvastatin Diabetes Study (CARDS) investigators. 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.

43.

Ridker PM JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292-7.

44.

Grover SA , Coupal L. , Zowall H. , Dorais M.

Cost-effectiveness of treating hyperlipidemia in the presence of diabetes: who should be treated?

Circulation 2000;102:722-7.

45.

Saydah SH , Fradkin J. , Cowie CC Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004; 291:335-42.

46.

Giorda C. , Maggini M. , Alegiani SS , Turco S. , Raschetti R. ; Diabetic Care Units Study. Secondary prevention of coronary artery disease in high-risk diabetic patients. Nutr Metab Cardiovasc Dis 2003;13:238-43.

47.

Wright DJ , Grayson AD , Jackson M. , Dainty C. The reality of treating dyslipidaemia in patients with coronary heart disease: a primary care survey. Int J Clin Pract 2003 ;57:488-91.

48.

Ellis JJ , Erickson SR , Stevenson JG , Bernstein SJ , Stiles RA , Fendrick AM Suboptimal statin adherence and discontinuation in primary and secondary prevention populations. J Gen Intern Med 2004 ;19:638-45.

49.

Andrews TC , Ballantyne CM , Hsia JA , Kramer JH Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med 2001;111:185-91.

50.

Jones P. , Kafonek S. , Laurora I. , Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582-7.

51.

Marz W. , Wollschlager H. , Klein G. , Neiss A. , Wehling M. Safety of low-density lipoprotein cholestrol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial) . Am J Cardiol 1999;84:7-13.

52.

Insull W. , Kafonek S. , Goldner D. , Zieve F. on behalf of the ASSET Investigators. Comparison of efficacy and safety of atorvastatin (10 mg) with simvastatin (10 mg) at six weeks. Am J Cardiol 2001;87:554-9.

53.

Betteridge JD , Gibson M. , on behalf of the ANDROMEDA study investigators Effect of rosuvastatin and atorvastatin on LDL-C and CRP levels in patients with type 2 diabetes: results of the ANDROMEDA study. 74th European Atherosclerosis Society Congress 2004. Atherosclerosis Supplements 2004;5:107-08, abstract M.464.

54.

Franken AAM , Wolffenbuttel BHR , Vincent HH on behalf of the Dutch CORALL study group. Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with type 2 diabetes. 74th European Atherosclerosis Society Congress 2004. Atherosclerosis Supplements 2004;5:118, abstract M.513.

55.

Cannon CP , Braunwald E. , McCabe CH et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

56.

Waters DD , Guyton JR , Herrington DM , McGowan MP , Wenger NK , Shear C.

TNT Steering Committee Members and Investigators. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?

Am J Cardiol 2004;93:154-8.

57.

MacMahon M. , Kirkpatrick C. , Cummings CE et al. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab Cardiovasc Dis 2000;10:195-203.

58.

Stein E. , Stender S. , Mata P. , Sager P. et al.; Ezetimibe Study Group. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J 2004;148:447-55.

59.

Kosoglou T. , Statkevich P. , Yang B. et al. Pharmacodynamic interaction between ezetimibe and rosuvastatin. Curr Med Res Opin 2004;20:1185-95.

60.

Brown BG , Zhao XQ , Chait A. et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.

61.

Durrington PN , Tuomilehto J. , Hamann A. , Kallend D. , Smith K. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia. Diabetes Res Clin Pract 2004;64:137-51.

62.

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.

63.

Ljung B. , Bamberg K. , Dahllof B. et al. AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. J Lipid Res 2002;43:1855-63.