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Semin Vasc Med 2004; 4(4): 321-332
DOI: 10.1055/s-2004-869589
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Statins and Diabetes

Rafael Carmena1 , 2 , D. John Betteridge3
  • 1Endocrine Service, Hospital Clínico Universitario, University of Valencia, Valencia, Spain
  • 2Department of Medicine, University of Valencia, Valencia, Spain
  • 3Department of Medicine, University College London, London, United Kingdom
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Publication History

Publication Date:
29 April 2005 (online)

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ABSTRACT

Lipid abnormalities play an important part in raising the cardiovascular risk in diabetic subjects. The main components of diabetic dyslipidemia are increased plasma triglycerides, low concentration of high-density lipoprotein cholesterol, preponderance of small, dense low-density lipoprotein, and excessive postprandial lipemia. Small, dense low-density lipoprotein, the elevation in remnant triglyceride-rich lipoprotein particles, and the low high-density lipoprotein are the most powerful atherogenic components. The coexistence of these three factors strongly aggravates the lipid accumulation in the arterial wall and the formation of atherosclerotic plaques. The position of diabetes in cardiovascular risk assessment has been recently reviewed in the Harmonized Clinical Guidelines on Prevention of Atherosclerotic Vascular Disease. In general, patients with diabetes carry a high risk for cardiovascular disease, but the absolute risk varies depending on the type of diabetes, age, and population baseline risk. The Adult Treatment Program III (ATP III) and the American Heart Association have designated diabetes as a high-risk condition and recommended intensive risk-factor management. Concerning therapeutic targets, both ATP III and the American Diabetes Association (ADA) guidelines have identified low-density lipoprotein cholesterol as the first priority of lipid lowering, and the optimal level was set at less than 2.6 mmol/L (100 mg/dL). There is strong evidence, coming from landmark secondary prevention studies, that LDL lowering in people with diabetes is associated with significant clinical benefits. The benefits of statin therapy in type 2 diabetics can no longer be questioned. Ongoing clinical trials will help clarify the question of whether increasing high-density lipoprotein cholesterol with fibrates in the presence of low low-density lipoprotein levels (lower than 3.4 mmol/L, or 130 mg/dL) will be more beneficial than statin therapy alone. The new paradigms in risk-reduction therapies for type 2 diabetic subjects are focused on cardiovascular disease prevention, rather than only on glucose or lipid control. Therapeutic lifestyle changes are considered primary therapies for hyperglycemia and coexisting metabolic syndrome, which can be diagnosed in more than half of type 2 diabetes subjects. New perspectives of lipid management in type 2 diabetes should take into account that insulin resistance, increased lipolysis, and overproduction of large, buoyant, very low density lipoprotein particles are at the base of diabetic dyslipidemia. Accordingly, drugs acting in the regulatory steps of very low density lipoprotein assembly should be developed. Activation of peroxisome proliferator activated receptor α (PPARα), as occurs with fibrates, lowers free fatty acids (FFAs) and triglyceride levels. PPARγ agonism, as demonstrated by the thiazolidinediones, increases triglyceride lipolysis, FFA transport, and conversion of FFAs to triglycerides. As separate activation of PPARα and PPARγ improves lipid metabolism, the development of new drugs integrating PPARα and PPARγ activity (PPAR-α/γ agonists) is a promising line that may further improve insulin resistance, FFA metabolism, and consequently, atherogenic diabetic dyslipidemia.

KEYWORDS

Diabetic dyslipidemia - statins - cardiovascular risk - combination therapy

REFERENCES

  • 1 Zimmet P Z, Alberti K GMM. The changing face of macrovascular disease in non-insulin-dependent diabetes mellitus: an epidemic in progress.  Lancet. 1997;  350(suppl I) 1-4
    CrossrefPubMedGoogle Scholar
  • 2 Bloomgarden Z T. Perspectives on the news. Approaches to cardiovascular disease and its treatment.  Diabetes Care. 2003;  26 3342-3348
    PubMedGoogle Scholar
  • 3 Taskinen M R. Diabetic dyslipidemia: from basic research to clinical practice.  Diabetologia. 2003;  46 733-749
    CrossrefPubMedGoogle Scholar
  • 4 Harris M I, Klein R, Wellborn T A, Knuiman M W. Onset of NIDDM occurs at least 4-7 years before clinical diagnosis.  Diabetes Care. 1992;  15 815-819
    CrossrefPubMedGoogle Scholar
  • 5 Haffner S M, Valdez R A, Hazuda H P, Mitchell B D, Morales P A, Stern M P. Prospective analysis of the insulin-resistance syndrome (syndrome X).  Diabetes. 1992;  41 715-722
    PubMedGoogle Scholar
  • 6 Lewis G F, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance on type 2 diabetes.  Endocr Rev. 2002;  23 201-229
    CrossrefPubMedGoogle Scholar
  • 7 Coppack S W, Evans R D, Fisher R M et al.. Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal.  Metabolism. 1992;  41 264-272
    CrossrefPubMedGoogle Scholar
  • 8 Chirieac D V, Chirieac L R, Corsetti J P, Cianci J, Sparks C E, Sparks J D. Glucose-stimulated insulin secretion suppresses hepatic triglyceride-rich lipoprotein and apoB production.  Am J Physiol Endocrinol Metab. 2000;  279 E1003-E1011
    PubMedGoogle Scholar
  • 9 Lin M CM, Gordon D, Wetterau J R. Microsomal triglyceride transfer protein (MTP) regulation in HEPG2 cells: insulin negatively regulates MTP gene expression.  J Lipid Res. 1995;  36 1073-1081
    PubMedGoogle Scholar
  • 10 Lewis G F, Uffelman K D, Szeto L W, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.  J Clin Invest. 1995;  95 158-166
    CrossrefPubMedGoogle Scholar
  • 11 Vakkilainen J, Mero N, Schweizer A, Foley J E, Taskinen M R. Effects of nateglinide and glibenclamide on postprandial lipid and glucose metabolism in type 2 diabetes.  Diabetes Metab Res Rev. 2002;  18 484-490
    CrossrefPubMedGoogle Scholar
  • 12 Eckel R H. Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases.  N Engl J Med. 1989;  320 1060-1068
    PubMedGoogle Scholar
  • 13 Wang C S, McConathy W J, Kloer H U, Alaupovic P. Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III.  J Clin Invest. 1985;  75 384-390
    PubMedGoogle Scholar
  • 14 Venkatesan S, Imrie H, Read S, Halliday D. Apo C subclasses from non-insulin-dependent diabetic patients-a quantitative comparison with control subjects.  Biochem Soc Trans. 1995;  23 278S
    PubMedGoogle Scholar
  • 15 Dallongeville J MA, Cottel D, Fruchart J C, Amouyel P, Helbecque N. Polymorphisms in the insulin response element of APOC-III gene promotor influence the correlation between insulin and triglycerides or triglyceride-rich lipoproteins in humans.  Int J Obes Relat Metab Disord. 2001;  25 1012-1017
    CrossrefPubMedGoogle Scholar
  • 16 Lee S-J, Moye L A, Campos H, Williams G H, Sacks F M. Hypertriglyceridemia but no diabetes status is associated with VLDL containing apolipoprotein CIII in patients with coronary heart disease.  Atherosclerosis. 2003;  167 293-302
    CrossrefPubMedGoogle Scholar
  • 17 Despres J P, Verdon M F, Moorjani S et al.. Apolipoprotein E polymorphism modifies relation of hyperinsulinemia to hypertriglyceridemia.  Diabetes. 1993;  42 1474-1481
    PubMedGoogle Scholar
  • 18 Lamarche B, Rashid S, Lewis G F. HDL metabolism in hypertriglyceridmeic states: an overview.  Clin Chim Acta. 1999;  286 145-161
    CrossrefPubMedGoogle Scholar
  • 19 Sniderman A D, Scantlebury T, Cianflone K. Hypertriglyceridemic hyperapoB: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus.  Ann Intern Med. 2001;  135 447-459
    PubMedGoogle Scholar
  • 20 Rainwater D L. Lipoprotein correlates of LDL particle size.  Atherosclerosis. 2000;  148 151-158
    CrossrefPubMedGoogle Scholar
  • 21 Gray R S, Robbins D C, Wang W et al.. Relation of LDL size to insulin resistance syndrome and coronary heart disease in American Indians. The Strong Heart Study.  Arterioscler Thromb Vasc Biol. 1997;  17 2713-2720
    PubMedGoogle Scholar
  • 22 Chapman M J, Guerin M, Bruckert E. Atherogenic, dense low-density lipoproteins: Pathophysiology and new therapeutic approaches.  Eur Heart J. 1998;  19(Suppl A) A24-A30
    PubMedGoogle Scholar
  • 23 Chait A, Wight T N. Interaction of native and modified low-density lipoproteins with extracellular matrix.  Curr Opin Lipidol. 2000;  11 451-456
    PubMedGoogle Scholar
  • 24 Després J O. Dyslipidemia and obesity.  Baillieres Clin Endocrinol Metab. 1994;  8 629-660
    CrossrefPubMedGoogle Scholar
  • 25 Ascaso J F, Sales J, Merchante A et al.. Influence of obesity on plasma lipoproteins, glycemia and insulinaemia in patients with familial combined hyperlipidemia.  Int J Obes Relat Metab Disord. 1997;  21 360-366
    CrossrefPubMedGoogle Scholar
  • 26 Stamler J, Vaccaro O, Neaton J D. Wentworth D for the Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.  Diabetes Care. 1993;  16 434-444
    CrossrefPubMedGoogle Scholar
  • 27 Turner R C, Millns H, Neil H AW et al.. Risk factors for coronary artery disease in non-insulin-dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23).  BMJ. 1998;  316 823-828
    PubMedGoogle Scholar
  • 28 Howard B V, Robbins D C, Sievers M L et al.. LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL. The Strong Heart Study.  Arterioscler Thromb Vasc Biol. 2000;  20 830-835
    PubMedGoogle Scholar
  • 29 Hokanson E, Austin M A. Plasma triglyceride is a risk factor for cardiovascular disease independent of high density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.  J Cardiovasc Risk. 1996;  3 213-219
    CrossrefPubMedGoogle Scholar
  • 30 Assmann E, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience).  Am J Cardiol. 1992;  70 733-737
    CrossrefPubMedGoogle Scholar
  • 31 Manninen V, Tenkanen H, Koskinen P et al.. Joint effects of triglycerides 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
    CrossrefPubMedGoogle Scholar
  • 32 Lehto S, Ronnemaa T, Pyorala K, Laakso M. Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death from coronary heart disease in patients with type 2 diabetes.  Diabetologia. 2000;  43 148-155
    CrossrefPubMedGoogle Scholar
  • 33 Lehto S, Ronnemaa T, Haffner S M, Pyorala K, Kallio V, Laakso M. Dyslipidaemia and hyperglycaemia predict coronary heart disease events in middle-aged patients with NIDDM.  Diabetes. 1997;  46 1354-1359
    PubMedGoogle Scholar
  • 34 Scandinavian Simvastatin Survival Study Group . Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study.  Lancet. 1994;  344 1383-1389
    PubMedGoogle Scholar
  • 35 Pyorala K, Pedersen T R, Kjekshus J, Faergeman O, Olsson A G, 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;  20 614-620
    CrossrefPubMedGoogle Scholar
  • 36 Haffner S M, Alexander C M, Cook T J et al.. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels. Subgroup analysis in the Scandinavian Simvastatin Survival Study.  Arch Intern Med. 1999;  159 2661-2667
    CrossrefPubMedGoogle Scholar
  • 37 Herman W H, Alexander C M, Cook J R et al.. Effect of simvastatin treatment on cardiovascular resource utilization in impaired fasting glucose and diabetes. Findings from the Scandinavian Simvastatin Survival Study.  Diabetes Care. 1999;  22 1771-1778
    PubMedGoogle Scholar
  • 38 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 2005-2016
    CrossrefPubMedGoogle Scholar
  • 39 Athyros V G, Papageorgiou A A, Mercouris B R. The Greek atorvastatin and coronary heart disease evaluation (GREACE) study.  Curr Med Res Opin. 2002;  18 220-228
    CrossrefPubMedGoogle Scholar
  • 40 Serruys P W, de Feyter P, Macaya C et al.. Lescol Intervention Prevention Study (LIPS) Investigators: Fluvastatin for the prevention of cardiac events following successful first percutaneous coronary intervention. A randomised controlled trial.  JAMA. 2002;  287 3215-3222
    CrossrefPubMedGoogle Scholar
  • 41 Colhoun H M, Thomason M J, Mackness M I et al.. Fuller JH and the CARDS Investigators. Design of the collaborative atorvastatin diabetes study (CARDS) in patients with type 2 diabetes.  Diabet Med. 2002;  19 201-211
    CrossrefPubMedGoogle Scholar
  • 42 Sever P S, Dahlof B, Poulter N R 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 1149-1158
    CrossrefPubMedGoogle Scholar
  • 43 Duez H, Fruchart J, Staels B. PPARs in inflammation, atherosclerosis and thrombosis.  J Cardiovasc Risk. 2001;  8 187-194
    CrossrefPubMedGoogle Scholar
  • 44 Frick M H, Elo O, Haapa K et al.. The Helsinki Heart Study: a primary prevention trial with gemfibrozil in middle-aged men with dyslipidaemia. Safety of treatment, changes in risk factors and incidence of coronary heart disease.  N Engl J Med. 1987;  317 1237-1245
    CrossrefPubMedGoogle Scholar
  • 45 Koskinen P, Manttari M, Manninen V, Huttunen J K, Heinonen O P, Frick M H. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study.  Diabetes Care. 1992;  15 820-825
    CrossrefPubMedGoogle Scholar
  • 46 Rubins H B, Robins S J, Collins D et al.. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high density lipoprotein cholesterol.  N Engl J Med. 1999;  341 410-418
    CrossrefPubMedGoogle Scholar
  • 47 Rubins H B, Robins S J, Collins D et al.. Diabetes, plasma insulin and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs High Density Lipoprotein Intervention Trial (VA-HIT).  Arch Intern Med. 2002;  162 2597-2604
    CrossrefPubMedGoogle Scholar
  • 48 Athyros V G, Papageorgiou A A, Athyrou V V, Demitriadis D S, Kontopoulos A G. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidaemia.  Diabetes Care. 2002;  25 1198-1202
    CrossrefPubMedGoogle Scholar
  • 49 Pan J, Lin M, Kesala R, Van J, Charles M. Niacin treatment of the atherogenic lipid profile and Lp(a) in diabetes.  Diabetes Obes Metab. 2002;  4 255-261
    CrossrefPubMedGoogle Scholar
  • 50 Garg A, Grundy S M. Nicotinic acid as therapy for dyslipidaemia in non insulin dependent diabetes mellitus.  JAMA. 1990;  264 723-726
    CrossrefPubMedGoogle Scholar
  • 51 Elam M B, Hunninghake D B, Davis K B et al.. Effect of niacin on lipid and lipoprotein levels and glycaemic control in patients with diabetes and peripheral arterial disease. The ADMIT study: a randomised trial.  JAMA. 2000;  284 1263-1270
    CrossrefPubMedGoogle Scholar
  • 52 Grundy S M, Vega G L, McGovern M E et al.. Diabetes Multicenter Research Group: efficacy, safety and tolerability of once daily niacin for the treatment of dyslipidaemia associated with type 2 diabetes; results of the assessment of diabetes control and evaluation of the efficacy of Niaspan trial.  Arch Intern Med. 2002;  162 1568-1576
    CrossrefPubMedGoogle Scholar
  • 53 Van J T, Pan J, Wasty T, Chan E, Wu X, Charles M A. Comparison of extended-release niacin and atorvastatin monotherapies and combination treatment of the atherogenic lipid profile in diabetes mellitus.  Am J Cardiol. 2002;  89 1306-1308
    CrossrefPubMedGoogle Scholar
  • 54 Brown B G, Zhao X Q, Chait A et al.. Simvastatin and niacin, antioxidant vitamins or the combination for the prevention of coronary disease.  N Engl J Med. 2001;  345 1583-1592
    CrossrefPubMedGoogle Scholar
  • 55 Stein E. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor.  Eur Heart J. 2001;  3(Supplement E) E11-E16
    PubMedGoogle Scholar
  • 56 International Arteriosclerosis Society .Harmonized guidelines on prevention of atherosclerotic vascular disease. Available at: http://www.athero.org. Accessed October 18, 2004
    Google Scholar
  • 57 National Institutes of Health . 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) final report.  Circulation. 2002;  106 3143-3421
    PubMedGoogle Scholar
  • 58 Grundy S M, Benjamin I J, Burke G L et al.. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.  Circulation. 1999;  100 1134-1146
    CrossrefPubMedGoogle Scholar
  • 59 Haffner S M. Management of dyslipidemia in adults with diabetes.  Diabetes Care. 2003;  26(Suppl 1) S83-S86
    PubMedGoogle Scholar
  • 60 American Diabetes Association . Position statement. Dyslipidemia management in adults with diabetes.  Diabetes Care. 2004;  27(Suppl 1) S68-S71
    PubMedGoogle Scholar
  • 61 Isomaa B, Almgren P, Tuomi T et al.. Cardiovascular morbidity and mortality associated with the metabolic syndrome.  Diabetes Care. 2001;  24 683-689
    CrossrefPubMedGoogle Scholar
  • 62 Girman C J, Rodees T, Mercuri M et al.. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and he Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).  Am J Cardiol. 2004;  93 136-141
    CrossrefPubMedGoogle Scholar
  • 63 Tan K CB, Chow W S, Tam S CF, Ai V HG, Lam C HL, Lam K SL. Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilataion in type 2 diabetes mellitus.  J Clin Endocrinol Metab. 2002;  87 563-568
    CrossrefPubMedGoogle Scholar
  • 64 Dalla Nora E, Passaro A, Zamboni P F, Calzoni F, Fellin R, Solini A. Atorvastatin improves metabolic control and endothelial function in type 2 diabetic patients: A placebo-controlled study.  J Endocrinol Invest. 2003;  26 73-78
    PubMedGoogle Scholar

 Prof.
R. Carmena

Department of Medicine, University of Valencia

Avda Blasco Ibañez, 15, 46010 Valencia, Spain

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