The Metabolic Syndrome: Targeting Dyslipidaemia to Reduce Coronary Risk

The metabolic syndrome is a complex constellation of disorders, each one a significant risk factor for the development of cardiovascular disease (CVD). The increasing prevalence of this condition is a major concern for healthcare providers both in Europe and North America. The concern surrounding the prevalence of the metabolic syndrome is reflected in the recently published National Cholesterol Education Program Adult Treatment Panel III guidelines. Although complex in nature, the individual components of the metabolic syndrome appear to be linked by the presence of insulin resistance. Concurrently treating the underlying insulin resistance along with the complex array of other disorders should form the core of any management strategy. Treatment of atherogenic dyslipidaemia should be a major aim, since it is associated with a significant risk of CVD. While lifestyle modifications form the cornerstone of any dyslipidaemia management strategy, many patients require the addition of lipid-modifying drugs. Several agents are available for the treatment of lipid abnormalities, including fibrates, bile acid sequestrants, niacin and hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins). Of these, statins should be used as the first treatment option in the majority of patients because they are efficacious for reducing low-density lipoprotein cholesterol, are effective across the lipid profile and are well tolerated in the majority of cases. Furthermore, the American Diabetes Association (ADA) recommends statins as first-line pharmacological treatment of dyslipidaemia in patients with diabetes mellitus. This review discusses the diagnosis and management of the metabolic syndrome and examines the potential of future treatment options.

[1]  P. Wahl,et al.  Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. , 2000, American journal of epidemiology.

[2]  G. Assmann,et al.  The Prospective Cardiovascular Münster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart disease. , 1988, American heart journal.

[3]  D L McGee,et al.  Diabetes and Glucose Tolerance as Risk Factors for Cardiovascular Disease: The Framingham Study , 1979, Diabetes Care.

[4]  L. DiPietro,et al.  Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study , 1999, Diabetologia.

[5]  Teven,et al.  MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION , 2000 .

[6]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[7]  J. Meigs,et al.  Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. , 2000, American journal of epidemiology.

[8]  L. Groop Insulin resistance: the fundamental trigger of type 2 diabetes , 1999, Diabetes, obesity & metabolism.

[9]  R. Evans,et al.  Improved insulin-sensitivity in mice heterozygous for PPAR-γ deficiency , 2000 .

[10]  B. Howard,et al.  A preponderance of small dense LDL is associated with specific insulin, proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects , 1995, Diabetologia.

[11]  Bezafibrate Infarction Prevention study Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. , 2000, Circulation.

[12]  G. Boden,et al.  Effects of a 48-h Fat Infusion on Insulin Secretion and Glucose Utilization , 1995, Diabetes.

[13]  W. Castelli Epidemiology of triglycerides: a view from Framingham. , 1992, The American journal of cardiology.

[14]  S. Haffner Management of Dyslipidemia in Adults With Diabetes , 1998, Diabetes Care.

[15]  B. Goldstein,et al.  Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue. , 1997, Metabolism: clinical and experimental.

[16]  A. Galecki,et al.  The independent and combined effects of weight loss and aerobic exercise on blood pressure and oral glucose tolerance in older men. , 1998, American journal of hypertension.

[17]  A. Gotto,et al.  Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. , 2002, The American journal of cardiology.

[18]  T. Willson,et al.  Peroxisome proliferator-activated receptor gamma and metabolic disease. , 2001, Annual review of biochemistry.

[19]  J. Flier,et al.  Adipose Tissue as an Endocrine Organ , 2014 .

[20]  A. Prentice,et al.  Long-term effects of ad libitum low-fat, high-carbohydrate diets on body weight and serum lipids in overweight subjects with metabolic syndrome. , 2002, The American journal of clinical nutrition.

[21]  T. Valle,et al.  Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. , 2001, The New England journal of medicine.

[22]  J. Devlin Effects of Exercise on Insulin Sensitivity in Humans , 1992, Diabetes Care.

[23]  J. Neaton,et al.  Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). , 1986, JAMA.

[24]  A. Gotto,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. , 1998, JAMA.

[25]  I. Shapira,et al.  Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety , 2000, Journal of internal medicine.

[26]  Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) , 1994, The Lancet.

[27]  S. Grundy,et al.  Treatment of dyslipidemia in non-insulin-dependent diabetes mellitus with lovastatin. , 1988, The American journal of cardiology.

[28]  P. Macfarlane,et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia , 1995 .

[29]  J. Auwerx,et al.  Peroxisome proliferator-activated receptors, orphans with ligands and functions. , 1997, Current opinion in lipidology.

[30]  R. Eckel Familial combined hyperlipidemia and insulin resistance : distant relatives linked by intra-abdominal fat? , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[31]  S. Grundy Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. , 1999, The American journal of cardiology.

[32]  Guoxun Chen,et al.  Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity. , 1997, The American journal of physiology.

[33]  Ames,et al.  PREVENTION OF CORONARY HEART DISEASE WITH PRAVASTATIN IN MEN WITH HYPERCHOLESTEROLEMIA , 2000 .

[34]  J. Huttunen,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. , 1987, The New England journal of medicine.

[35]  J. Isaacsohn,et al.  Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. , 1996, JAMA.

[36]  Philipp E. Scherer,et al.  A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[37]  Y. Matsuzawa,et al.  Improvement of glucose and lipid metabolism associated with selective reduction of intra-abdominal visceral fat in premenopausal women with visceral fat obesity. , 1991, International journal of obesity.

[38]  R. Bergman,et al.  Extreme insulin resistance of the central adipose depot in vivo. , 2002, Diabetes.

[39]  R. Collins,et al.  MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebo-controlled trial , 2002 .

[40]  R. Bergman,et al.  Free Fatty Acids and Pathogenesis of Type 2 Diabetes Mellitus , 2000, Trends in Endocrinology & Metabolism.

[41]  G. Boden,et al.  Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. , 1995, The Journal of clinical investigation.

[42]  T. Wilt,et al.  Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. , 1999, The New England journal of medicine.

[43]  J. Slattery,et al.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. , 1994, Atherosclerosis. Supplements.

[44]  T. Buchanan,et al.  Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. , 2002, Diabetes.

[45]  L. Groop,et al.  Cardiovascular morbidity and mortality associated with the metabolic syndrome. , 2001, Diabetes care.

[46]  R. Paoletti,et al.  Rosuvastatin Demonstrates Greater Reduction of Low-Density Lipoprotein Cholesterol Compared with Pravastatin and Simvastatin in Hypercholesterolaemic Patients: A Randomized, Double-Blind Study , 2001, Journal of cardiovascular risk.

[47]  J. Flier,et al.  Lilly Lecture: Syndromes of Insulin Resistance: From Patient to Gene and Back Again , 1992, Diabetes.

[48]  N. Chaiyakunapruk,et al.  Pharmaco-Economic Impact of HMG-CoA Reductase Inhibitors in Type 2 Diabetes , 2001, Journal of cardiovascular risk.

[49]  G. Rosenhamer,et al.  Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. , 2009, Acta medica Scandinavica.

[50]  B. Egan,et al.  Insulin resistance and cardiovascular disease. , 2001, American journal of hypertension.

[51]  W. Dietz,et al.  Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. , 2002, JAMA.

[52]  D. O'Neal,et al.  Atorvastatin and simvastatin reduce elevated cholesterol in non-insulin dependent diabetes , 1996 .

[53]  J. Auwerx PPARγ, the ultimate thrifty gene , 1999, Diabetologia.

[54]  S. Grundy,et al.  Primary hypertriglyceridemia with borderline high cholesterol and elevated apolipoprotein B concentrations. Comparison of gemfibrozil vs lovastatin therapy. , 1990, JAMA.

[55]  D L Rothman,et al.  Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. , 1996, The New England journal of medicine.

[56]  R. Knopp,et al.  Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia: preliminary report. , 1994, The American journal of cardiology.

[57]  D. Capuzzi,et al.  Treatment of hyperlipidemia with combined niacin-statin regimens. , 1998, The American journal of cardiology.

[58]  G. Reaven,et al.  Pathophysiology of insulin resistance in human disease. , 1995, Physiological reviews.

[59]  Loyd,et al.  SIMVASTATIN AND NIACIN , ANTIOXIDANT VITAMINS , OR THE COMBINATION FOR THE PREVENTION OF CORONARY DISEASE , 2001 .

[60]  G. Shulman,et al.  Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. , 1999, Diabetes.

[61]  M. Linton,et al.  Current perspectives on statins. , 2000, Circulation.

[62]  K. Polonsky,et al.  Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. , 2000, The Journal of clinical investigation.

[63]  R. Collins,et al.  Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. , 1998, The New England journal of medicine.

[64]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[65]  S. Yamashita,et al.  Insulin Resistance and Body Fat Distribution: Contribution of visceral fat accumulation to the development of insulin resistance and atherosclerosis , 1996, Diabetes Care.

[66]  Millard H. Lambert,et al.  PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ∞ AND METABOLIC DISEASE , 2001 .

[67]  M. Mercuri,et al.  Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia. , 2000, The American journal of cardiology.

[68]  B. Davis,et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. , 1996, The New England journal of medicine.

[69]  R. Evans,et al.  Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. , 2000, The Journal of clinical investigation.

[70]  B. Davis,et al.  Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. , 1998, Circulation.

[71]  A. Dunaif,et al.  Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. , 1997, Endocrine reviews.

[72]  E. Bonora Relationship between regional fat distribution and insulin resistance , 2000, International Journal of Obesity.

[73]  R. Krauss,et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. , 1996, JAMA.

[74]  J S Yudkin,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-�, in Vivo* , 2022 .

[75]  S. Coppack,et al.  Adipose Tissue Leptin Production and Plasma Leptin Kinetics in Humans , 1996, Diabetes.

[76]  S. O’Rahilly,et al.  Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension , 1999, Nature.

[77]  S. Haffner,et al.  Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. , 1999, Archives of internal medicine.

[78]  W. Kannel,et al.  Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study. , 2020, Annals of internal medicine.

[79]  HOMAS,et al.  The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels , 2000 .

[80]  Vesa Manninen,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 , 1992, Circulation.

[81]  G. Reaven Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[82]  S. Haffner,et al.  Predicting risk reduction of coronary disease in patients who are glucose intolerant: a comparison of treatment with fenofibrate and other lipid-modifying agents. , 2000, Managed care interface.

[83]  S. Fowler,et al.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. , 2002 .

[84]  D L Rothman,et al.  Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. , 1999, The Journal of clinical investigation.

[85]  C. Ballantyne,et al.  Influence of Low High-Density Lipoprotein Cholesterol and Elevated Triglyceride on Coronary Heart Disease Events and Response to Simvastatin Therapy in 4S , 2001, Circulation.

[86]  J. Flier,et al.  Obesity and insulin resistance. , 2000, The Journal of clinical investigation.

[87]  L. Rossetti Glucose toxicity: the implications of hyperglycemia in the pathophysiology of diabetes mellitus. , 1995, Clinical and investigative medicine. Medecine clinique et experimentale.

[88]  R. McPherson,et al.  Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. , 1998, The American journal of cardiology.

[89]  A Tremblay,et al.  Visceral Obesity in Men: Associations With Glucose Tolerance, Plasma Insulin, and Lipoprotein Levels , 1992, Diabetes.

[90]  T. Lüscher,et al.  Efficacy and tolerability of fluvastatin and bezafibrate in patients with hyperlipidemia and persistently high triglyceride levels. , 2000, Journal of cardiovascular pharmacology.

[91]  J. Shepherd Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety. , 1995, European heart journal.

[92]  R. Heine,et al.  Pravastatin compared to bezafibrate in the treatment of dyslipidemia in insulin‐treated patients with Type 2 diabetes mellitus , 2000, Diabetes/metabolism research and reviews.

[93]  M. Lazar,et al.  The hormone resistin links obesity to diabetes , 2001, Nature.