Skip to main content

Metabolic Syndrome: Therapeutic Considerations

  • Chapter
Atherosclerosis: Diet and Drugs

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 170))

Abstract

The metabolic syndrome is a constellation of metabolic risk factors for atherosclerotic cardiovascular disease (ASCVD) occurring in one individual. There are five cardiovascular risk factors that accompany the metabolic syndrome: atherogenic dyslipidemia [elevated apolipoprotein B (apo B), elevated triglyceride, small low-density lipoprotein (LDL) particles, and low high-density lipoprotein (HDL)cholesterol], elevated blood pressure, elevated glucose, a prothrombotic state, and a proinflammatory state. The likelihood of an individual developing metabolic syndrome is enhance by underlying risk factors, notably, obesity, insulin resistance, lack of physical activity, advancing age, and hormonal factors (e.g., androgens and corticosteroids). Besides being at higher risk for ASCVD, persons with the metabolic syndrome are at increased risk for type 2 diabetes. Persons with the metabolic syndrome deserve management in the clinical setting to reduce the risk for both ASCVD and type 2 diabetes. The two major therapeutic strategies for treatment of affected persons are modification of the underlying risk factors and separate drug treatment of the particular metabolic risk factors when appropriate. First-line therapy for underlying risk factors is therapeutic lifestyle changes, i.e., weight loss in obese persons, increased physical activity, and anti-atherogenic diet. These changes will improve all of the metabolic risk factors. Whether use of drugs to reduce insulin resistance is effective, safe, and cost-effective before the onset of diabetes awaits the results of more clinical research. Turning to individual risk components, for atherogenic dyslipidemia, drug therapies that promote lowering of apo B and raise HDL cholesterol will be needed for higher risk patients. Treatment of categorical hypertension with drugs has become standard practice. When hyperglycemia reaches the diabetic level, glucose-lowering agents will become necessary when dietary control is no longer effective, and reduction of a prothrombotic state with low-dose aspirin may be indicated in higher-risk patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 429.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 549.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abate N, Carulli L, Cabo-Chan A Jr, Chandalia M, Snell PG, Grundy SM(2003) Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. J Clin Endocrinol Metab 88:5927–5934

    Article  PubMed  Google Scholar 

  • Abbott KC, Bakris GL (2004) What have we learned from the current trials? Med Clin North Am 88:189–207

    PubMed  Google Scholar 

  • Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553

    Article  PubMed  Google Scholar 

  • Alexander CM, Landsman PB, Teutsch SM, Haffner SM; Third National Health and Nutrition Examination Survey (NHANES III); National Cholesterol Education Program (NCEP) (2003) NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 52:1210–1214

    PubMed  Google Scholar 

  • ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group (2002) The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288:2981–2997

    Google Scholar 

  • Anonymous (1998)Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med 158:1855–1867

    Google Scholar 

  • Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. National Institutes of Health, 1998. Obes Res 6:51S–209S

    Google Scholar 

  • Aronson D, Rayfield EJ (2002) How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol 1:1–10

    Article  PubMed  Google Scholar 

  • Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J (2001) Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 104:3046–3051

    PubMed  Google Scholar 

  • Bays HE, McGovern ME (2003) Once-daily niacin extended release/lovastatin combination tablet has more favorable effects on lipoprotein particle size and subclass distribution than atorvastatin and simvastatin. Prev Cardiol 6:179–188

    PubMed  Google Scholar 

  • Boden G, Cheung P, Mozzoli M, Fried SK (2003) Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes. Metabolism 52:753–759

    Article  PubMed  Google Scholar 

  • Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP (2002) Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796–2803

    PubMed  Google Scholar 

  • Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or atorvastatin evaluation and infection therapythrombolysis in myocardial infarction 22 investigators (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495–1504

    Article  PubMed  Google Scholar 

  • Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, Liddle C, Samarasinghe D, George J (2002) Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 36:403–409

    Article  PubMed  Google Scholar 

  • Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo J Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ (2003) National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, National High Blood Pressure Education Program Coordinating Committee: The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 289:2560–2572

    PubMed  Google Scholar 

  • Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group (2003) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361:2005–2016

    PubMed  Google Scholar 

  • Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356

    PubMed  Google Scholar 

  • De Pergola G, Pannacciulli N (2002) Coagulation and fibrinolysis abnormalities in obesity. J Endocrinol Invest 25:899–904

    PubMed  Google Scholar 

  • Einhorn D (2003) ACE position statement on insulin resistance syndrome. Endocr Pract 9:237–252

    PubMed  Google Scholar 

  • Ek I, Arner P, Ryden M, Holm C, Thorne A, Hoffstedt J, Wahrenberg H (2002) A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 51:484–492

    PubMed  Google Scholar 

  • Engfeldt P, Arner P (1988) Lipolysis in human adipocytes, effects of cell size, age and of regional differences. Horm Metab Res Suppl 19:26–29

    PubMed  Google Scholar 

  • Garg A (2004) Acquired and inherited lipodystrophies. N Engl J Med 350:1220–1234

    Article  PubMed  Google Scholar 

  • Gruen R, Kava R, Greenwood MR (1980) Development of basal lipolysis and fat cell size in the epididymal fat pad of normal rats. Metabolism 29:246–253

    Article  PubMed  Google Scholar 

  • Grundy SM (1999) The optimal ratio of fat-to-carbohydrate in the diet. Annu Rev Nutr 19:325–341

    Article  PubMed  Google Scholar 

  • Grundy SM (2002) Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein B as targets of lipid-lowering therapy. Circulation 106:2526–2529

    Article  PubMed  Google Scholar 

  • Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP; Diabetes Multicenter Research Group (2002) Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med 162:1568–1576

    PubMed  Google Scholar 

  • Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; American Heart Association; National Heart, Lung, and Blood Institute (2004a) Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109:433–438

    Article  PubMed  Google Scholar 

  • Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA; American Heart Association; National Heart, Lung, and Blood Institute; American Diabetes Association (2004b) Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 109:551–556

    Article  PubMed  Google Scholar 

  • Hall JE (2003) The kidney, hypertension, and obesity. Hypertension 41:625–633

    PubMed  Google Scholar 

  • Haque M, Sanyal AJ (2002) The metabolic abnormalities associated with non-alcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 16:709–731

    PubMed  Google Scholar 

  • Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7–22

    Google Scholar 

  • Hotamisligil GS (2003) Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 27(Suppl 3):S53–S55

    Article  PubMed  Google Scholar 

  • Hunt K, Resendez R, Williams K, Haffner S, Stern M (2003) NCEP versus WHO metabolic syndrome in relation to all cause and cardiovascular mortality in the San Antonio Heart Study (SAHS). Diabetes 52:A221

    Google Scholar 

  • Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Group L (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683–689

    PubMed  Google Scholar 

  • Kannel WB, Wilson PW (1995) An update on coronary risk factors. Med Clin North Am 79:951–971

    PubMed  Google Scholar 

  • Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403

    PubMed  Google Scholar 

  • Krauss RM (1995) Dense low density lipoproteins and coronary artery disease. Am J Cardiol 75:53B–57B

    PubMed  Google Scholar 

  • Krauss RM (1998) Atherogenicity of triglyceride-rich lipoproteins. Am J Cardiol 81:13B–17B

    Article  PubMed  Google Scholar 

  • Krum H, Skiba M, Gilbert RE (2003) Comparative metabolic effects of hydrochlorothiazide and indapamide in hypertensive diabetic patients receiving ACE inhibitor therapy. Diabet Med 20:708–712

    Article  PubMed  Google Scholar 

  • Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716

    Article  PubMed  Google Scholar 

  • LeRoith D (2002) Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. Am J Med 113(Suppl 6A):3S–11S

    PubMed  Google Scholar 

  • Lyon CJ, Law RE, Hsueh WA (2003) Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 144:2195–2200

    Article  PubMed  Google Scholar 

  • Misra A, Vikram NK (2003) Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Nutrition 19:457–466

    Article  PubMed  Google Scholar 

  • Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O'Leary DH, Genuth S (2003) Diabetes Control and Complications Trial; Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 348:2294–2303

    PubMed  Google Scholar 

  • Newgard CB, McGarry JD (1995) Metabolic coupling factors in pancreatic beta-cell signal transduction. Annu Rev Biochem 64:689–719

    Article  PubMed  Google Scholar 

  • Nie L, Wang J, Clark LT, Tang A, Vega GL, Grundy SM, Cohen JC (1998) Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence postheparin plasma hepatic lipase activity. J Lipid Res 39:1127–1130

    PubMed  Google Scholar 

  • Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN; REVERSAL Investigators (2004) Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291:1071–1080

    Article  PubMed  Google Scholar 

  • Olefsky JM (1977) Insensitivity of large rat adipocytes to the antilipolytic effects of insulin. J Lipid Res 18:459–464

    PubMed  Google Scholar 

  • Olijhoek JK, van der Graaf Y, Banga JD, Algra A, Rabelink TJ, Visseren FL; the SMART Study Group (2004) The metabolic syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripheral arterial disease or abdominal aortic aneurysm. Eur Heart J 25:342–348

    Article  PubMed  Google Scholar 

  • Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, Franklin BA, Goldstein LB, Greenland P, Grundy SM, Hong Y, Miller NH, Lauer RM, Ockene IS, Sacco RL, Sallis JF Jr, Smith SC Jr, Stone NJ, Taubert KA (2002) AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 106:388–391

    Article  PubMed  Google Scholar 

  • Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, Rothman DL, Shulman GI (1996) Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 335:1357–1362

    PubMed  Google Scholar 

  • Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142

    Article  PubMed  Google Scholar 

  • Reynisdottir S, Ellerfeldt K, Wahrenberg H, Lithell H, Arner P (1994) Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. J Clin Invest 93:2590–2599

    PubMed  Google Scholar 

  • Ridker PM (2003a) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107:363–369

    Article  PubMed  Google Scholar 

  • Ridker PM, Buring JE, Cook NR, Rifai N (2003b) C-reactive protein, the metabolic syndrome, and the risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 107:391–397

    Article  PubMed  Google Scholar 

  • Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group (1999) Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 341:410–418

    Article  PubMed  Google Scholar 

  • Ryden M, Dicker A, van Harmelen V, Hauner H, Brunnberg M, Perbeck L, Lonnqvist F, Arner P (2002) Mapping of early signaling events in tumor necrosis factor alpha-mediated lipolysis in human fat cells. J Biol Chem 277:1085–1091

    Article  PubMed  Google Scholar 

  • Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ, Strassmann PG, Wajchenberg BL (1999) Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 48:1836–1841

    PubMed  Google Scholar 

  • Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM (2003) C-reactive protein and the risk of developing hypertension. JAMA 290:2945–2951

    Article  PubMed  Google Scholar 

  • Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176

    PubMed  Google Scholar 

  • 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) (2002) Final Report. Circulation 106:3143–3421

    Google Scholar 

  • Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, Berra K, Blair SN, Costa F, Franklin B, Fletcher GF, Gordon NF, Pate RR, Rodriguez BL, Yancey AK, Wenger NK; American Heart Association Council on Clinical Cardiology Subcommittee on Exercise, Rehabilitation, and Prevention; American Heart Association Council on Nutrition, Physical Activity, and Metabolism Subcommittee on Physical Activity (2003) Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 107:3109–3116

    Article  PubMed  Google Scholar 

  • Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M; Finnish Diabetes Prevention Study Group (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350

    Article  PubMed  Google Scholar 

  • Vague P, Raccah D, Scelles V (1995) Hypofibrinolysis and the insulin resistance syndrome. Int J Obes Relat Metab Disord 19(Suppl 1):S11–S15

    Google Scholar 

  • Vega GL, Grundy SM (1996) Hypoalphalipoproteinemia (low high density lipoprotein) as a risk factor for coronary heart disease. Curr Opin Lipidol 7:209–216

    PubMed  Google Scholar 

  • Vega GL, Ma PT, Cater NB, Filipchuk N, Meguro S, Garcia-Garcia AB, Grundy SM (2003) Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 91:956–960

    PubMed  Google Scholar 

  • White MF (2002) IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 283:E413–E422

    PubMed  Google Scholar 

  • Yazbek N, Bapat A, Kleiman N (2003) Platelet abnormalities in diabetes mellitus. Coron Artery Dis 14:365–371

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Grundy, S. (2005). Metabolic Syndrome: Therapeutic Considerations. In: von Eckardstein, A. (eds) Atherosclerosis: Diet and Drugs. Handbook of Experimental Pharmacology, vol 170. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27661-0_3

Download citation

Publish with us

Policies and ethics