Metabolic Syndrome

Synonyms: syndrome X

The metabolic syndrome refers to a clustering of cardiovascular disease (CVD) risk factors whose underlying pathophysiology may be related to insulin resistance. However, there is uncertainty as to whether all patients with the syndrome are indeed insulin resistant, so the aetiology has been broadened to include concepts of obesity, adipose tissue disorders and other factors.¹

The clustering of CVD risk factors with type 2 diabetes, hyperlipidaemia, hypertension and obesity was first noted in the 1960s-1970s. The concept of the metabolic syndrome was proposed in 1988, when Reaven published a landmark paper describing syndrome X.² Subsequently, the name metabolic syndrome was coined to reflect the range of metabolic features involved.

How useful is the concept of metabolic syndrome?^3,4

More recently, the usefulness of the 'metabolic syndrome' concept has been questioned - at least in so far as clinical practice is concerned:

• It is accepted that cardiovascular risk factors often "cluster", and that insulin resistance has an important part in this risk factor clustering.
• However, recent evidence suggests that, in clinical practice, the diagnosis of metabolic syndrome is no better at predicting cardiovascular risk than the standard methods of cardiovascular risk calculation - indeed, metabolic syndrome may perform worse in cardiovascular prediction than the standard methods.
• Also, in terms of predicting diabetes, a fasting plasma glucose is a better predictor than the diagnosis of metabolic syndrome.

There have been various definitions of the metabolic syndrome since 1998.^5,6 Scottish Intercollegiate Guidelines Network (SIGN) guidelines on CVD prevention use the following definition:

The prevalence of the metabolic syndrome varies with country, race and the definition used. One study in the USA, using the Adult Treatment Panel III criteria, found a prevalence of 24%, increasing to 44% in the over-60s.

It is likely that the prevalence of metabolic syndrome will increase together with the rising rates of obesity which have been observed, both in the West and in the developing world.¹⁰

The underlying aetiology of the metabolic syndrome is still debated. Various factors seem to be involved:^11,9

• Insulin resistance
• Obesity
• Lack of physical activity
• Atherogenic diet and atherogenic dyslipidaemia
• Prothrombotic and proinflammatory states
• Other possible factors, e.g. catecholamines,¹² antiretroviral therapy;¹³ many others are discussed in the literature.

The management of the metabolic syndrome is not specific to the syndrome, but comprises:

• Management of the underlying risk factors for CVD and diabetes (see box below).
• Treatment of any established disease such as hypertension, heart disease, diabetes or chronic kidney disease.
• Evaluation and treatment of all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the metabolic syndrome.^1,5

CVD risk factors to evaluate and treat^7,14

• Lifestyle - smoking, physical inactivity, unhealthy diet
• Hypertension
• Obesity
• Adverse lipid profile
• Hypercoagulation
• Inflammation

Unalterable risk factors are age, sex, race, family history.

Lifestyle modification

Drug treatment

• The manifestations and complications of metabolic syndrome should be treated according to established guidelines for the treatment of hyperlipidaemia, CVD, hypertension and diabetes.^1,5 This may therefore involve the use of:
  • Low-dose aspirin
  • Antihypertensives
  • Statins and/or fibrates
  • Antidiabetic drugs
• There is no specific drug treatment for the metabolic syndrome itself. Metformin, glitazones and acarbarose have been suggested as either improving the syndrome or delaying progression to type 2 diabetes,^7,26 though recent safety concerns do not favour glitazones. The AHA currently does not recommend drugs solely for the purpose of preventing diabetes, because their cost-effectiveness and safety in this role has not been documented.⁶ Metformin may have a role in polycystic ovarian syndrome.²⁷

Follow-up

• Regular follow-up to monitor progress in reducing cardiovascular risk.⁷
• Arguably, a glucose tolerance test should be performed for people with the metabolic syndrome who have normal fasting glucose, as this may identify some with occult diabetes.⁶

Concerns regarding the concept³

• Definitions/criteria vary and the rationale for thresholds is not clear.
• It is not certain whether or not there is a unifying pathological process (such as insulin resistance).
• CVD risk depends on the specific risk factors present rather than the 'metabolic syndrome' label.
• Treatment of the syndrome is no different from treatment for each of its components.
• Therefore, the value of diagnosing the syndrome is unclear.
• Some argue that 'metabolic syndrome' is a medicalisation of Western lifestyle and will label large numbers of people as diseased.¹²

Diet modification - areas of controversy

Fats
There is an established conception that low fat diets are beneficial to cardiovascular risk, and that unsaturated fats are preferable to saturated fat. However, there are concerns about this advice:¹²

• Diets containing too little fat can exacerbate dyslipidaemia.¹⁷ Meanwhile, we are left with a variety of recommendations as to the ideal fat content of the diet, varying from <30%¹⁵ to 30-35%.⁶
• High vegetable oil intakes are a new phenomenon in the history of mankind's diet.²³ There are concerns about the increasing use of refined vegetable oils in the developing world.¹⁰
• High intakes of unsaturated fats will generally be of the omega-6 class; this increases the n-6:n-3 fatty acid ratio, which is unfavorable to cardiovascular health.²³

1. Kahn R, Buse J, Ferrannini E, et al; The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005 Sep;28(9):2289-304. [abstract]
2. Reaven GM; Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595-607. [abstract]
3. Kahn R; Metabolic syndrome--what is the clinical usefulness? Lancet. 2008 Jun 7;371(9628):1892-3. Epub 2008 May 22.
4. Sattar N, McConnachie A, Shaper AG, et al; Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Lancet. 2008 Jun 7;371(9628):1927-35. Epub 2008 May 22. [abstract]
5. Reaven GM; The metabolic syndrome: is this diagnosis necessary?; Am J Clin Nutr. 2006 Jun;83(6):1237-47 [abstract]
6. Grundy SM, Cleeman JI, Daniels SR, et al; Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005 Oct 25;112(17):2735-52. Epub 2005 Sep 12.
7. SIGN guideline: Risk estimation and prevention of cardiovascular disease, Feb 2007
8. Zimmet P, Alberti G, Kaufman F, et al; The metabolic syndrome in children and adolescents. Lancet. 2007 Jun 23;369(9579):2059-61.
9. Kolovou GD, Anagnostopoulou KK, Cokkinos DV; Pathophysiology of dyslipidaemia in the metabolic syndrome. Postgrad Med J. 2005 Jun;81(956):358-66. [abstract]
10. Prentice AM; The emerging epidemic of obesity in developing countries. Int J Epidemiol. 2006 Feb;35(1):93-9. Epub 2005 Dec 2. [abstract]
11. Dandona P, Aljada A, Chaudhuri A, et al; Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005 Mar 22;111(11):1448-54.
12. Rapid responses to: editorials: Khunti K and Davies M: Metabolic syndrome; BMJ 2005; 331: 1153-1154
13. Barbaro G, Barbarini G; Highly active antiretroviral therapy-associated metabolic syndrome and cardiovascular risk. Chemotherapy. 2006;52(4):161-5. Epub 2006 May 2. [abstract]
14. Lipid modification, NICE Clinical Guideline (May 2008); (Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease.)
15. No authors listed, JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005 Dec;91 Suppl 5:v1-52.
16. Sreenivasa Baba C, Alexander G, Kalyani B, et al; Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 2006 Jan;21(1 Pt 1):191-8. [abstract]
17. Feldeisen SE, Tucker KL; Nutritional strategies in the prevention and treatment of metabolic syndrome. Appl Physiol Nutr Metab. 2007 Feb;32(1):46-60. [abstract]
18. Mukuddem-Petersen J, Oosthuizen W, Jerling JC; A systematic review of the effects of nuts on blood lipid profiles in humans. J Nutr. 2005 Sep;135(9):2082-9. [abstract]
19. Wien MA, Sabate JM, Ikle DN, et al; Almonds vs complex carbohydrates in a weight reduction program. Int J Obes Relat Metab Disord. 2003 Nov;27(11):1365-72. [abstract]
20. Esposito K, Marfella R, Ciotola M, et al; Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004 Sep 22;292(12):1440-6. [abstract]
21. Meckling KA, Sherfey R; A randomized trial of a hypocaloric high-protein diet, with and without exercise, on weight loss, fitness, and markers of the Metabolic Syndrome in overweight and obese women. Appl Physiol Nutr Metab. 2007 Aug;32(4):743-52. [abstract]
22. Gardner CD, Kiazand A, Alhassan S, et al; Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and JAMA. 2007 Mar 7;297(9):969-77. [abstract]
23. Benatti P, Peluso G, Nicolai R, et al; Polyunsaturated fatty acids: biochemical, nutritional and epigenetic properties. J Am Coll Nutr. 2004 Aug;23(4):281-302. [abstract]
24. Wang C, Harris WS, Chung M, et al; n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, Am J Clin Nutr. 2006 Jul;84(1):5-17. [abstract]
25. Mozaffarian D, Aro A, Willett WC; Health effects of trans-fatty acids: experimental and observational evidence. Eur J Clin Nutr. 2009 May;63 Suppl 2:S5-21. [abstract]
26. Petersen JL, McGuire DK; Impaired glucose tolerance and impaired fasting glucose--a review of diagnosis, clinical implications and management. Diab Vasc Dis Res. 2005 Feb;2(1):9-15. [abstract]
27. Hopkinson ZE, Sattar N, Fleming R, et al; Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology. BMJ. 1998 Aug 1;317(7154):329-32.