Treatment of Metabolic Syndrome

Certain metabolic disturbances, when grouped together in a single individual patient, comprise the cluster known as metabolic syndrome. The National Cholesterol Education Program's Adult Treatment Panel III (ATP III) defines these metabolic disturbances as[1]:

• Abdominal obesity

• Atherogenic dyslipidemia

• Sustained elevated blood pressure (>140/90 mm Hg)

• Insulin resistance ± glucose intolerance

• Prothrombotic state

• Proinflammatory state

These factors together increase the risk of coronary heart disease (CHD), and insulin resistance combined with the other factors is a primary cause of type 2 diabetes. Obesity, physical inactivity, and genetic factors are the root causes of metabolic syndrome.[1] In the US, 21.8% of the population is estimated to have metabolic syndrome.[2]

TABLE 1. ATP III clinical identification of metabolic syndrome

Metabolic syndrome = Three or more criteria

Other definitions of metabolic syndrome have been developed but are not as useful as ATP III for diagnosing the condition. In 1999, the World Health Organization (WHO) developed a working definition of metabolic syndrome.[3] The WHO definition included insulin resistance as a diagnostic criterion, requiring oral glucose testing beyond routine clinical assessment, which complicates diagnosis.[4] The American Association of Clinical Endocrinologists (AACE) definition of metabolic syndrome does not call for the inclusion of a set number of risk factors for diagnosis, leaving diagnosis up to the clinician.[4,5] AACE, like the WHO, also calls for an oral glucose tolerance test to confirm a diagnosis.[4]

Treating metabolic syndrome

First-line therapy for treating metabolic syndrome is lifestyle modification that targets the root causes by reducing weight and obesity, improving the amount of physical activity, and diet modification.[4] Overweight and obesity are defined as body mass index of 25 to 29.9 kg/m² and >30 kg/m², respectively.[6,7] Abdominal obesity apart from general obesity presents a particular risk factor for metabolic syndrome.[1] Abdominal obesity is defined as a waist circumference >102 cm (40 inches) in men or >88 cm (35 inches) in women.[6,7] Through behavior modification (increased physical activity and dietary modification), patients should expect to reduce their weight by 7% to 10% over 6 to 12 months.[6]

Physical activity should consist of a minimum of 30 minutes of moderate-intensity physical activity most days of the week.[6] It has been shown that physical activity can treat metabolic syndrome. In a study of 621 healthy adults with metabolic syndrome, 30.5% of the participants were no longer classified with metabolic syndrome after 40 weeks of aerobic exercise training.[8] Another study of white women showed that leisure-time physical activity levels are inversely associated with the prevalence of metabolic syndrome.[9]

Dietary modification also plays an important role in the treatment of metabolic syndrome. Dietary recommendations are the same as those for managing diabetes. Carbohydrate intake should include whole grains, fruits, vegetables, and low-fat milk. The total amount of carbohydrate consumed, rather than the type or source of the carbohydrate, determines the glycemic effect—sucrose does not increase glycemia any more than isocaloric amounts of starch. Saturated fats should be reduced.[10] Although very high carbohydrate diets may exacerbate dyslipidemia, it has not been proven that substituting unsaturated fats in place of some carbohydrates will improve the lipid profile.[4]

A second treatment approach addresses the metabolic risk factors— insulin resistance, dyslipidemia, hypertension, and prothrombotic state—individually through nonpharmacologic and pharmacologic therapies.[1]

Insulin Resistance

Insulin resistance is believed to be the main factor of metabolic syndrome,[4] which is why metabolic syndrome is sometimes referred to as the insulin resistance syndrome. Weight loss and increased physical activity lower insulin resistance.[11,12] Diets with a lower glycemic load and increased dietary fiber are also associated with lower insulin resistance. Fiber from cereal has been shown to be inversely related to prevalence of metabolic syndrome, but the same was not found for fiber from fruit, vegetables, and legumes.[13] If lifestyle changes do not improve insulin resistance, it can be treated with pharmacotherapy. Metformin, an insulin sensitizer that has been used for more than 40 years, improves insulin sensitivity and some of the components of the metabolic syndrome by improving glucose uptake. Pioglitazone and rosiglitazone are thiazolidinediones, which increase insulin sensitivity by improving insulin-mediated muscle glucose uptake.[14]

Dyslipidemia

Dyslipidemia often responds to lifestyle changes. If ATP III goals (Table 2) for LDL cholesterol (the primary target of lipid-lowering therapy) cannot be reached by using diet and exercise, drug alternatives may be used. Statins and fibrates are commonly prescribed for dyslipidemia. Clinical trials have shown the efficacy of various statin medications, such as lovastatin, atorvastatin, pravastatin, fluvastatin, and simvastatin, in lowering LDL cholesterol and reducing the risk of coronary heart disease (CHD). No clinical trials have conclusively shown the benefit of one statin over another.[15] The fibrate medications gemfibrozil and fenofibrate have also been shown to be effective in improving dyslipidemia and are sometimes used in combination with statins.[4]

Table 2. New NCEP/ATP III proposed cholesterol goal modifications[16]

*Risk factors include cigarette smoking, hypertension (BP ≥140/90 mm Hg or on antihypertensive medication), HDL cholesterol <40 mg/dL, family history of premature CHD (male <55 years, females <65 years) and age (males >45 years, females >55 years).

†LDL goal of <70 mg/dL is a reasonable therapeutic option in patients at very high risk for CVD (diabetes plus CVD). Recommendation based on new clinical trial evidence.

‡LDL goal of <100 mg/dL is a reasonable therapeutic option in patients at moderately high risk for CVD (2+ risk factors and 10-year risk 10% to 20%). Recommendation based on new clinical trial evidence.

Hypertension

Hypertension that does not respond to weight loss and dietary modification can be treated with antihypertensive agents. Antihypertensive agents seem to be equally effective in treating patients with metabolic syndrome. Beta blockers and diuretics are appropriate at low doses. Some clinical trials have suggested that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may offer advantages over other medications for patients with diabetes, but this has not been proven.[4]

Prothrombosis

Elevated blood serum levels of fibrinogen, plasminogen activator inhibitor 1 (PAI-1), and other coagulation factors indicate a prothrombotic state, but these blood tests are not routine. Aspirin therapy can reduce the risk for thrombotic events. The American Heart Association recommends aspirin therapy for patients whose 10-year risk for CHD is ≥10%, and this guideline would apply to metabolic syndrome patients. Treatment of insulin resistance with thiazolidinediones improves PAI-1 and fibrinolytic activity.[17,18]

Inflammatory markers

Markers of inflammation accompany metabolic syndrome. Such markers include elevated plasma C-reactive protein and elevated white blood cell counts and metalloproteinase. [9,14] Thiazolidinedione treatment improves the proinflammatory state in the metabolic syndrome patient.[19]

References

1. U.S. Department of Health and Human Services. 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. National Cholesterol Education Program National Heart, Lung, and Blood Institute National Institutes of Health. NIH Publication No. 02-5215. September 2002. II-26.
2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults. JAMA. 2002;287:356-359.
3. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus. Geneva, Switzerland: World Health Organization; 1999. Available at: http://whqlibdoc.who.int/hq/1999/WHO_NCD_NCS_99.2.pdf. Accessed May 3, 2004. 9-11, 64.
4. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation. 2004;109:433-438.
5. Einhorn D, Reaven GM, Cobin RH, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract. 2003;9:237-252.
6. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults — the evidence report. NIH Pub. No. 98-4083. Bethesda, MD: National Heart, Lung and Blood Institute, 1998.
7. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults — the evidence report. Obesity Res. 1998;6(suppl 2):51S-209S.
8. Katzmarzyk PT, Leon AS, Wilmore JH, et al. Targeting the metabolic syndrome with exercise: evidence from the HERITAGE Family Study. Med Sci Sports. 2003;35:1703-1709.
9. Irwin ML, Ainsworth BE, Mayer-Davis EJ, Addy CL, Pate RR, Durstine JL. Physical activity and the metabolic syndrome in a tri-ethnic sample of women. Obes Res. 2002;10:1030-1037.
10. American Diabetes Association Task Force for Writing Nutrition Principles and Recommendations for the Management of Diabetes and Related Complications. American Diabetes Association position statement: evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. J Am Diet Assoc. 2002;102:109-118.
11. Ahmad F, Considine RV, Bauer TL, Ohannesian JP, Marco CC, Goldstein BJ. Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue. Metabolism. 1997;46:1140-5.
12. Perseghin G, Price TB, Petersen KF, et al. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med. 1996;335:1357-1362.
13. McKeown NM, Meigs JB, Liu S, Saltzman E, Wilson PWF, Jacques PF. Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham Offspring Cohort. Diabetes Care. 2004;27:538-546.
14. Lebovitz HE, Banerji MA. Treatment of insulin resistance in diabetes mellitus. Eur J Pharmacol. 2004;490:135-146.
15. Snow V, Aronson MD, Hornbake ER, Mottur-Pilson C, Weiss KB. Lipid control in the management of type 2 diabetes mellitus: a clinical practice guidelines from the American College of Physicians. Ann Intern Med. 2004;140:644-649.
16. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
17. Kruszynska YT, Yu JG, Olefsky JM, Sobel BE. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Diabetes. 2000;49:633-639.
18. Harte AL, McTernan PG, McTernan CL, Sith SA, Barnett AH, Kumar S. Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes. Diabetes Obes Metab. 2003;5:302-310.
19. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes. Circulation. 2002;106:679-684