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Each individual issue of LipidManagement™ is now certified for CME credit–see page 3 for details on how to apply for instant CME credit through lipidhealth.org.
YOUR NEW PATIENT HANDOUT!
See page 5 for Considering Cholesterol, our patient-education tool. Photocopy and distribute this plain-language review of facts and figures to keep your patients better informed about their health.

This issue's article: Gender Differences in Heart Disease






Antonio M. Gotto, Jr, MD, DPhil
Joan and Sanford I. Weill Medical
   College of Cornell University

Elizabeth Barrett-Connor, MD
University of California, San Diego,
   School of Medicine

Peter Ganz, MD
Harvard Medical School
Brigham and Women's Hospital

Scott M. Grundy, MD, PhD
University of Texas Southwestern
   Medical Center at Dallas

Steven M. Haffner, MD
University of Texas Health Science Center

 Donald B. Hunninghake, MD
University of Minnesota Medical School

 Ronald M. Krauss, MD
Lawrence Berkeley National Laboratory
University of California, Berkeley

 John C. LaRosa, MD
SUNY Downstate Medical Center

 Peter Libby, MD
Harvard Medical School
Brigham and Women's Hospital

 Harry L. Metcalf, MD
SUNY/Buffalo School of Medicine and
   Biomedical Sciences

Copyright © 2003 Thomson Professional Postgraduate Services® (PPS), 150 Meadowlands Parkway, Secaucus, NJ 07094-2304 USA. All rights reserved.

This material may not be reproduced without the express written permission of PPS. LipidManagement™ is an educational initiative of the National Lipid Education Council™. NLEC, National Lipid Education Council and LipidManagement are trademarks used herein under license.



Supported by an unrestricted educational grant from Pfizer Inc


 

Related information on this website:

In the Current Literature section:
The Metabolic Syndrome, LDL Particle Size, and Atherosclerosis. The Atherosclerosis and Insulin Resistance (AIR) Study

Insulin Resistance and Cardiovascular Events With Low HDL Cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT)

Prevalence of the Metabolic Syndrome Among US Adults: Findings from the Third National Health and Nutrition Examination Survey


In the Newsletter section:
The Metabolic Syndrome Tied Closely to Abdominal Obesity

Obesity and Cardiovascular Disease

Case Study: 66-Year-Old Female With the Metabolic Syndrome


In the Slide Library section:
ATP III: The Metabolic Syndrome

ATP III: Management of Diabetic Dyslipidemia

Progression to Atherosclerotic Clinical Events in Patients With Diabetes

NHANES III: Aged-Adjusted Prevalence of Individual Risk Factors for the Metabolic Syndrome

NHANES III: Aged-Adjusted Prevalence of >3 Risk Factors for the Metabolic Syndrome

NHANES III: Aged-Adjusted Prevalence of the Metabolic Syndrome
Dyslipidemia and the Metabolic Syndrome

The metabolic syndrome poses a serious risk to health. Compared with persons who do not have the metabolic syndrome, those who are affected have a twofold risk of developing cardiovascular disease (CVD) and at least a fourfold risk for type 2 diabetes.1 Because it affects more than 1 in 5 US adults,2,3 and because its prevalence is expected to increase as overweight and obesity become more widespread, most medical practitioners can expect to encounter the syndrome frequently.4,5 Physicians can help reduce the incidence of CVD and diabetes by recognizing the features of the metabolic syndrome and by implementing clinical interventions aimed at managing the associated risk factors.2-4,6,7

What Are the Characteristics?
The metabolic syndrome is a constellation of coronary heart disease (CHD) risk factors: insulin resistance, atherogenic dyslipidemia, hypertension, elevated fasting blood glucose, obesity (especially abdominal obesity), and prothrombotic and proinflammatory states.1,8-11 The dyslipidemia of the syndrome is characterized by elevated TG levels, low HDL-C levels, and small, dense LDL particles. LDL-C—a major determinant of CHD risk—is typically not elevated in the metabolic syndrome, but the syndrome enhances the risk for CHD at any LDL-C level.11
    The importance of the metabolic syndrome as a CVD risk factor is receiving increased attention. The 2001 National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) has gone beyond ATP II (1993) by identifying the metabolic syndrome and recommending intensified therapeutic lifestyle changes (TLC) for persons with this constellation of risk factors.11 ATP III also differs from ATP II by calling for a more aggressive approach to lipid management in persons with established CHD or CHD risk equivalents (ie, conditions, including diabetes, that require the same vigilance as that used in treating CHD), and in those with >2 risk factors that confer a 10-year CHD risk of 10% to 20%.12,13
    The metabolic syndrome is more prevalent among Mexican-Americans than in other ethnic groups, and among persons with a higher body mass index (BMI). Those with the following characteristics are at increased risk: physical inactivity, older age, postmenopausal status, current smoking, and high carbohydrate intake.2,3 Obesity is a prominent component of the metabolic syndrome: The syndrome is present in approximately 60% of moderately obese persons (BMI ~35 kg/m2). Less than 6% of normal-weight persons (BMI <25 kg/m2) have the metabolic syndrome.3
    Many factors interplay to cause the metabolic syndrome and its complications, including heredity, obesity, body fat distribution, physical inactivity, and insulin resistance.8,14 Insulin resistance is a central factor in the development of the metabolic syndrome. It is also related to vascular endothelial dysfunction, thrombosis, and inflammation, which promote the process of atherosclerosis.9 Moreover, some components of the metabolic syndrome are associated with mildly or moderately elevated levels of C-reactive protein in a state of systemic low-grade inflammation.15

Diagnosis
The diagnosis of the metabolic syndrome can be made through the use of clinical measures and criteria set by ATP III (see Table 1).3,9,11 According to ATP III criteria, the presence of any three of the following five risk factors is sufficient for a diagnosis of the syndrome: abdominal obesity (indicated by the circumference of the waist measured transversely halfway between the anterior ischial crest and the lower rib margin, with the abdomen fully relaxed),9 elevated level of TG, low level of HDL-C, elevated blood pressure, and elevated fasting glucose level.11 Recent research has begun to elucidate the mechanisms linking obesity to the atherogenic dyslipidemia characteristic of the metabolic syndrome.8 However, other possible causes of hypertriglyceridemia include type 2 diabetes, certain genetic lipid disorders, chronic renal failure, nephrotic syndrome, and drugs such as estrogens, retinoids, higher doses of ß-adrenergic-blocking agents, and corticosteroids.11

Table 1. ATP III:
The Metabolic Syndrome

Treatment
Every patient with the metabolic syndrome should be started on a program of increased physical activity. Obese patients should also begin a weight-reduction diet, and smokers should be helped to stop smoking. Weight reduction and physical activity address the syndrome’s major causes and help modify the associated risk factors.11 Antihypertensive drug therapy should be administered when indicated, and aspirin is recommended for patients with CHD to treat the thrombotic state.11 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are the preferred antihypertensive agents.9
    Based on the ATP III guidelines, management of dyslipidemia begins with a determination of TC, LDL-C, TG, and HDL-C, and an assessment of risk category. This helps ascertain when to initiate TLC and drug therapy (see Table 2). In all patients, including those with the metabolic syndrome, drug therapy is first directed at modifying LDL-C levels.

Table 2. ATP III: LDL-C Goals and Cutpoints for Therapy

    ATP III sets LDL-C goals for three levels of CHD risk (see Table 2): <100 mg/dL for a person with CHD or a CHD risk equivalent; <130 mg/dL for a person with two or more risk factors; <160 mg/dL for a person with zero or one risk factor.11 Some authorities reduce the LDL-C goal by 30 mg/dL for patients with diabetes and by 20 mg/dL for patients with insulin resistance.9 LDL-C goals may have to be adjusted to accommodate a patient’s desires, level of risk within a risk class, quality of life, and life expectancy.9
    The ATP III guidelines identify elevated TG as an independent CHD risk factor most frequently observed in persons with the metabolic syndrome.11 In clinical practice, very-low LDL-C (VLDL-C) is the most readily available measure of TG-rich remnant lipoproteins (ie, partially degraded VLDL-C). Therefore, for patients with TG levels of 200–499 mg/dL, non–HDL-C (ie, LDL-C plus VLDL-C, or TC minus HDL-C) can be a secondary target of cholesterol-lowering therapy. Because a VLDL-C goal <30 mg/dL is considered normal, the non–HDL-C goal is customarily set at 30 mg/dL higher than the LDL-C goal.
    ATP III recommends instituting TLC from the outset, even when LDL-C is above goal level. The essential features of TLC are reduced intake of saturated fats (<7% of total calories) and cholesterol (<200 mg/day), optional use of plant stanols/sterols (2 g/day), increased intake of soluble fiber (10–25 g/day), weight reduction, and increased physical activity.11 Referral to a dietitian should be considered at any stage of management.
    Drug Therapy Choices. If lifestyle changes are not sufficient, the primary drugs employed for reaching LDL-C goal levels are the statins—HMG-CoA reductase inhibitors.9,11 This is true for all patients, including those with the metabolic syndrome. In the United States, these drugs are lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin. A growing body of evidence from basic research and clinical trials suggests that statins exert beneficial direct effects on the vasculature that are independent of LDL-C lowering, probably by increasing nitric oxide (NO) production and promoting NO-dependent vasorelaxation, reducing inflammation and coagulation, and decreasing adhesion of platelets and white cells to the vascular endothelium.9,16
    Bile-acid sequestrants (cholestyramine, colestipol, colesevelam), nicotinic acid, and fibric acids (gemfibrozil and fenofibrate) reduce LDL-C less effectively than statins.9,11 To reduce LDL-C levels, a bile-acid sequestrant may be added to a statin when statin monotherapy is not sufficiently effective at acceptable doses. Recently, ezetimibe, the first in a new class of cholesterol-absorption inhibitors, has been approved as monotherapy or in combination with a statin to reduce LDL-C levels.17 However, clinical trial evidence is not yet available concerning the specific effect of ezetimibe in patients with the metabolic syndrome. The risk of myopathy is increased when statins are used in combination with certain fibrates.9
    Elevated Triglycerides. Management of elevated TG levels (>150 mg/dL) includes weight reduction and increased physical activity.11 When pharmacologic therapy is required,9,11 it may consist of increased doses of an LDL-C–lowering drug to reduce the non–HDL-C level further or the addition of a fibrate or nicotinic acid to lower the VLDL-C component of non–HDL-C. Although ATP III recommends drug therapy for TG levels of 200–499 mg/dL, some experts consider drug therapy appropriate when fasting TG levels are >150 mg/dL in diabetic, insulin-resistant, or other high-risk patients.9 Because of the risk for myopathy, extreme caution and careful monitoring are needed if a decision is made to add a fibrate to statin therapy. Reduced fat intake (<15% of calorie intake) is required for very high TG levels (>500 mg/dL).11
    Low HDL-C. Management of low HDL-C first involves therapy to bring LDL-C to goal, with weight reduction and increased physical activity for patients with the metabolic syndrome. Although the guidelines consider an HDL-C level <40 mg/dL to be a CHD risk factor, in women with the metabolic syndrome, it is <50 mg/dL. Nicotinic acid or a fibrate can be considered for raising HDL-C.11 When both TG and HDL-C are primary lipid targets, fibrates and niacin may be combined.9 However, ATP III considers that there is insufficient evidence to specify a goal for raising HDL-C, and also that currently available drugs do not robustly raise this lipid subfraction. Therefore, in patients with a low HDL-C level, the primary lipid goal is LDL-C reduction and the secondary goal is non–HDL-C reduction. According to the guidelines, HDL-C is a therapeutic target only when TG levels are <200 mg/dL (isolated low HDL-C).11
    When dyslipidemia treatment is begun with TLC and without drug therapy, the LDL-C level should be rechecked after 6 weeks. If goal level is not achieved, reduction in saturated fat and cholesterol intake should be reinforced and consideration should be given to adding plant stanols/sterols and increasing fiber intake. If the LDL-C goal level is not reached after another 6 weeks, weight reduction and physical activity should be intensified and drug therapy should be considered. Adherence to TLC should be checked every 4 to 6 months.11
    After starting LDL-C–lowering drug therapy, it is advisable to check the LDL-C level after 6 weeks. If goal level is not reached, consideration should be given to increasing the drug dose and the LDL-C level should be rechecked after another 6 weeks. If the LDL-C level is then reached, treatment should be directed to TG and HDL-C, and response and adherence to therapy should be checked every 4 to 6 months; if the LDL-C goal level is still not reached, consideration should be given to referring the patient to a lipid specialist.11 Once the LDL-C goal has been achieved, other lipid risk factors can be addressed.

Conclusion
Physicians can play a significant role in reducing the morbidity and mortality of CVD and diabetes by being aware of and aggressively treating the metabolic syndrome, which now affects ~50 million American adults.2 Treatment of the syndrome is approached through diet aimed at weight reduction combined with a program of regular physical exercise and through drug therapy for associated lipid and nonlipid risk factors.


References*
1. Meigs JB. Am J Manag Care. 2002;8(suppl 11):S283-S292.
2. Ford ES et al. JAMA. 2002;287:356-359.
3. Park YW et al. Arch Intern Med. 2003;163:427-436.
4. Keller KB et al. Am J Crit Care. 2003;12:167-170.
5. Goran MI et al. J Clin Endocrinol Metab. 2003;88:1417-1427
6. Kendall DM et al. Am J Manag Care. 2002;8(suppl 20): S635-S653.
7. Grundy SM. Circulation. 2002;105:2696-2698.
8. Grundy SM. Endocrine. 2000;13:155-165.
9. Brinton EA. Curr Diab Rep. 2003;3:65-72.
10. Steinmetz A et al. Exp Clin Endocrinol Diabetes. 2001;109:S548-S559.
11. Executive Summary of the Adult Treatment Panel III. JAMA. 2001;285:2486-2497.
12. Executive Summary of the Adult Treatment Panel II. JAMA. 1993;269:3015-3023.
13. Safeer RS et al. Am Fam Physician. 2002;65:871-880.
14. Abate N. J Diabetes Complications. 2000;14:154-174.
15. Tamakoshi K et al. Int J Obes Relat Metab Disord. 2003;27:443-449.
16. Sowers JR. Am J Cardiol. 2003;91:14B-22B.
17. Ezetimibe [package insert]. Merck/Schering-Plough Pharmaceuticals. October 2002.

*For complete citations, please click here.

This article was reviewed for medical accuracy by Antonio M. Gotto, Jr, MD, DPhil, chairman of the National Lipid Education Council™. Dr Gotto has indicated a financial interest or affiliation as noted: consultant for AstraZeneca, Bayer Corporation, Bristol-Myers Squibb Company, Merck & Co., Inc., Pfizer Inc, and Reliant Pharmaceuticals.