Diagnosis and Management of the Metabolic Syndrome
An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement: Executive Summary
This Executive Summary is a synopsis of the full scientific statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI), which is intended to provide up to date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults.
The metabolic syndrome has received increased attention in the past few years. It consists of multiple, interrelated risk factors of metabolic origin that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD). This constellation of metabolic risk factors is strongly associated with type 2 diabetes mellitus or the risk for this condition. The metabolic risk factors consist of atherogenic dyslipidemia (elevated triglycerides and apolipoprotein B, small LDL particles, and low HDL cholesterol [HDL-C] concentrations), elevated blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state.
At present, it is not clear whether the metabolic syndrome has a single cause, and it appears that it can be precipitated by multiple underlying risk factors. The most important of these underlying risk factors are abdominal obesity and insulin resistance. Other associated conditions include physical inactivity, aging, hormonal imbalance, and genetic or ethnic predisposition.
Prospective population studies show that the metabolic syndrome confers an &2-fold increase in relative risk for ASCVD events, and in individuals without established type 2 diabetes mellitus, an &5-fold increase in risk for developing diabetes as compared with people without the syndrome. This finding implies that the metabolic syndrome imparts a relatively high long-term risk for both ASCVD and diabetes. In the absence of diabetes, the absolute short-term (10-year) risk for major coronary heart disease (CHD) events is not necessarily high. In the Framingham Heart Study data, the 10-year risk for CHD depends on other risk factors in addition to the metabolic syndrome components contained in Framingham scoring (ie, blood pressure, HDL-C). These other risk factors are age, sex, serum total or LDL-C, and smoking status. For individuals with the metabolic syndrome who do not have established ASCVD or type 2 diabetes mellitus, the absolute 10-year risk is best assessed by Framingham risk scoring.
Clinical Diagnosis of the Metabolic Syndrome
Several different sets of criteria have been proposed during the past decade for diagnosis of the metabolic syndrome. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) proposed a simple set of diagnostic criteria based on common clinical measures including waist circumference, triglycerides, HDL-C, blood pressure, and fasting glucose level. The presence of defined abnormalities in any 3 of these 5 measures constitutes a diagnosis of the metabolic syndrome. The ATP III criteria for the metabolic syndrome have been widely used in both clinical practice and epidemiological studies. The criteria also have the advantage of avoiding emphasis on a single cause. In the absence of compelling scientific reasons for change, the AHA and NHLBI affirm the overall utility and validity of the ATP III criteria and propose that they continue to be used with minor modifications and clarifications (Table 1). These modifications and clarifications include allowing for adjustment of waist circumference to lower thresholds when individuals or ethnic groups are prone to insulin resistance; allowing triglycerides, HDL-C levels, and blood pressure to be counted as abnormal when a person is taking drug treatment for these factors; clarifying that the definition of elevated blood pressure is a level that exceeds the threshold for either systolic or diastolic pressure; and reducing the threshold for counting elevated fasting glucose from ≥110 mg/dL to ≥100 mg/dL, in accordance with the American Diabetes Association’s (ADA’s) revised definition of impaired fasting glucose (IFG).
Recently, the International Diabetes Federation (IDF) has proposed a set of clinical criteria that are similar to those of the updated ATP III criteria. In fact, thresholds are identical for triglycerides, HDL-C, blood pressure, and plasma glucose. The major difference is that the IDF proposed that waist circumference thresholds be adjusted for different ethnic groups. This suggestion is consistent with emerging information on the variable relationship between waist circumference and metabolic risk factors in different populations. The updated AHA/NHLBI diagnostic criteria maintain ATP III waist circumference thresholds for Americans, except that a lower threshold can be invoked for individuals who are especially prone to insulin resistance, particularly Asian Americans. Abdominal obesity is highly correlated with and easier to measure than other indicators of insulin resistance. The IDF therefore concluded that abdominal obesity incorporates both concepts of obesity and insulin resistance as being the 2 major underlying risk factors of the metabolic syndrome; thus, they made increased waist circumference a required element for diagnosing the metabolic syndrome. Another major reason for this recommendation was to make possible rapid identification of individuals who are likely candidates for the metabolic syndrome. In the updated ATP III classification, increased waist circumference is not deemed a necessity if 3 other risk factor criteria are present. Despite these minor differences in criteria for diagnosis, in the US population, updated ATP III and IDF criteria identify essentially the same individuals as having the metabolic syndrome. Moreover, recommendations for the clinical management of the metabolic syndrome are virtually identical in updated ATP III and IDF reports.
Clinical Management of the Metabolic Syndrome
The primary goal of clinical management of the metabolic syndrome is to reduce risk for clinical atherosclerotic disease. A closely related goal is to decrease the risk for type 2 diabetes mellitus in those patients who do not yet manifest clinical diabetes. Management of the metabolic syndrome should be carried out in the context of global cardiovascular disease-prevention efforts. For reduction of ASCVD events, the first-line therapy is to reduce the major risk factors: stop cigarette smoking and reduce LDL-C, blood pressure, and glucose levels to the recommended goals. Choice and intensity of risk factor reduction therapy depend in part on the absolute risk of patients. Patients with established ASCVD and diabetes are at high risk in the short-term (within 10 years) and deserve intensive intervention. The level of short-term risk for individuals without these conditions depends on the mix and severity of risk factors used in Framingham risk scoring; hence, even in individuals with the metabolic syndrome, 10-year risk assessment depends on Framingham scoring. For patients who manifest the metabolic syndrome, long-term risk also is elevated regardless of the Framingham score. Thus, long-term risk must be considered a high priority for clinical management of people with the metabolic syndrome.
For management of long-term as well as short-term risk, lifestyle therapies are first-line interventions to reduce the metabolic risk factors. The major lifestyle interventions include weight loss in overweight or obese subjects, increased physical activity, and modification of an atherogenic diet (Table 2). These changes will produce a reduction in all of the metabolic risk factors simultaneously. In the long run, the greatest benefit for those with the metabolic syndrome will be derived from effective lifestyle intervention.
For individuals at higher 10-year risk, consideration must be given to specific therapies for the metabolic risk factors (see Table 3). A person’s 10-year risk status will determine the intensity of therapy for each risk factor and, particularly, whether drug therapy should be employed. No specific drugs are currently recommended for people with the metabolic syndrome independent of those agents most appropriate for specific, abnormal risk factors. Recommendations for drug therapy are based on current guidelines for each risk factor that are established by the AHA, NHLBI, and ADA. The following sections summarize the recommended approaches to the management of each of the risk factors of the metabolic syndrome.
Recommendations for treatment of atherogenic dyslipidemia are based on NCEP guidelines. A few comments can be made to amplify the goals of therapy listed in Table 3 for the 3 cholesterol targets LDL-C, non-HDL-C, and HDL-C. These targets still hold for people with atherogenic dyslipidemia. The primary target of lipid-lowering therapy is LDL-C. The level of LDL-C should be reduced to that recommended by NCEP guidelines as determined by risk category. Four categories of absolute 10-year risk for CHD are identified for cholesterol-lowering therapy: high-risk (>20%), moderately high risk (10% to 20% with ≥2 risk factors), moderate risk (<10% with ≥2 risk factors), and lower risk (<10% with 0 to 1 risk factor). LDL-C goals for each risk category are listed in Table 3. If TG levels are ≥200 mg/dL, non-HDL-C is a secondary target of treatment after the LDL-C goal is achieved; the non-HDL-C goal is 30 mg/dL higher than that specified for LDL-C. If TG are ≥500 mg/dL, reduction of TG to <500 mg/dL takes primacy over LDL reduction as the primary goal because of the immediate need to reduce risk for acute pancreatitis. After LDL-C and non-HDL-C goals are achieved, a tertiary target is HDL-C. No goals for raising HDL-C are specified, but an effort should be made to raise HDL-C to the extent possible with standard therapies.
For patients with atherogenic dyslipidemia who enter clinical cholesterol management, lifestyle intervention should be employed as the basic therapy. In addition, however, for some individuals, lipid-lowering drugs may be required to achieve goals, depending on 10-year risk estimates. For LDL-C reduction, the standard LDL-lowering drugs are statins, ezetimibe, and bile acid sequestrants. Other drugs that can produce moderate reductions of LDL-C are nicotinic acid and fibrates; these 2 agents are considered to be secondary drugs to lower non-HDL-C and to raise HDL-C after LDL-C goals are achieved. Caution must be exercised in using fibrates (particularly gemfibrozil) with statins because of the accentuated risk for severe myopathy. The fibrates or nicotinic acid are a first-line therapy for patients with severe hypertriglyceridemia for the purpose of preventing acute pancreatitis.
Elevated Blood Pressure
Basic guidelines for blood pressure management are presented in the 7th Report of the Joint National Commission (JNC 7). For individuals with blood pressure in the range of “prehypertension” (blood pressure 120 to 139/80 to 90 mm Hg), lifestyle changes designed to maximize the lowering of blood pressure should be used. At higher pressures (≥140/90 mm Hg), drug therapies should be considered according to current hypertension guidelines. When either diabetes or chronic renal disease is present, reducing the blood pressure to <130/80 mm Hg, with drugs if necessary, is recommended.
Elevated Plasma Glucose
As shown by recent clinical trials, when IFG is present as one component of the metabolic syndrome, progression to type 2 diabetes mellitus can be delayed or prevented by instituting lifestyle changes, especially weight reduction and increased physical activity. At present, drug therapies to reduce plasma glucose or insulin resistance are not recommended for patients with IFG. Once diabetes develops, drug therapy often is needed to achieve the recommended ADA goal for hemoglobin A1c of <7%. In addition to lifestyle therapies, serious consideration should be given to drug therapies for managing atherogenic dyslipidemia and hypertension in patients with type 2 diabetes mellitus; the efficacy of these therapies for reducing risk for ASCVD has been amply demonstrated in clinical trials.
Prothrombotic and Proinflammatory States
Most individuals with the metabolic syndrome exhibit a prothrombotic state characterized by elevations of plasminogen activator inhibitor-1 and fibrinogen. Although there are no specific therapies available to treat these abnormalities, the use of low-dose aspirin can be recommended for patients with the metabolic syndrome who have a 10-year risk for CHD ≥10%, those with overt type 2 diabetes mellitus or ASCVD, or others in the high-risk category. In patients with ASCVD in whom aspirin is contraindicated, consideration should be given to use of clopidogrel. In addition, the metabolic syndrome frequently is accompanied by a proinflammatory state, characterized by elevations of C-reactive protein. At present, no specific drug therapies are available that specifically target a proinflammatory state; nevertheless, several of the drugs used to treat other metabolic risk factors will also reduce C-reactive protein levels.
This AHA/NHLBI update on the metabolic syndrome reaches several conclusions. The writing group found the ATP III criteria for clinical diagnosis of the metabolic syndrome to be a robust and clinically useful tool. This scientific statement recommends that the ATP III diagnostic criteria be maintained with minor modifications. It is recognized that the metabolic syndrome is a complex disorder, with no single factor as the cause. Nevertheless, its prevalence rises with increasing obesity, particularly abdominal obesity. The presence of the syndrome is associated with increased long-term risk for both ASCVD and type 2 diabetes mellitus, and thus requires attention in clinical practice. Lifestyle interventions deserve prime consideration for risk reduction across a lifetime; these interventions include weight control, increased physical activity, and a diet designed to reduce the risk for ASCVD. In patients with the metabolic syndrome found to be at a relatively high 10-year risk for ASCVD, drug therapy of both major and metabolic risk factors can contribute to risk reduction. Drug therapies should be used according to current recommendations for individual risk factors. At the present time, drug therapy is not recommended specifically to reduce risk for type 2 diabetes mellitus independent of treatments to prevent ASCVD. Additional research is required both to better understand the underlying pathophysiology of the metabolic syndrome and to identify new targets for therapy.
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
The Executive Summary of this Scientific Statement was approved by the American Heart Association Science Advisory and Coordinating Committee on August 10, 2005, and by the National Heart, Lung, and Blood Institute in July 2005. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0336. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-528-4121, fax 410-528-4264, or E-mail firstname.lastname@example.org. To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.
The Executive Summary of this Scientific Statement will also appear in the December 2005 issue of Critical Pathways in Cardiology, the November/December 2005 issue of Cardiology in Review, the January 2006 issue of Current Opinion in Cardiology, and the Journal of Cardiovascular Nursing.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifier=3023366.