RECOGNITION OF THE METABOLIC SYNDROME

THE METABOLIC SYNDROME IN CLINICAL PRACTICE Michael H. Davidson, MD* ABSTRACT Patients with the metabolic syndrome remain at significantly elevated risk of morbidity and mortality associated with coronary heart disease and type 2 diabetes mellitus despite the fact that the risk factors comprising the metabolic syndrome are, for the most part, modifiable through diet, increased physical activity, and the use of medications. The National Cholesterol Education Program's Adult Treatment Panel (ATP) III guidelines recommend lipoprotein analysis (ie, total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides) as an initial screening test for assessing cardiovascular risk. As a cardinal component of the metabolic syndrome, dyslipidemia is one of the primary targets of management. The choice of interventions for dyslipidemia is guided by the principle that intensity of treatment should be directly related to the degree of risk for coronary heart disease events. According to ATP III guidelines, LDL cholesterol is a primary target of treatment in patients with the metabolic syndrome. Secondary targets are other metabolic syndrome components including other lipid risk factors. Diet and exercise are core components of the management of multiple metabolic syndrome components. LDL-lowering pharmacotherapy is considered (but may not always be required) in patients with LDL levels of 100 mg/dl or higher. Therapy to address atherogenic dyslipidemia (ie, triglycerides 150 mg/dl and HDL cholesterol *Director of Preventive Cardiology, Rush University Medical Center, Chicago, Illinois. Address correspondence to: Michael H. Davidson, MD, Director of Preventive Cardiology, Rush University Medical Center, 1725 West Harrison Street, Suite 1159, Chicago, IL 60612. E-mail: michaeldavidson@radiantresearch.com. <40 mg/dl) is initiated after the LDL treatment goal is achieved with therapeutic lifestyle changes or pharmacotherapy. Combination therapy with a statin, which is most effective at modifying LDL cholesterol, and a fibrate or niacin, which are more effective for modifying HDL cholesterol and triglyceride, may further reduce the residual risk associated with the mixed dyslipidemia occurring in the metabolic syndrome compared to monotherapy. (Adv Stud Med. 2005;5(6A):S503-S510) Patients with the metabolic syndrome remain at significantly elevated risk of morbidity and mortality associated with coronary heart disease and type 2 diabetes mellitus despite the fact that the risk factors comprising the metabolic syndrome are, for the most part, modifiable through diet, increased physical activity, and the use of medications. This paper discusses clinical management of the metabolic syndrome with particular emphasis on the management of dyslipidemia, one of the core abnormalities in the metabolic syndrome. RECOGNITION OF THE METABOLIC SYNDROME The metabolic syndrome constitutes a cluster of physiologic abnormalities that together confer greater cardiovascular and metabolic risk than that posed by the abnormalities individually. 1 Cardiovascular risk factors including but not limited to being overweight or obese, blood lipid abnormalities, abdominal obesity, and hypertension should alert the healthcare provider to the possible presence of the metabolic syndrome and prompt further assessment to determine whether metabolic and/or cardiovascular intervention Advanced Studies in Medicine S503

is warranted. The Adult Treatment Panel III (ATP III) criteria proposed by the National Cholesterol Education Program specify that the metabolic syndrome is present if at least 3 of the following criteria are met: Waist circumference larger than 102 cm in men and larger than 88 cm in women; Serum triglyceride concentration of 150 mg/dl or higher; Serum high-density lipoprotein (HDL) concentration less than 40 mg/dl in men and less than 50 mg/dl in women; Blood pressure of 130/85 mm Hg or higher or therapy with antihypertensive medication; Fasting plasma glucose of 110 mg/dl or higher. 2 The ATP III guidelines recommend an analysis of multiple lipids and lipoproteins (ie, total cholesterol, low-density lipoprotein [LDL] cholesterol, HDL cholesterol, and triglycerides) as an initial screening test for assessing cardiovascular risk. 2 Similarly, the US Preventive Services Task Force recommends that screening for lipid disorders include the measurement of total cholesterol and HDL levels. 3 These recommendations, made in the context of evidence suggesting that the various lipoproteins constitute independent cardiovascular risk factors, contrast with the previously common practice of focusing on LDL as a primary or sole determinant of cardiovascular risk. The ATP III guidelines are useful in identifying patients with the metabolic syndrome, but they may be too restrictive for identifying some at-risk individuals who are candidates for intervention to delay or to prevent type 2 diabetes mellitus and its cardiovascular correlates. Data from one study suggest that application of these criteria would result in missing more than 50% of individuals who are insulin-resistant and may benefit from intervention to prevent cardiovascular disease and type 2 diabetes mellitus. 4 In this study, which enrolled overweight individuals, the most useful metabolic markers for identifying insulin resistance were plasma triglyceride concentration, ratio of triglyceride to HDL cholesterol, and insulin concentration. Optimal cut-points were 130 mg/dl for triglycerides, 3.0 (traditional units) for the triglyceride-hdl cholesterol ratio, and 109 pmol/l for insulin. The presence of one component of the metabolic syndrome heightens the risk of the patient having one or more of the other components, and the degree of health risk associated with the metabolic syndrome is directly related to the number of components present. 1 Although the clustering of risk factors is important in determining the risk status of the patient and in deciding on an intervention strategy, the absence of one or more major risk factors should not be interpreted as reflecting reduced or low cardiovascular or metabolic risk. In a study of 465 healthy volunteers, 36% of the individuals who were most insulin-resistant were also obese; steady-state plasma glucose and body mass index were significantly correlated findings consistent with the clustering of risk factors observed in the metabolic syndrome. 5 However, 16% of the individuals who were most insulin-resistant, thus at high cardiovascular and metabolic risk, were of normal weight. Therefore, although the metabolic syndrome is relatively uncommon in the absence of obesity, the absence of obesity does not signify the absence of metabolic and cardiovascular risk. These data underline the importance of taking into account multiple risk factors in assessing cardiovascular and metabolic risk. FOCUS ON DYSLIPIDEMIA CARDIOVASCULAR RISK ASSESSMENT As a cardinal component of the metabolic syndrome, dyslipidemia is one of the primary targets of management. The choice of interventions for dyslipidemia is guided by the principle that the intensity of treatment should be directly related to the degree of risk for coronary heart disease events. 2 The ATP III report identifies 3 major risk categories (ie, high, intermediate, and low) for coronary heart disease. High risk is defined as the confirmed presence of coronary heart disease or a coronary heart disease risk-equivalent. Coronary heart disease risk-equivalents, so designated because they carry a risk of major coronary events equivalent to that of established coronary heart disease, include diabetes; other clinical forms of atherosclerotic disease (ie, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease); or the presence of multiple risk factors conferring a greater than 20%, 10-year risk for coronary heart disease. Intermediate risk is defined as the presence of 2 or more risk factors listed in Table 1. 2 Low risk is defined as the presence of 1 or no risk factors. The ATP III report advocates a 2-step procedure for determining risk status in individuals without clin- S504 Vol. 5 (6A) June 2005

ically manifest coronary heart disease or other forms of atherosclerotic disease. First, the number of risk factors present is counted. Then, for individuals with 2 or more risk factors, a 10-year risk assessment is calculated based on the Framingham Heart Study scoring to identify those patients whose 10-year risk warrants intervention. This second step is not completed for individuals with 0 or 1 risk factors because they are thought to be at too low a risk to require intervention. The Framingham system considers primary, independent risk factors for the presence of coronary heart disease operationally defined as angina pectoris, recognized myocardial infarction, unrecognized myocardial infarction (defined by electrocardiogram), unstable angina, and coronary heart disease deaths to include cigarette smoking (any amount), elevated systolic blood pressure, elevated serum total cholesterol and LDL cholesterol, low serum HDL cholesterol, diabetes mellitus, and advancing age. 6 As revealed in the Framingham study and other investigations, the relationship between values of these factors and risk of coronary heart disease is continuous. Furthermore, the risk factors confer additive risk of coronary heart disease. Therefore, the total risk for an individual can be estimated by totaling the risks associated with each factor. By using Framingham algorithms, absolute risk (defined as the probability of developing coronary heart disease in a given time period) and relative risk (defined as the risk of coronary heart disease relative to low-risk status) can be calculated. According to the Framingham report, low-risk status is a patient who does not smoke, does not have diabetes, and whose test results show the following values: serum total cholesterol, 160 to 199 mg/dl; LDL cholesterol, 100 to 129 mg/dl; HDL cholesterol, at least 45 mg/dl in men and at least 55 mg/dl in women; and blood pressure, less than 120 mm Hg systolic and less than 80 mm Hg diastolic. 7 American Heart Association guidelines for primary prevention of cardiovascular disease and stroke now recommend that risk-factor screening be conducted every 2 to 5 years beginning at age 20 years and that global risk-factor estimation be conducted every 5 years (or more often, in the presence of changing risk factors) in adults. 8 As patients and healthcare providers increasingly follow this recommendation, more patients will have current cardiovascular risk-status information as part of their medical record. The predictive ability of these and other risk-assessment models may be enhanced by increasing their complexity to include factors such as inflammatory markers, genetic susceptibility, lifestyle, and other variables. 9 The Multi-Ethnic Study of Atherosclerosis is Table 1. Major Risk Factors for Coronary Heart Disease in ATP III Guidelines Cigarette smoking Hypertension (ie, blood pressure >140/90 mm Hg or on antihypertensive medication) High LDL cholesterol (ie, >159 mg/dl) Low HDL cholesterol (ie, <40 mg/dl) Family history of premature coronary heart disease (ie, <55 years of age in male first-degree relative or <65 years of age in female first-degree relative) Age (men at least 45 years and women at least 55 years) ATP = Adult Treatment Panel; HDL = high-density lipoprotein; LDL = lowdensity lipoprotein. Data from 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). Baltimore, MD: US Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. September 2002; NIH publication 02-5215. 2 Table 2. LDL Cholesterol Goals by Coronary Heart Disease Risk Level Risk Level LDL-C Goal CHD and CHD Risk Equivalent <100 mg/dl Multiple (2+) Risk Factors <130 mg/dl 0 1 risk factor <160 mg/dl CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol. Reprinted from 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). Baltimore, MD: US Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. September 2002; NIH publication 02-5215. 2 Advanced Studies in Medicine S505

evaluating whether new predictive markers of cardiovascular risk are useful in a National Heart, Lung, and Blood Institute study that involves 18 000 subjects and is to be completed in 2010. THERAPEUTIC GOALS FOR DYSLIPIDEMIA According to ATP III guidelines, LDL cholesterol is the primary target of treatment in patients at cardiovascular risk. 2 Secondary targets are HDL cholesterol and triglycerides. LDL cholesterol also constitutes the primary target of treatment in patients with the metabolic syndrome. Secondary targets in these patients are other metabolic syndrome components including other lipid risk factors. LDL goals by risk category are shown in Table 2. 2 INTERVENTION: LIFESTYLE MODIFICATIONS Diet and exercise are core components of the management of multiple metabolic syndrome components including dyslipidemia. Dietary modifications recommended in ATP III guidelines include reductions in saturated fat, reductions in dietary cholesterol, and weight loss. 2 Reduction of saturated fats to less than 7% of calories, dietary cholesterol to less than 200 mg/day, and weight loss of 10 lbs can result in LDL reductions ranging from 8% to 10%, 3% to 5%, and 5% to 8%, respectively. 2 Weight loss in overweight or obese patients can also decrease triglyceride levels and blood pressure and can improve insulin sensitivity and glucose utilization, in addition to decrease the requirements for insulin therapy or oral hypoglycemics in patients with type 2 diabetes mellitus. Adult Treatment Panel III guidelines emphasize the benefits of exercise, particularly in the management of the metabolic syndrome. 2 Exercise can improve lipid profiles by decreasing triglycerides, total cholesterol, and, in some individuals, LDL cholesterol and by increasing HDL cholesterol. Exercise can also facilitate weight loss and increase insulin sensitivity by lowering blood glucose and glycosylated hemoglobin levels. ATP III guidelines suggest that physicians provide specific recommendations for moderate, sustained physical activity appropriate to the patient's physical status. Examples of moderate physical activity and ways to Table 3. Examples of Moderate Physical Activity for Healthy Adults Brisk walking (3 4 mph) for 30 40 minutes Swimming laps for 20 minutes Bicycling for pleasure or transportation, 5 miles in 30 minutes Volleyball (noncompetitive) for 45 minutes Moderate lawn mowing (push a powered mower) for 30 minutes Home care heavy cleaning Basketball for 15 20 minutes Golf pulling a cart or carrying clubs Social dancing for 30 minutes Reprinted from 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). Baltimore, MD: US Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. September 2002; NIH publication 02-5215. 2 Table 4. Ways to Incorporate More Physical Activity into the Day Walk more look for opportunities! Park farther away in parking lots near a mall so you have a longer walk Walk or bike if your designation is just a short distance away Walk up or down 1 2 flights of stairs instead of always taking the elevator Walk after work for 30 minutes before getting in the car and sitting in traffic Walk home from the train or bus take a longer route so it takes 20 minutes instead of 5 10 Walk with a colleague or friend at the start of your lunch hour for 20 minutes Do heavy house cleaning, push a stroller, or take walks with your children Exercise at home while watching television Go dancing or join an exercise program that meets several times per week If wheelchair bound, wheel yourself for part of every day in a wheelchair Reprinted from 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). Baltimore, MD: US Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. September 2002; NIH publication 02-5215. 2 S506 Vol. 5 (6A) June 2005

increase physical activity during normal daily activities are listed in Tables 3 and 4, respectively. 2 Besides diet and exercise, smoking cessation is important in reducing cardiovascular risk among atrisk patients who smoke. INTERVENTION: PHARMACOTHERAPY Low-density lipoprotein-lowering pharmacotherapy is considered (but may not always be required) in patients with LDL cholesterol 100 mg/dl or higher. 2 Therapy to address atherogenic dyslipidemia (ie, triglycerides 150 mg/dl and HDL cholesterol <40 mg/dl), defining characteristic of the metabolic syndrome, is initiated after the LDL treatment goal is achieved with therapeutic lifestyle changes or pharmacotherapy. Clinical trials of cholesterol-lowering drugs, primarily the statins and the fibrates, demonstrate their efficacy in primary prevention and secondary prevention of cardiovascular morbidity and mortality. For example, statin therapy significantly reduced the risk for major coronary events in the West of Scotland Coronary Prevention Study (WOSCOPS) 10 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), 11 both of which are major primary-prevention trials. In WOSCOPS, patients (n = 6595; baseline LDL 192 mg/dl) were treated with pravastatin 40 mg/day or a placebo for up to 4.9 years. 10 Over the follow-up period, LDL cholesterol concentrations were decreased by 26% with the statin compared to a placebo. The risks of major coronary events were reduced by 31%, coronary mortality by 33%, and total mortality by 22%. The AFCAPS/TexCAPS study observed 6605 patients (baseline LDL 150 mg/dl) for up to 5 years during treatment with lovastatin (20 mg/40 mg daily) or a placebo. 11 Over the follow-up period, LDL cholesterol concentrations were decreased by 35% with the statin compared to a placebo, and the risk of a major coronary event was reduced by 37%. The difference between active treatment and placebo was not statistically significant with respect to reductions in coronary mortality and total mortality in this study. Secondary-prevention trials, including the Scandinavian Simvastatin Survival Study, 12 the Cholesterol and Recurrent Events Study, 13 and the Long-Term Intervention with Pravastatin in Ischemic Disease Study, 14 demonstrate reductions over followup periods of at least 5 years in recurrent myocardial infarction, coronary mortality, and stroke. The relationship between LDL cholesterol concentrations and coronary events in several major clinical studies of statins is illustrated in the Figure. 2 Fibrates and niacin have also been demonstrated effective in modifying dyslipidemia, and they can be added to statins to decrease triglyceride and HDL cholesterol concentrations. 2 The benefits of fibrates are illustrated by the results of the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Interventional Trial (VA-HIT), 15 a double-blind, placebo-controlled, secondary-prevention study of patients with dyslipidemia whose baseline LDL concentrations were 100 to 120 mg/dl. Over a 5.1-year follow-up period, gemfibrozil (1200 mg/day) did not change LDL cholesterol levels as compared to Figure. Relationship Between LDL Cholesterol Concentrations and Coronary Events in Clinical Studies of Statins Major coronary event rate, % 30 25 20 15 10 LIPID CARE Post-CABG 5 AFCAPS/TexCAPS 0 60 80 100 120 140 160 180 200 LDL-C during trial 4S LRC-CPPT WOSCOPS 4S = Scandinavian Simvastatin Survival Study; AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; CARE = Cholesterol and Recurrent Events Study; LDL-C = low-density lipoprotein cholesterol; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; LRC-CPPT = Lipid Research Clinics Coronary Primary Prevention Trial; WOSCOPS = West of Scotland Coronary Prevention Study. Reprinted from 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). Baltimore, MD: US Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. September 2002; NIH publication 02-5215. 2 Advanced Studies in Medicine S507

placebo, but it increased HDL cholesterol concentrations by 6% and decreased triglyceride concentrations by 31%. These changes were associated with a 22% reduction in the incidence of nonfatal myocardial infarction and coronary heart disease death, a 22% reduction in coronary heart disease death, a 23% reduction in nonfatal myocardial infarction, and an 11% reduction in total mortality. These findings support the potential for additional cardiovascular risk reduction through increasing HDL cholesterol and decreasing triglycerides, even among patients with moderately elevated LDL cholesterol. A statin-niacin combination was also shown to be effective in the HDL Atherosclerosis Treatment Study. 16 Patients (n = 160) with coronary artery disease, low HDL, and normal LDL received simvastatin + niacin, antioxidant vitamins, simvastatin + niacin + antioxidant vitamins, or a placebo for up to 3 years. The results show that coronary artery stenosis progressed by 0.4% with simvastatin + niacin, 0.7% with simvastatin + niacin + antioxidants, and 1.8% with antioxidants as compared to 3.9% with placebo (P <.05 for both groups treated with simvastatin and niacin). The incidence of a cardiovascular event (ie, death, myocardial infarction, stroke, revascularization) was lowest with simvastatin + niacin (3%) followed by simvastatin + niacin + antioxidants (14%), antioxidants (21%), and a placebo (24%). The authors concluded that simvastatin + niacin markedly improves clinical and angiographic measures in patients with coronary heart disease with low HDL levels, but the use of antioxidant vitamins in these patients should be questioned. 16 In controlled clinical trials including VA-HIT, cardiovascular benefits of statins are often greater in subgroups of patients with components of the metabolic syndrome as compared to overall study populations defined primarily by elevated LDL cholesterol concentrations. 17 This observation underlines the importance of statin therapy for patients with the metabolic syndrome. Although statin therapy is well suited for these patients, monotherapy with a statin may not be sufficient for managing their mixed dyslipidemia. 17,18 Because the metabolic syndrome is associated with a constellation of lipid abnormalities including but not limited to LDL elevations, combination statin/fibrate therapy may be indicated. Combination therapy may more effectively target the mixed dyslipidemia occurring in the metabolic syndrome than monotherapy with statins, which most effectively target LDL cholesterol. The ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial should provide information germane to this issue. The ACCORD trial is comparing cardiovascular outcomes in patients with diabetes who were administered a statin alone (ie, simvastatin 20 mg) with those outcomes in patients who received a statin with a fibrate (ie, simvastatin 20 mg + fenofibrate 160 mg). The results of this study are expected to become available in approximately 4 years. Safety concerns have limited the use of fibrates such as gemfibrozil. 17 Other fibrates, such as fenofibrate, appear to have a better safety profile than gemfibrozil, especially in combination with a statin. Modified formulations of fenofibrate (145-mg tablet [Tricor] and 130-mg capsule [Antara]) have recently been introduced in the United States. These treatments, in conjunction with diet, are approved to reduce elevated LDL cholesterol, total cholesterol, and triglycerides and increase HDL cholesterol in patients with primary hypercholesterolemia or mixed dyslipidemia and in patients with hypertriglyceridemia. In 4 randomized, double-blind, parallel-group, placebocontrolled studies involving patients with hypercholesterolemia and mixed dyslipidemia treated with fenofibrate at a dose equivalent to 145-mg tablet or placebo for 3 to 6 months, patients receiving fenofibrate at a dose equivalent to 145-mg tablet showed lower LDL cholesterol (-20.6% vs -2.2%), total cholesterol (-18.7% vs -0.4%), and triglycerides (-28.9% vs +7.7%) and increased HDL cholesterol (+11.0% vs +0.7%). 19 Fenofibrate at a dose equivalent to 145-mg tablet reduced serum triglycerides in 2 randomized, double-blind, placebo-controlled clinical trials in patients with hypertriglyceridemia. 19 Significant reduction in triglycerides with fenofibrate at a dose equivalent to 145-mg tablet versus placebo was observed in patients with baseline triglyceride levels of 350 to 499 mg/dl (-46.2% vs -0.5%) and in those patients with baseline triglyceride levels of 500 to 1500 mg/dl (-54.5% vs +7.2%). Fenofibrate capsule produces the same results at the equivalent dose of 130 mg daily. 20 Neither fenofibrate 145-mg tablet nor fenofibrate 130-mg capsule interacts with food, a property that may be associated with improved patient compliance. Therefore, these modified formulations S508 Vol. 5 (6A) June 2005

can be taken without regard to meals. The lack of interaction of fenofibrate 130-mg capsule with food is demonstrated by the results of the TRIMS (Triglyceride Reduction in Metabolic Syndrome) study, a randomized, double-blind, placebo-controlled trial that assessed the efficacy of fenofibrate 130-mg capsule with and without food in patients with hypertriglyceridemia and the metabolic syndrome. 21 Patients with the metabolic syndrome and hypertriglyceridemia received fenofibrate 130-mg capsule with food (n = 40), without food (n = 40), or placebo for 8 weeks in conjunction with a low-fat diet. The results show that fenofibrate 130-mg capsule significantly reduced triglycerides and improved other lipid parameters versus placebo regardless of whether it was given with food. The magnitude of effect of fenofibrate 130-mg capsule on lipid parameters was nearly identical when it was given with food versus without food. At the end of the treatment period, triglyceride levels were 295 mg/dl in the group given fenofibrate 130-mg capsule with food and 296 mg/dl in the group given fenofibrate 130-mg capsule without food compared to 474 mg/dl in placebo-treated patients (P <.001; both groups receiving fenofibrate 130-mg capsule vs placebo). Calculated LDL cholesterol levels at the end of treatment were 134 mg/dl in each of the groups receiving fenofibrate 130-mg capsule compared to 114 mg/dl in the placebo group. HDL cholesterol levels at the end of treatment were 40 mg/dl in the group receiving fenofibrate 130-mg capsule with food and 41 mg/dl in the group receiving fenofibrate 130-mg capsule without food compared to 35 mg/dl in placebo-treated patients. CONCLUSIONS The validation of the metabolic syndrome as a clinical entity provides the clinician with an opportunity to identify at-risk patients who previously may not have been identified as candidates for risk-modifying interventions. 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