The Metabolic Syndrome: Pharmacology and Clinical Aspects


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As noted in ATP III, 1 some people will manifest features of insulin resistance and the metabolic syndrome with only moderate increases in waist circumference ie, between 94 and cm in men or 80 and 87 cm in women. Obvious differences are 2-fold: IDF requires abdominal obesity as 1 factor and sets lower thresholds for abdominal obesity than used in the United States.

For this reason, in the United States, for the most part the same individuals will be identified by either definition. The primary goal of clinical management in individuals with the metabolic syndrome is to reduce risk for clinical atherosclerotic disease. Even in people with the metabolic syndrome, first-line therapy is directed toward the major risk factors: LDL-C above goal, hypertension, and diabetes. Prevention of type 2 diabetes mellitus is another important goal when it is not present in a person with the metabolic syndrome.

For individuals with established diabetes, risk factor management must be intensified to diminish their higher risk for ASCVD. The prime emphasis in management of the metabolic syndrome per se is to mitigate the modifiable, underlying risk factors obesity, physical inactivity, and atherogenic diet through lifestyle changes. Effective lifestyle change will reduce all of the metabolic risk factors.

Then, if absolute risk is high enough, consideration can be given to incorporating drug therapy to the regimen. The priority of drug therapy is elevations of LDL-C, blood pressure, and glucose; current guidelines for their management should be followed. Moreover, efforts should be made to bring about smoking cessation in any cigarette smokers. Table 3 summarizes the current goals and recommendations for management of each of the risk factors of the metabolic syndrome. The evidence bases for most of the recommendations have been presented in background documents for obesity, physical inactivity, lipids, 1 high blood pressure, 91 and diabetes.

TABLE 3. TABLE 4. A series of studies 63—73 have found that many middle-aged people with the metabolic syndrome are at increased absolute risk for ASCVD in the near future eg, year risk. Moreover, as stated previously, because of the high relative risk for ASCVD, long-term lifetime risk for ASCVD is increased even when year risk is not considered to be high, eg, in young adults who develop the syndrome. An exacerbating factor raising lifetime risk for ASCVD is an increased likelihood for developing premature type 2 diabetes mellitus.

To reduce lifetime risk for ASCVD, all individuals found to have the metabolic syndrome deserve long-term management and follow-up in the clinical setting. The primary aim is to reduce the underlying risk factors. Such individuals need to be categorized according to absolute year risk. Thus, detecting metabolic syndrome is only one part of overall risk assessment for cardiovascular disease. The metabolic syndrome per se is not an adequate tool to estimate year risk for CHD.

Although patients with the metabolic syndrome are at higher lifetime risk, in the absence of diabetes they do not necessarily have a high year risk. Estimating year risk entails key risk factors beyond those of the syndrome, ie, age, sex, smoking, and total cholesterol. Moreover, risk factors of the metabolic syndrome are not graded for severity as are the risk factors contained in Framingham scoring. Framingham investigators find little or no increase in predictive power for CHD by adding abdominal obesity, triglycerides, or fasting glucose to their year risk algorithm.

In individuals with diabetes, the coexistence of other metabolic syndrome factors denotes a higher risk for future development of ASCVD.


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IGT in fact exceeds IFG in frequency; it consequently uncovers more individuals at increased risk for diabetes. OGTT nonetheless remains an option in normoglycemic individuals who appear to be at elevated risk for developing diabetes. Although many people may be genetically susceptible to the metabolic syndrome, rarely does it become clinically manifested in the absence of some degree of obesity and physical inactivity.

Consequently, therapies to mitigate these underlying risk factors constitute first-line intervention. If cigarette smoking, another risk factor for ASCVD, is present, then it likewise deserves intensive cessation effort. The reason to modify underlying risk factors is to prevent or delay onset of ASCVD; and if type 2 diabetes mellitus is not already present, a concomitant goal is to prevent it as well.

Weight reduction deserves first priority in individuals with abdominal obesity and the metabolic syndrome. This will require decreasing caloric intake by to calories per day. Greater physical activity helps to enhance caloric deficit. Achieving the recommended amount of weight loss will reduce the severity of most or all of the metabolic risk factors. Maintenance of a lower weight is just as important; this requires long-term follow-up and monitoring. Currently available weight-loss drugs possess limited utility in the management of obesity.

Nevertheless, in some patients they may be helpful. Bariatric surgery is being used increasingly in the United States for severe obesity. Individuals at high risk for the complications of obesity may benefit.

A Comprehensive Review on Metabolic Syndrome

Weight-loss surgery is not without risk, however. Selection of patients must be made with a team of healthcare professionals who are qualified to make appropriate clinical judgments about the pros and cons of this approach. Increasing physical activity assists in weight reduction; it also has beneficial effects on metabolic risk factors; and importantly, it reduces overall ASCVD risk. Thus, going beyond current recommendations will be particularly beneficial for people with the metabolic syndrome.

Sixty minutes or more of continuous or intermittent aerobic activity, preferably done every day, will promote weight loss or weight-loss maintenance. Preference is given to 60 minutes of moderate-intensity brisk walking to be supplemented by other activities. Self-monitoring of physical activity can help to achieve adherence to an activity program. This includes a detailed history of physical activity.

For high-risk patients eg, those with recent acute coronary syndromes or recent revascularization , physical activity should be carried out under medical supervision.


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AHA guidelines further recommend exercise testing before vigorous exercise in selected patients with cardiovascular disease and other patients with symptoms or those at high risk. It is not necessary, however, that all individuals beginning an exercise program of moderate intensity that is moderately progressive undergo an exercise stress test, although this issue remains controversial.

Beyond weight control and reduction of total calories, the diet should be low in saturated fats, trans fats, cholesterol, sodium, and simple sugars.

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There has long been an interest in the question of whether changing the macronutrient content of the diet can promote weight reduction. For many years, a low-fat diet was advocated because the high caloric density of fat could increase the likelihood of obesity. More recently, interest has grown in the possibility that high-protein, low-carbohydrate diets will enhance weight reduction. That this effect of fat and protein on satiety makes the diet more effective for producing weight loss is a disputable hypothesis.

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In fact, after 1 year of consumption of low-carbohydrate diets, severely obese patients show no more weight reduction than those eating a conventional weight-loss diet. High-protein diets of any sort are not well tolerated by individuals with chronic renal disease who have markedly reduced glomerular filtration rate; excess protein enhances phosphorus load, which can cause acidosis and worsen insulin resistance. Effective weight loss requires a combination of caloric restriction, physical activity, and motivation; effective lifelong maintenance of weight loss essentially requires a balance between caloric intake and physical activity.

Beyond lifestyle therapies directed toward underlying risk factors, attention must be given to the metabolic risk factors. If ASCVD or diabetes is present, or if the year risk as determined by Framingham risk factors is relatively high, then drug therapies for risk factors may be required as defined by current guidelines. Other lipid risk factors are secondary.

The LDL-C goals depend on estimates of absolute risk. A related and potential secondary target is an elevated total apoB ; this measure denotes the number of atherogenic lipoproteins in circulation. If a statin is being used for LDL-C lowering, fenofibrate seems preferable to gemfibrozil because risk for severe myopathy appears to be lower for fenofibrate in combination with statins.

Patients with IFG, IGT, or diabetes who are treated with nicotinic acid deserve careful monitoring for worsening of hyperglycemia.

Whether adding a fibrate or nicotinic acid to statin therapy will reduce cardiovascular events more than a statin alone has not been evaluated adequately in randomized clinical trials; consequently the use of this combination probably should be limited largely to high-risk individuals who stand to gain the most from it.

If a fibrate or nicotinic acid is used with a statin, higher doses of the statin generally should be avoided to minimize risks for myopathy or hepatic effects.

Metabolic Syndrome: A Risky Diagnosis

Mild elevations of blood pressure often can be effectively controlled with lifestyle therapies: weight control, increased physical activity, alcohol moderation, sodium reduction, and increased consumption of fresh fruits and vegetables and low-fat dairy products, in accord with the Dietary Approaches to Stop Hypertension DASH diet. Some investigators support angiotensin-converting enzyme ACE inhibitors as first-line therapy for hypertension in the metabolic syndrome, especially when either type 2 diabetes mellitus or chronic renal disease is present.

The results of a large clinical trial raised the possibility that use of diuretics in patients with IFG or IGT may increase the likelihood of progression to type 2 diabetes mellitus, although diuretics do in fact lower the risk for cardiovascular events.

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In metabolic syndrome patients with IFG or IGT if assessed , weight reduction, increased physical activity, or both will delay or prevent the onset of type 2 diabetes mellitus. Except for a preliminary trial with acarbose, no clinical trial evidence is yet available to document that oral hypoglycemic agents will lessen risk for cardiovascular events. Moreover, neither metformin nor thiazolidinediones are recommended in this statement solely for the purpose of preventing diabetes because their cost-effectiveness and long-term safety have not been documented.

For patients with established type 2 diabetes mellitus, clinical trials confirm a reduction in cardiovascular risk from treatment of dyslipidemia —,— and hypertension. People with the metabolic syndrome typically manifest elevations of fibrinogen, plasminogen activator inhibitor-1, and other coagulation factors.

The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects
The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects
The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects
The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects
The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects
The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects
The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects
The Metabolic Syndrome: Pharmacology and Clinical Aspects The Metabolic Syndrome: Pharmacology and Clinical Aspects

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