The Metabolic Syndrome
Importance and Management of Dyslipidemia in the Metabolic Syndrome

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ABSTRACT:

The metabolic syndrome is a common disorder characterized by central obesity, impaired glucose tolerance, hypertension, and atherogenic dyslipidemia (including the combination of hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, and a preponderance of small, dense low-density lipoprotein particles). In this manuscript, we review the pathogenesis and significance of dyslipidemia in the metabolic syndrome, the role of nonpharmacologic therapy with therapeutic lifestyle changes, and drug therapies, including statins, fibrates, nicotinic acid, and omega-3 fatty acids or fish oils, alone or in drug combinations, to improve lipids and reduce the chance of subsequent cardiovascular disease events.

Section snippets

Clinical Features of the Metabolic Syndrome

The prevalence of the metabolic syndrome, particularly in the United States, is alarmingly high. Furthermore, trends predict that as the rates of obesity and diabetes increase, worldwide prevalence will continue to rise. Metabolic syndrome as defined by ATP III was examined by the Third National Health and Nutrition Examination Survey (NHANES III) in 8814 adults.6 In the United States, the prevalence of metabolic syndrome in adults over the age of 20 was nearly a quarter of the population

Association of Diabetes Mellitus and Cardiovascular Disease Risk

It is recognized that many of the individual criteria for the metabolic syndrome place a person at a higher risk for developing both diabetes and CVD, especially CHD. Thus, aggressive screening and treatment, particularly of dyslipidemia, is of vital importance for those at high risk. The San Antonio Heart Study evaluated 1734 nondiabetics with the metabolic syndrome and evaluated impaired glucose tolerance (IGT)/insulin levels as an independent predictor of type 2 diabetes at an 8-year

Significance of Dyslipidemia in the Metabolic Syndrome

As stated previously, two of the components of the ATP III classification of the metabolic syndrome are elevated triglycerides and decreased levels of HDL cholesterol. Considerable data from epidemiologic, lipid intervention, and serial coronary angiographic trials indicate that HDL is the lipid particle that correlates best with overall CHD. Although there is an inverse relationship between triglycerides and HDL, and high triglycerides are associated with many other factors related to coronary

Therapeutic Strategies

The goals for managing the metabolic syndrome are aimed at preventing predictable complications, including type 2 diabetes and CVD events.28 The clinical management of dyslipidemia in the metabolic syndrome involves both therapeutic lifestyle changes and pharmacotherapy.

Nonpharmacologic Therapy

Therapeutic lifestyle changes include dietary restriction of calories, simple carbohydrates, and saturated fat and increased intake of soluble fiber, monounsaturated fats, and omega-3 fatty acids or fish oils. In addition, a mainstay of therapy is increasing regular aerobic exercise and intense efforts at achieving and maintaining an ideal body weight.4

In the Diabetes Prevention Program of 3234 patients with IGT, one group received placebo, another group received metformin titrated to 850 mg

Drug Therapy

Although the atherogenic dyslipidemia in the metabolic syndrome mainly involves elevated triglycerides and low HDL, initial pharmacologic therapy is aimed at lowering LDL levels (Table 2).4 After LDL cholesterol goals are achieved, secondary goals include non-HDL cholesterol levels (total cholesterol - HDL), and the goal for non-HDL levels in patients with elevated triglycerides and/or low HDL are generally 30 mg/dL higher than for LDL (i.e., if the LDL goal is less than 100 mg/dL, the non-HDL

Statins

The statin family inhibits the rate-determining step in cholesterol biosynthesis and is effective in the metabolic syndrome by reducing all ApoB containing lipoproteins, as well as hs-CRP. In the 4S study, patients post myocardial infarction with only high LDL had a 21% placebo event rate and had a 14% event reduction with simvastatin. On the other hand, the placebo event rate was 36% and 51%, respectively, in patients with the metabolic syndrome and diabetes and these groups had a greater than

Drug Combinations

Substantial data indicate the efficacy and safety of statin therapy to improve plasma lipids and reduce major CVD events in multiple groups of patients, including those with metabolic syndrome and/or diabetes. As reviewed elsewhere, plant stanols, plant sterols, and soluble fiber can all be added to statin therapy to aid in further lowering of LDL cholesterol.48 However, more potent therapies are also available to treat dyslipidemia, either as monotherapy or, more commonly, combined with

Fibrates

The two fibrates currently used clinically are gemfibrozil and fenofibrate. These agents mitigate atherogenic dyslipidemia and appear to reduce the risk of CVD in patients with metabolic syndrome.13 These agents are the drugs of choice for markedly elevated triglycerides, lowering triglycerides at times by more than 50% (25-30% reduction in patients with low levels of triglycerides) and generally increasing levels of HDL by 10% (but increases of over 25% can occur in patients with

Niacin

Nicotinic acid, or niacin, is perhaps the most underutilized agent to treat patients with dyslipidemia.48., 53., 54. It produces significant improvements in almost all aspects of the lipid profile, including lowering total cholesterol and LDL by 15%, reducing triglyceride by 25% to 30%, and reducing hs-CRP by 15% to 25% and is the best drug to increase HDL (generally by 25-30% but by more than 40% in patients with low HDL and hypertriglyceridemia). In addition, it is also the best drug to

Ezetimibe

Therapy with ezetimibe reduces intestinal cholesterol absorption by 54%, and 10 mg daily doses have produced 15% to 20% reductions in LDL cholesterol when used as monotherapy, and 20% to 25% additional LDL cholesterol reductions when added to statin therapy. In addition, ezetimibe slightly raises HDL and reduces the level of triglycerides by approximately 10%. Ezetimibe can be safely added to statin therapy without significant drug interactions. Besides adding to a statin's effects to lower LDL

Omega-3 Fatty Acids (Fish Oil)

Because of substantial effects on reperfusion arrhythmias, improving autonomic function, and reducing the risk of sudden cardiac death, we routinely recommend fish oils for our patients with known atherosclerosis or those with high-risk (e.g., patients with the metabolic syndrome and/or diabetes).66 However, for this purpose, we recommend doses of eicosapentaenoic acid and docosahexaenoic acid of 800 to 1000 mg/day, doses that may prevent sudden cardiac death but that do not lower triglycerides.

Conclusion

Substantial data support the critical role that atherogenic dyslipidemia plays in the metabolic syndrome and overall CVD risk. These risks can be substantially reduced by lipid intervention using therapeutic lifestyle changes and vigorous pharmacologic therapy, including statins alone or combined with other potent pharmacologic therapies, as discussed in this review.

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