Summary of the state of affairs

Metabolic syndrome refers to a group of risk factors that includes dyslipidemia, hypertension, and abnormal glycemic metabolism due to insulin resistance and abdominal obesity (Grundy, 2004). Metabolic syndrome is increasingly recognized as a harbinger of excess morbidity and a higher mortality rate predominantly from cardiovascular disease. Cardiovascular mortality in metabolic syndrome is increased 2-fold compared to people without metabolic syndrome.

With the increasing incidence of obesity in the United States, the prevalence of metabolic syndrome is on the rise. In the adult US population, 20% are estimated of have metabolic syndrome, with prevalence approaching 50% in elderly individuals. Prevalence of metabolic syndrome among overweight US adolescents exceeds 30% (Duncan, 2004). Prevalence of metabolic syndrome in adult Europeans is 15%, with double the risk of cardiovascular disease mortality and a 40% greater risk of all-cause mortality compared to adults without metabolic syndrome (Hu, 2004).

Dyslipidemia is an established independent cardiovascular risk factor. Risk of cardiovascular morbidity is increased when additional components of metabolic syndrome are present. Recent studies suggest that the dyslipidemia in metabolic syndrome is more atherogenic even at similar levels of total cholesterol. In a study of 2225 men with cardiovascular disease, Onat found that dyslipidemic hypertension increased cardiovascular risk attributable to metabolic syndrome by 50% (2005).

The typical profile in metabolic syndrome is one of more atherogenic small, dense LDL-C particles, a low HDL-C level, and elevated triglyceride levels. This knowledge has led to further elucidation of culprit lipid subfractions that are increasingly targeted for optimal risk reduction.

Recent guidelines

The Adult Treatment Panel (ATP) III diagnostic criteria define metabolic syndrome as a constellation of any 3 or more of the following factors: obesity with waist circumference greater than 35 inches (88 cm) in women and greater than 40 inches (102 cm) in men, hypertension with blood pressure greater than 130/85 mm Hg, a fasting triglyceride level greater than 150 mg/dL (1.69 mmol/L), an HDL-C level lower than 50 mg/dL (1.29 mmol/L) in women and lower than 40 mg/dL (1.04 mmol/L) in men, and a fasting glucose level greater than 110 mg/dL (6.1 mmol/L) (Grundy, 2004). Metabolic syndrome is now a recognized reimbursable diagnostic entity, making it clinically treatable. The more components of metabolic syndrome an individual has, the higher the likelihood of cardiovascular morbidity in that individual. The presence of dyslipidemia and hypertension with metabolic syndrome increases the risk of cardiovascular morbidity (Onat, 2005; Lindblad, 2001). Smoking increases the cardiovascular risk.

Role of the expanded lipid profile and emerging risk factors

Recognition of the differences in cardiovascular morbidity in metabolic syndrome has led to further elucidation of the relative contribution of culprit cholesterol particles Small, dense LDL-C particles (pattern B) are more atherogenic than large, fluffy, buoyant LDL-C particles (pattern A) (Gotto, 2001; Hulthe, 2000). Using particle size centrifugation from commercially available laboratories in clinical practice to distinguish individuals with the more atherogenic pattern B from those with the less atherogenic pattern A makes setting more stringent lipid control targets clinically feasible. A recent study found that patients with metabolic syndrome had higher levels of oxidized LDL-C that was associated with more myocardial infarctions (Holvoet, 2004). Differences in HDL-C subtypes show HDL-C type 2 is more cardioprotective. Higher levels of VLDL-C contribute to a worse outcome. Elevated levels of lipoprotein(a) (Lp[a]) and apolipoprotein B (apoB) increase atherogenesis.

Other emerging risk factors shown to contribute to cardiovascular morbidity include prothrombotic and proinflammatory markers. Elevated levels of homocystine and type-1 plasminogen activator inhibitor (PAI-1) are prothrombotic cardiovascular risk markers, while highly sensitive cardioselective C-reactive protein is used as a proinflammatory marker. The outcome of treating emerging dyslipidemia risk factors is not as firmly established as is the outcome of targeting LDL-C.

Treatment guidelines for dyslipidemia in metabolic syndrome

The treatment of metabolic syndrome focuses on both general measures and targeted treatment of the different components of the metabolic syndrome. Goals of treatment for dyslipidemia in metabolic syndrome are similar to established goals for individuals with diabetes mellitus: target LDL-C level under 100 mg/dL, triglyceride level under 150 mg/dL, and HDL-C level greater than 40 mg/dL in men and 50 mg/dL in women.

• Lifestyle changes of weight loss, diet, and exercise should be initiated and continued.
• Persistent elevated LDL-C levels may require therapy with statins with or without ezetimibe (Zetia).
• LDL-C particle size can be favorably altered with exercise and niacin and thiazolidinedione therapy.
• Persistent elevated triglyceride levels may require therapy with fibrates.
• Persistently low HDL-C, however, is more difficult to treat and may require addition of niacin, statins, and fibrates (Gotto, 2001).
• Clinical trials targeting elevation of HDL-C levels are underway.
• Elevated apoB levels may be reduced with statins.
• Lp(a) levels may be lowered through treatment with niacin and estrogen but with much less reliability than treatment for reduction of apoB levels.

Prevention

Epidemiologic studies such as the Diabetes Prevention Program that emphasize lifestyle changes have shown regression of metabolic syndrome features. The Bogalusa Heart Study suggests that preventing the progression of metabolic syndrome requires starting early in life (Chen, 2004). A multifaceted approach spanning from the individual to the national level and facilitating favorable lifestyle changes is important. Further studies involving unconventional risk factors and personalized medications are still needed.

References

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