Metabolic syndrome: When and how to intervene

Unique lipid triad

High triglycerides, small LDL particles, and low HDL form the characteristic lipid profile of women with metabolic syndrome. For classification of the different levels of cholesterol, see TABLE 1.

High triglycerides heighten risk. High triglyceride levels carry an increased, independent risk of cardiovascular disease, particularly in women. As levels exceed 200 mg/dL, that risk rises sharply (FIGURE 2).⁹ Other studies, including a metaanalysis, have confirmed this finding.

Low HDL cholesterol is another independent risk factor for cardiovascular disease— one that is independent of standard risk markers such as LDL cholesterol. At high total cholesterol levels, the risk of cardiovascular disease increases, but that risk is even higher when HDL is low.¹⁰

Small LDL cholesterol particles. The characteristic LDL abnormality in patients with metabolic syndrome is not elevated levels, but a shift in size from larger to smaller LDL particles. In fact, the cardiovascular disease risk associated with small LDL particles is several times higher than the risk associated with the larger particles.

Smaller particles are more atherogenic than larger LDL particles despite their lower cholesterol content. The reasons:

They are cleared more slowly from plasma, taken up more readily by the artery wall, and more actively retained.

They are more rapidly oxidized, an important step in the atherogenic process.

At any level of LDL, there are more particles circulating.

Individuals tend to cluster into 2 groups based on LDL particle size: those with larger LDL particles, who usually have relatively lower triglyceride levels, and those with smaller LDL particles, who tend to have higher triglycerides. At triglyceride levels above 150 mg/dL—the cutoff for metabolic syndrome—individuals are more likely to have smaller LDL particles.

What is the risk associated with smaller particles? A study from 2001 by St. Pierre and colleagues¹¹ showed that, at any level of triglycerides, LDL cholesterol, or apolipoprotein B (another LDL-related risk marker), the risk of coronary heart disease associated with small LDL particles is more than 3 times the risk associated with larger LDL particles.

TABLE 1

ATP III classification of LDL, total, and HDL cholesterol (mg/dL)

C-reactive protein is an important marker

C-reactive protein is an important marker of the inflammation linked to heart disease. Elevated C-reactive protein also is associated with insulin resistance and adiposity. The trigger for the liver’s production of C-reactive protein is a cytokine released in large part by adipose tissue and endothelial cells.

Because a standardized, highly sensitive assay to measure plasma C-reactive protein is now available, there is a movement to include it in the definition of metabolic syndrome. As a recent study shows, the level of C-reactive protein rises with the number of components of metabolic syndrome.¹² Levels tend to be higher in women than in men.

In addition, as Ridker et al¹³ and others have shown, as the levels of C-reactive protein rise from low (3 mg/L), so does the risk of cardiovascular disease.

Moreover, high C-reactive protein levels add to the risk associated with standard cholesterol-based risk factors. Thus, adding plasma C-reactive protein to standard lipid screening may help predict the risk of cardiovascular disease in women with high as well as low cholesterol levels.¹³ For example, if an individual has both elevated C-reactive protein and the metabolic syndrome, the relative risk of cardiovascular disease is more than twice the risk in women with high C-reactive protein alone.

First-line therapies are weight loss, exercise

According to ATP III2, the aims of managing metabolic syndrome are:

• to reduce causes of the syndrome, such as obesity and inactivity, and
  
• to treat lipid and nonlipid risk factors.
  

Weight loss enhances efforts to lower LDL cholesterol and reduces the impact of all risk factors for metabolic syndrome.²

Physical activity can reduce the risk of cardiovascular disease by improving cardiovascular fitness and coronary blood flow. Regular physical activity reduces very-lowdensity lipoprotein (VLDL) cholesterol levels, increases HDL cholesterol, and can lower LDL levels in some individuals. It also may help reduce blood pressure and insulin resistance.

ATP III recommends regular physical activity as a key component of managing high serum cholesterol.² For more information on these interventions, see “Integrating evidence and experience”.

Why aggressive lipid lowering?

The current goal is reducing LDL cholesterol to less than 100 mg/dL when metabolic syndrome is present. Even lower levels, eg, less than 70 mg/dL, may be advisable when both cardiovascular disease and metabolic syndrome are present.¹⁴