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Clinical Reviews


Metabolic syndrome: When and how to intervene

Ob/Gyns are in a position to intervene early enough to make a difference in diabetes and heart disease risk—and intervention does reduce risk.

January 2005 · Vol. 17, No. 1

 

 

KEY POINTS

  • First-line therapies for both lipid and nonlipid risk factors? Weight loss and regular exercise.
  • Reduce low-density lipoprotein (LDL) cholesterol to less than 100 mg/dL when metabolic syndrome is present.
  • Lower the total of LDL and very-low-density lipoprotein (VLDL) cholesterol to less than 130 mg/dL, especially in patients with borderline (150 to 199 mg/dL) or high (200 mg/dL or above) triglycerides.
  • When drug intervention is needed to lower non-HDL cholesterol, use an LDL-lowering drug or add nicotinic acid or fibrate to reduce VLDL.

Before you ask why another set of risk factors deserves your attention, consider this: Metabolic syndrome is a veritable epidemic, affecting at least 1 of every 5 patients. Among 60- to 69-year-olds, almost half the population meets the diagnostic criteria.1

This risk are serious. Metabolic syndrome amplifies morbidity and mortality due to diabetes mellitus and cardiovascular disease to such an extent that the National Cholesterol Education Program identifies it as a critical target of risk reduction, second only to reducing low-density lipoprotein (LDL) cholesterol.2

In our primary care capacity, Ob/Gyns are likely to be the first to identify metabolic syndrome and intervene—and intervention makes a difference. An aggressive approach to lipid lowering is critical. However, solid evidence confirms that weight loss and physical activity eliminate some or all of the risk factors in many patients. There’s the challenge. Notably, research reported in theNew England Journal of Medicine found that, with a nutritionist’s guidance, many patients who were counseled about these lifestyle changes reduced their risk of type 2 diabetes by 58% over 3 years.3

This article reviews key studies linking metabolic syndrome to heart disease, diabetes, and death; and describes diagnostic and management fundamentals.

What defines metabolic syndrome?

Women with 3 or more of these factors have metabolic syndrome:

  • Abdominal obesity; ie, waist circumference exceeding 35 inches (88 cm).
  • Triglyceride level of 150 mg/dL or more.
  • High-density lipoprotein (HDL) cholesterol below 50 mg/dL.
  • Blood pressure 130/85 mm Hg or above.
  • Fasting glucose of 100 mg/dL or above.2

Note that lipids should be measured when the patient is in a fasting state.

Women being treated for hypertension or diabetes can be presumed to meet the criteria for those components of metabolic syndrome.

Though the syndrome affects men and women equally overall, Hispanic and African-American women have a 26% and 57% higher incidence, respectively, than men of the same ethnic and racial background.1

Obesity and age drive full-blown syndrome

Insulin resistance, dyslipidemia, and other components of metabolic syndrome exist because of intrinsic genetic susceptibility, which occurs to varying degrees throughout the population.

Some conditions cause this genetic susceptibility to blossom into the full-blown syndrome. Obesity is the driving force for much of this expression.

Age is a highly important factor. Prevalence of metabolic syndrome climbs sharply above the age of 40—in both men and women—so much so that the syndrome is close to becoming the common feature for older age groups (FIGURE 1).

Studies find link to diabetes, cardiovascular disease

What evidence do we have that this syndrome is associated with an increased risk of diabetes, heart disease, and death?

In a study of slightly more than 1,000 males with 10 years of follow-up, Lakka et al 4 found a 3.5-fold increased risk of cardiovascular disease mortality with metabolic syndrome. This risk is as high as or higher than the risk for cardiovascular disease in men with type 2 diabetes, which has been described in many other studies.

Risk rises with number of components

A more recent study explored the impact of the number of components of metabolic syndrome present.5 After controlling for age, family history of diabetes, alcohol intake, and cigarette smoking, investigators found a multivariate-adjusted relative risk of cardiovascular disease, compared with an absence of components, of 3.18, 3.48, 12.55, and 14.15 (P<.001) for the presence of 1, 2, 3, and 4 or more components, respectively. The corresponding relative risks of type 2 diabetes were 1.92, 4.36, 6.44, and 15.08 (P<.001).

Another recent study used the coronary artery calcium score as a surrogate for cardiovascular disease.6 This measure is increasingly recognized as a marker of underlying atherosclerosis. In both men and women, the amount of calcium in the coronary arteries increased with the number of metabolic syndrome components.

Dyslipidemia is a critical component

Several studies have identified dyslipidemia as the key component of metabolic syndrome. That is not to say that other components are unimportant—only that lipid abnormalities appear to have the greatest impact.

In a trial from the Third National Health and Nutrition Examination Study (NHANES III),7 the large dataset that has been studied extensively for this disorder, low HDL cholesterol and high blood pressure in the presence of overt diabetes appeared to account for much of the excess risk associated with metabolic syndrome. In fact, blood pressure, HDL cholesterol, and diabetes—but not metabolic syndrome per se—were significant multivariate predictors of prevalent CHD.7

Twice the risk of myocardial infarction and stroke

Another recent study8 found twice the risk of myocardial infarction and stroke when metabolic syndrome was present.

Investigators used logistic regression to estimate the association of the syndrome as a whole and each of its 5 component conditions separately with a history of myocardial infarction (MI), stroke, and either MI or stroke (MI/stroke).

Metabolic syndrome was significantly related in multivariate analysis to MI (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.53 to 2.64), stroke (OR, 2.16; 95% CI, 1.48 to 3.16), and MI/stroke (OR, 2.05; 95% CI, 1.64 to 2.57).

Among the 5 component conditions of metabolic syndrome, the following were independently and significantly related to MI/stroke8:

  • insulin resistance (OR, 1.30; 95% CI, 1.03 to 1.66),
  • low HDL cholesterol (OR, 1.35; 95% CI, 1.05 to 1.74),
  • hypertension (OR, 1.44; 95% CI, 1.00 to 2.08), and
  • high triglycerides (OR, 1.66; 95% CI, 1.20 to 2.30).

INTEGRATING EVIDENCE AND EXPERIENCE

With nutritionist counseling, glucose-impaired patients lost weight

Can lifestyle adjustments alone prevent type 2 diabetes to any great extent? Can anything be done to get overweight patients with impaired glucose to stick to a diet and exercise regimen?

Yes to both questions, according to researchers who conducted a randomized, controlled trial3 of lifestyle changes among 522 middle-aged, overweight men (n = 172) and women (n = 350) with impaired glucose tolerance and a mean body mass index of 31.

Chief intervention was nutritionist counseling

Nevertheless, getting the study participants to live healthier was a complex undertaking. The intervention group received individualized counseling to encourage them to:

  • reduce their weight by 5% or more
  • reduce fat consumption to less than 30%
  • limit saturated fat intake to less than 10%
  • eat 15 g or more of fiber per 1,000 kcal of intake
  • exercise moderately for at least 30 minutes daily
  • eat whole-grain products, fruits and vegetables, low-fat dairy products and meat, and vegetable oils rich in monounsaturated fatty acids.

Each person in the intervention group met with a nutritionist 7 times during the first year of the study and every 3 months thereafter. Dietary advice was based on 3-day diaries of food intake, completed quarterly.

Endurance exercise was recommended to increase aerobic capacity and improve cardiorespiratory function. In addition, progressive, individually tailored, circuit-type resistance training was offered to improve muscle strength. During the first year of the study, the rate of participation in these resistance training sessions ranged from 50% to 85%.

A very different picture for controls

In contrast to the individualized attention focused on the intervention group, controls received general oral and written information about diet and exercise at the beginning of the trial and at each annual visit, but no detailed counseling. They also completed a 3-day food diary at the beginning of the study and at each annual visit.

Risk of type 2 diabetes 58% lower

The percentage of patients in the intervention group who achieved a particular goal ranged from 25% (fiber consumption) to 86% (exercise). Net weight loss at the end of the second year was 3.5 ± 5.5 kg in the intervention group versus 0.8 ± 4.4 kg in the control group (P<.001 for both comparisons).

While this weight loss was not dramatic, the differences between groups was substantial. For example, individuals who lost at least 5% of their baseline weight had an odds ratio for diabetes of 0.3 (95 percent confidence interval, 0.1 to 0.7).

Over the duration of the trial, the cumulative incidence of type 2 diabetes was 58% lower in the intervention group than in the control group (P<.001).3 When women were singled out, the incidence of diabetes was 54% lower in the intervention group than among controls.

The failure to make any changes in lifestyle led to an incidence of diabetes very near the 35% estimate for this high-risk population.

Patients willingly stuck to diet, exercise

The dropout rate was low, and the researchers concluded that patients with impaired glucose tolerance are “willing and able to participate in a demanding intervention program if it is made available to them.”13

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)

LEVEL

STATUS

LDL cholesterol

<100

Optimal

100–129

Near or above optimal

130–159

Borderline high

160 –189

High

≥190

Very high

Total cholesterol

<200

Desirable

200–239

Borderline high

≥240

High

HDL cholesterol

<40

Low

≥60

High

LDL = low-density lipoprotein

HDL = high-density lipoprotein

Source: NCEP.2 Reprinted with permission

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.

Continued...
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