W. Evaluation and Treatment of Metabolic Syndrome

objective

Identify therapeutic treatment options for individuals with metabolic syndrome.

background

A recent study assessing the magnitude of the association between the NCEP ATP-III (2002) definition of metabolic syndrome and CVD found that individuals without diabetes or CVD, but with metabolic syndrome, are at increased risk for long-term CV outcomes, although statistical models suggested that most of that risk was accounted for by the Framingham Risk Score (FRS).  Nevertheless, identification of individuals with metabolic syndrome may provide opportunities to intervene earlier in the development of shared disease pathways that predispose individuals to both CVD and diabetes (McNiell et al., 2005).

Specific recommendations for the management of lipid disorders in those with metabolic syndrome have been described in NCEP ATP-III (2002).  The recommendations emphasize lifestyle management (weight loss, physical activity, dietary fat restriction).  Medications can potentially favorably alter low levels of HDL-C and high level of TG and in theory, reduce the risk of CVD in individuals with metabolic syndrome.  However, specific treatment targets and recommendations have not been fully clarified, particularly with regards to drug therapy, largely on the basis of a lack of hard outcomes data from clinical trials.  Further clinical trial data will be required before more specific recommendations regarding the treatment of low levels of HDL and high levels of TGs in metabolic syndrome can be made.  These issues will be addressed in detail in future revisions of the guidelines as more definitive data become available.

recommendations

1. TLC should be initiated for patients diagnosed with metabolic syndrome.  [B]
2. Lifestyle modification for weight reduction through diet and increased physical activity is indicated for patients diagnosed with metabolic syndrome.  [B]
3. Drug therapy to alter insulin resistance or low HDL-C or elevated TG has not been demonstrated to improve CVD outcomes in patients with metabolic syndrome and as such, clinicians will have to individualize therapy.  [I]

discussion

Metabolic syndrome is a diagnosis that has evolved since the late 1980s when “Syndrome X” was first described by Dr Gerald Reaven as a constellation of abnormalities including glucose intolerance, hyperinsulinemia, elevated TG, low HDL and HTN.  Often coexisting with “Syndrome X” was central obesity.  In 2002, NCEP ATP-III Guidelines defined the metabolic syndrome (see Box 8) and noted the root causes to be overweight/obesity, physical inactivity, and genetic factors.  Metabolic syndrome is closely associated with insulin resistance, which can be either a genetic predisposition or acquired.

Regardless, insulin resistance and metabolic syndrome increase the risk for CVD in diabetic and non-diabetic patients and at any given level of LDL-C.  Most patients with metabolic syndrome are overweight or obese; clinical studies have noted a high correlation between abdominal obesity and factors characteristic of metabolic syndrome (elevated TG, low HDL-C, insulin resistance, and high blood pressure).

Closely associated with abdominal obesity is an elevation of serum TGs.  A higher TG level is usually accompanied by lower HDL-C concentrations.  HDL-C levels <40 mg/dL occur commonly in men with insulin resistance.  Further, moderate reductions of HDL-C levels are observed commonly in women with the syndrome; thus for women, HDL-C <50mg/dL counts as an indicator of the presence of metabolic syndrome.  A moderately strong association exists between insulin resistance and hypertension.  Insulin resistance also is associated with high-normal blood pressure or pre-HTN (Chobanian et al, 2003).

Impaired fasting glucose (110–125 mg/dL) usually is an indicator of insulin resistance and is frequently accompanied by other metabolic risk factors.  A portion of persons with impaired fasting glucose will eventually develop Type 2 diabetes, which further enhances risk for CVD.  Other components of the metabolic syndrome (proinflammatory state and prothrombotic state) are not easily identified by routine clinical evaluation.  However, in the presence of abdominal obesity, they often are present.  For practical purposes, metabolic syndrome is identified by the presence of three or more of the following components:

Box 8. Criteria for Identifying Metabolic Syndrome
Risk Factor	Defining Level
Abdominal Obesity	Waist Circumference
Men†	>40 in (>102 cm)
Women	>35 in (>88 cm)
Triglycerides	>150 mg/dL
HDL Cholesterol
Men	<40 mg/dL
Women	<50 mg/dL
Blood Pressure	>130/85 mmHg
Fasting Glucose	>110 mg/dL

NCEP ATP-III, 2002
† Some male persons can develop multiple metabolic risk factors when the waist circumference is only marginally increased, e.g., 94–102 cm (37–39 in). Such persons may have a strong genetic contribution to insulin resistance. They should benefit from changes in life habits, similarly to men with categorical increases in waist circumference.

 

Treatment

The full effect of risk reduction in a patient treated for high LDL-C will be lost if metabolic syndrome is ignored.  In fact, the presence of metabolic syndrome accentuates CVD risk accompanying any given level of LDL.  To achieve maximal benefit from modification of multiple metabolic risk factors, the underlying insulin resistant state must become a target of therapy.  The most well-studied, effective, and preferred means to reduce insulin resistance is weight reduction in overweight/obese persons with or without increased physical activity.  (For the management of obese patient see the VA/DoD Guideline for Management of Obesity.)

Drug treatment of several individual components of metabolic syndrome will reduce CVD risk.  Risk reductions by lowering blood pressure with anti-hypertensive drugs and treating the prothrombotic state with aspirin are well documented.  However, lowering serum glucose or reducing insulin resistance with drugs in patients with metabolic syndrome has not yet been documented to reduce risk for CVD.  Similarly, while there may be a strong trend toward reduced CVD risk with drug treatment for atherogenic dyslipidemia (low HDL and elevated TG), there are no CV outcomes studies to date that have been completed (nor designed) to specifically answer this question.  Clinicians will have to individualize treatment for any given patient when contemplating drug treatment for insulin resistance or dyslipidemia associated with metabolic syndrome.

The presence of the metabolic syndrome provides the option to intensify LDL-lowering therapy after LDL-C goals are set with the major risk factors.  Primary emphasis nonetheless, should be given to modifying the underlying risk factors (overweight/obesity and physical inactivity) and other risk factors associated with metabolic syndrome.