Metabolic Syndrome

Abstract

The United States is experiencing its greatest life expectancy ever. Nonetheless, the general health of the US population is far from at an all-time high. An important contributor to the pandemic of cardiovascular disease is that overweight and obesity are also the major determinants of metabolic syndrome, an all too common and all too serious clinical and public health challenge. Clinicians have traditionally evaluated each of the major risk factors contributing to metabolic syndrome on an individual basis. There is evidence, however, that the risk factors are more than additive. The overlap of these factors in each disease state, resulting in increased atherogenic risks, is worth examining as a broader entity rather than separately. While therapeutic lifestyle changes (TLCs) should be strongly recommended, clinicians should not let the perfect be the enemy of the possible. Evidence-based doses of statins, aspirin and angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers should be prescribed as adjuncts, not alternatives, to TLCs. In fact, there is cogent evidence that the benefits of these pharmacologic therapies may also be at least additive.

The United States is experiencing its greatest life expectancy ever. Nonetheless, the general health of the US population is far from at an all-time high. The gains in United States life expectancy have been less than those realized by other industrialized nations, mostly owing to a stagnation or even a decline in the life expectancy among a number of US counties, especially among women. The poor health in these counties is correlated with many factors, including rising rates of overweight and obesity, especially in women. ¹ Overweight and obesity are major risk factors for many major causes of US deaths, as well as worldwide, including coronary heart disease, stroke, and cancers of the large intestine, kidney, uterus, and breast in postmenopausal women. In fact, obesity is emerging as perhaps the leading avoidable cause of premature death in the United States as well as worldwide. ²

An important contributor to the pandemic of cardiovascular disease (CVD) is that overweight and obesity are also the major determinants of metabolic syndrome, an all too common and all too serious clinical and public health challenge. As defined by the US National Heart, Lung and Blood Institute and American Heart Association Consensus Statement, metabolic syndrome is a constellation of 3 or more risk factors, which include abdominal obesity, high triglycerides, low- and high-density lipoprotein cholesterol, high blood pressure, and elevated fasting blood glucose (Table 1). From the perspectives of both individual clinicians as well as the health of the general public, metabolic syndrome is a major contributor to the epidemic of CVD in the United States as well as the emerging pandemic. Alarmingly, in the US National Health and Nutrition Examination Survey, more than 1 in 3 adults have metabolic syndrome. More alarmingly, about 40% of adults aged 40 and older have metabolic syndrome. Finally, and most alarmingly, participants with metabolic syndrome are largely asymptomatic but have a 10-year risk of a first coronary event, based on the Framingham Risk Score, of 16% to 18% which is nearly as high as a patient who has already experienced a prior coronary event. At present, however, there is underdiagnosis and undertreatment of metabolic syndrome. ³ This situation is somewhat analogous to that of hypertension, the original silent killer, in the 1970s at the time of the establishment of the National High Blood Pressure Education Program. At that time, only 51% of individuals were aware of their diagnosis and only slightly more than half of these were treated and still less than half of these patients were adequately treated for hypertension. ⁴

Table 1.

Clinical Diagnosis of the Metabolic Syndrome.

Risk Factors	Defining Level
Abdominal obesity, given as waist circumferencea,b
Men	>102 cm (>40 in)
Women	>88 cm (>35 in)
Triglycerides	≥150 mg/dL
HDL cholesterol
Men	<40 mg/dL
Women	<50 mg/dL
Blood pressure	≥130/≥85 mm Hg
Fasting glucose	≥110 mg/dL

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein.

^aOverweight and obesity are associated with insulin resistance and the metabolic syndrome. However, the presence of abdominal obesity is more highly correlated with the metabolic risk factors than is an elevated BMI. Therefore, the simple measure of waist circumference is recommended to identify the body weight component of the metabolic syndrome.

^bSome male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased, for example, 94 to 102 cm (37 to 39 in). Such patients 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.

Clinicians have traditionally evaluated each of the major risk factors contributing to metabolic syndrome on an individual basis. There is evidence, however, that the risk factors are more than additive. ⁵ One of the main factors thought to accelerate the pathway is insulin resistance, which to a certain degree is genetically predetermined. It is the presence of specifically a high waist circumference which appears to contribute to the process. The visceral fat component of abdominal obesity leads to not only insulin resistance but also the release of nonesterified free fatty acids from adipose tissue. Thus, lipids accumulate in other sites such as liver and muscle, further predisposing to insulin resistance and dyslipidemia. Additionally, adipose tissue may produce various adipokines that may separately impact insulin resistance and CVD risk factors. These characteristics coupled with elevated blood pressure and dyslipidemia tend to be commonly manifested as prothrombotic and proinflammatory states. It is the cascade of these closely coupled states that further increase the rate of atherogenesis. The overlap of these factors in each disease state, resulting in increased atherogenic risks, is worth examining as a broader entity rather than separately. ⁵

With respect to the pathophysiology of metabolic syndrome, visceral fat and its clinically more easily measured correlate of waist circumference are gaining increasing attention as strong predictors of the metabolic syndrome, even independent of body mass index (BMI). ⁶ Increased interleukin 6 and other inflammatory markers increase with metabolic syndrome scores that have a positive predictive value for coronary heart disease diagnosed angiographically. ⁷ These correlations offer a plausible explanation for the observed increased risk of CVD among participants with so-called normal weight central obesity. These high-risk patients represent an important population for clinicians to screen for the metabolic syndrome despite their normal BMI.

Though this may produce many more millions of Americans classified as having metabolic syndrome, fortunately metabolic syndrome is not a condition without treatment options. The Diabetes Prevention Program regimen, published in 2002, showed that therapeutic lifestyle changes (TLCs) had a far greater impact than pharmacologic options. Thus, their key interventions included dietary modifications and 150 minutes of physical activity a week. The recommendations also included individual case management and frequent contact with lifestyle coaches. ⁸ Today, however, even getting 1 visit to a nutritionist paid for by health insurance presents a challenge to clinicians. Thus, while TLCs should be strongly recommended, clinicians should not let the perfect be the enemy of the possible. Evidence-based doses of statins, aspirin and angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers should be prescribed as adjuncts, not alternatives, to TLCs. In fact, there is cogent evidence that the benefits of statins and aspirin are at least additive. Specifically, in data from 2 large randomized trials of statins and a meta-analysis of 5 trials, patients on aspirin who were randomized to a statin experienced greater benefits than those on each agent alone on myocardial infarction, stroke, and a composite CVD end point. These findings were also apparent among those randomized to a statin who did or did not take aspirin. In these data, the probability of synergy, or an effect greater than additivity, was 0.92. ⁵ Furthermore, it has recently been estimated that 44% of the decrease seen in CVD mortality from 1980 to 2000 is attributable to risk factor modification, with 24% (of the 44%) being attributed to reductions in cholesterol and 20% attributed to reductions in blood pressure. ⁹ Statins produce statistically significant and clinically important reductions in risks of CVD, including myocardial infarction, stroke, and CV death, in women and men in secondary prevention, in high-risk primary prevention participants, including those with diabetes and those at high risk of developing diabetes, as well as in low-risk primary prevention participants. In contrast, the totality of evidence is unclear about whether there is a valid statistical association between statins and newly diagnosed diabetes. Specifically, the data from trials not designed a priori to test a hypothesis should be viewed as hypothesis formulating, not hypothesis testing. Furthermore, with respect to the randomized evidence, there should be substantial differences between how trial evidence is interpreted for the prespecified main effects of statins on CVD in contrast to somewhat unexpected side effects of statins on newly diagnosed diabetes for which no trial has been designed a priori to test the hypothesis. Furthermore, some trials show inverse relationships or no association. From the perspective of individual patients as well as the health of the general public, there is marked underutilization of statins in the United States. Many premature deaths will occur needlessly if patients for whom statins should be prescribed do not agree to take the drug or if patients prescribed statins stop taking the drug as a result of concerns about the development of diabetes. ⁵ Even if real, the most plausible estimate of increased risk is about 9%. ¹⁰ The authors of this meta-analysis concluded that, even if causal, 255 patients would have to be treated with a statin for 4 years to produce 1 case of diabetes whereas 9 vascular events would have been prevented. Despite this persuasive totality of randomized evidence on benefits in clinical CVD outcomes and controversy about whether there is an increase in diabetes, there has been hesitancy to prescribe statins. One hypothesis generated but not tested relates to increases in plasma adenopectin. ¹¹ Thus, from a clinical perspective, it seems prudent to use the particular statin best suited to the needs of an individual patient rather than relying on a particular brand related to the hypothesized but unproven risk of diabetes and inconsistent data on glycemic parameters.

In conclusion, the clinical and public health challenges in metabolic syndrome include prevention, early diagnosis, and aggressive multifactorial medical management. These strategies must include the adoption of the TLCs of weight loss and increased physical activity as well as the use of adjunctive pharmacologic therapies for many patients with metabolic syndrome, whose risks of a first coronary event are almost as high as those who have survived a prior event.