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The Metabolic Syndrome: Prevalence and Controversies in Clinical Context
The metabolic syndrome (MetS) is defined as clustering of metabolic components that occur together more often than by chance alone and predispose to atherosclerotic vascular disease and diabetes. First descriptions of associated metabolic diseases occurred at the beginning of the last century when Kylin reported a connection between hyperglycemia, hypertension, and gout. Thus, the intention with the introduction of MetS was primarily to get a clinical tool or common term for an interrelated cluster of metabolic diseases. Later, Vague realized the central role of android obesity in this cluster of diseases and connected MetS with atherosclerotic vascular disease. This then was extended to “plurimetabolic syndrome,” associated with increased risk of cardiovascular disease (CVD), by Crepaldi and colleagues. In 1981 the first definition of MetS was published, connecting classical interrelated metabolic diseases with hypertension and atherosclerotic vascular diseases:
“The metabolic syndrome represents the common prevalence of obesity, hyper- and dys-lipoproteinaemia, maturity onset diabetes (type 2), gout and hypertension associated with increased incidence of atherosclerotic vascular disease, fatty liver and gallstones that develop on the basis of genetic susceptibility combined with over-nutrition and physical inactivity. If this working hypothesis can be confirmed it provides the basis for integrated diagnostics and prevention of this cluster of diseases, which is of central importance for health care.”
Despite these clear descriptions of the main components of MetS that might identify individuals at higher risk of atherosclerotic vascular disease that extend beyond classic risk factors—for example, age, sex, low-density lipoprotein (LDL) cholesterol, and smoking—the clinical and scientific usefulness of the concept of MetS is still an issue of debate. The main reason for this controversy might be the lack of a generally accepted definition of the syndrome: simple clinical measures are used to identify complex disorders, and cutoff limits were defined without sufficient epidemiologic data.
With the introduction of arbitrary cutoff limits for accepted components, there are now different definitions put forth by international and national institutions, including the World Health Organization (WHO), the American Heart Association(AHA) and U.S. National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI), and the International Diabetes Federation (IDF) ( Table 4-1 ).
Table 4-1
Definitions of Metabolic Syndrome According to WHO, AHA/NHLBI, and IDF at the Beginning of the 21st Century and Consensus Statement 2009
| WHO (1999) | AHA/NHLBI (2005) | IDF (2005) | Consensus Statement Criteria (2009) |
|---|---|---|---|
| NGT: Two criteria plus insulin resistance (highest quartiles of HOMA-IR) IFG or IGT: Two criteria |
Three or more criteria | Central obesity as precondition Waist: Male ≥ 94 cm Female ≥ 80 cm Plus two or more criteria |
|
| Dyslipidemia: TG ≥ 1.7 mmol/L (150 mg/dL) and/or HDL-C ↓: Male < 0.9 (35 mg/dL) Female < 1.0 mmol/L (40 mg/dL) Hypertension: ≥ 140/90 mm Hg Obesity: BMI > 30 kg/m 2 WHR: Male > 0.9 Female > 0.85 Microalbuminuria: ≥ 20 μg/min |
Hypertriglyceridemia: TG ≥ 1.7 mmol/L (150 mg/dL) or Rx HDL-C ↓: Male < 1.04 (40 mg/dL) Female < 1.29 mmol/L (50 mg/dL) or Rx Hypertension: ≥ 130/85 * mm Hg or Rx Central obesity: Male ≥ 102 cm Female ≥ 88 cm WC Fasting PG: ≥ 6.1 mmol/L (110 mg/dL) or Rx |
Hypertriglyceridemia: TG ≥ 1.7 mmol/L (150 mg/dL) or Rx HDL-C ↓: Male < 1.04 (40 mg/dL) Female < 1.29 mmol/L (50 mg/dL) or Rx Elevated blood pressure: ≥ 130/85 * mm Hg or Rx Fasting PG: ≥ 5.6 mmol/L (100 mg/dL) (OGTT recommended) |
Hypertriglyceridemia: TG ≥ 1.7 mmol/L (150 mg/dL) HDL-C ↓: Male < 1.03 (40 mg/dL) Female: < 1.29 mmol/L (50 mg/dL) Blood pressure: ≥ 130/85 mmHg Obesity/waist: depends on country-specific definitions Fasting PG: ≥ 5.6 mmol/L (100 mg/dL) or Rx |
AHA = American Heart Association; BMI = body mass index; HDL-C = high-density lipoprotein cholesterol; HOMA-IR = homeostatic model assessment, insulin resistance; IDF = International Diabetes Federation; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; NGT = normal glucose tolerance; NHLBI = National Heart, Lung, and Blood Institute; OGTT = oral glucose tolerance test; PG = plasma glucose; TG = triglycerides; WC = waist circumference; WHO = World Health Organization; WHR = waist-to-hip ratio.
The consequence of these different definitions based on arbitrary cutoff limits was a different estimation of the prevalence of patients with MetS. , Moreover, MetS according to IDF criteria had only a weak relationship to cardiovascular risk, because it was focused on insulin resistance, obesity, and dysglycemia as risk factors for diabetes. Thus it was not surprising that the usefulness of the concept was questioned in a joint statement of the ADA and the European Association for the Study of Diabetes (EASD).
To overcome confusion and the waste of resources resulting from competing parallel investigations, a unifying concept and definitions were recently adopted (see Table 4-1 ).
Here we analyze the association of MetS with CVD according to the primary idea behind a syndrome that is a tool to search for other components interrelated with the lead trait or disease.
Association between Metabolic Syndrome and Cardiovascular Disease in the Population
The global prevalence of MetS in the adult population varies from 15% to 50%. The estimated prevalence is affected by multiple factors such as age, sex, nutrition habits, lifestyle factors, socioeconomic conditions, and ethnicity as major determinants in addition to variability in the proposed definitions. ,
MetS is not an absolute risk indicator because it does not involve many of the factors that determine absolute cardiovascular risk—for example, smoking, age, sex, and LDL cholesterol level. Therefore it is not surprising that the usefulness of MetS as an independent cardiovascular risk indicator is a matter of controversy.
Most studies have revealed an increased risk for the development of CVD associated with MetS. A meta-analysis of 36 longitudinal studies found a hazard ratio of 1.78 (95% confidence interval [CI] 1.58-2.00) for incident CVD events and death in individuals with MetS. An analysis of the Framingham database also demonstrated an increased age-adjusted CVD risk of 2.88 (95% CI 1.99-4.16) for men and 2.25 (95% CI 1.31-3.88) for women with MetS. Obviously there is an association between the increase of CVD risk and the number of features of MetS. Recently published data from a large population-based meta-analysis that included more than 900,000 patients showed a twofold increase in cardiovascular events and a 1.5-fold increase in all-cause mortality rates in patients with MetS. The cardiovascular risk was still high in patients with MetS but without diabetes. MetS according to National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III) criteria could also be confirmed to be associated with CVD in Asian populations. ,
There are few contradictory studies. In two large prospective studies, Sattar and colleagues found that MetS had only a weak or no association with cardiovascular risk in an elderly population representative of the United Kingdom. In these prospective studies, however, MetS was a major risk factor for type 2 diabetes. Therefore the authors concluded that there is no common soil for diabetes and CVD based on MetS classification. Overall, there is sufficient evidence that patients with MetS are at twice the risk of developing CVD over the next 5 to 10 years, and in all related studies there was an approximately twofold higher prevalence of MetS in comparable cohorts with major CVDs (coronary heart disease, cerebrovascular disease, stroke). ,
It is interesting to see that in the United States, obesity, diabetes, and coronary heart disease develop in parallel, with some lag time for development of coronary heart disease ( Table 4-2 ).
Table 4-2
Prevalence of the Metabolic Syndrome According to Criteria of the National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP-III); 1998 and 1999 World Health Organization Criteria, Diabetes (DM) and Coronary Heart Disease (CHD) by Age Group among U.S. Population ≥ 20 years
Data from Alexander CM, Landsman PB, Teutsch SM, et al: NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older, Diabetes 52:1210; 2003.
| Age | 1998 WHO (N = 35.8 M) |
1999 WHO (N = 41.3 M) |
NCEP-ATP-III (N = 48.4 M) |
DM (N = 14.0 M) |
CHD (N = 12.2 M) |
|---|---|---|---|---|---|
| 20-29 years (36 M) |
4.9% | 4.9% | 6.0% | 0.5% | 1.9% |
| 30-39 years (42 M) |
11.0% | 11.1% | 14.2% | 2.0% | 3.4% |
| 40-49 years (42 M) |
19.3% | 21.2% | 24.6% | 5.0% | 4.5% |
| 50-59 years (30 M) |
28.5% | 32.4% | 36.5% | 12.9% | 7.5% |
| 60-69 years (20 M) |
35.3% | 42.0% | 48.1% | 17.7% | 11.9% |
| 70-79 years (16 M) |
35.0% | 44.3% | 48.4% | 18.4% | 16.1% |
| 80 + years (9 M) |
22.4% | 27.7% | 43.3% | 15.5% | 17.9% |
The same phenomenon can be observed in the process of globalization and westernization in numerous other countries.
The next question that arises is whether the outcome of CVD might be associated with MetS. In the Acute Coronary Syndrome (ACS) Israeli Survey, the outcomes of 1060 patients with ACS have been evaluated. Multivariable analysis identified MetS as a strong independent predictor of 30-day and 1-year mortality after ACS events, with hazard ratios of 2.54 (95% CI 1.22-5.31) and 1.96 (95% CI 1.18-3.24), respectively.
In a study of 633 consecutive patients hospitalized with acute myocardial infarction, patients with (n = 290) and without (n = 343) MetS were compared. Acute myocardial infarction characteristics and left ventricular ejection fraction at admission were not statistically different between the groups. In-hospital case fatality was higher in patients with MetS compared with those without, as was the incidence of severe heart failure (Killip class II or greater). In multivariable analysis, MetS was a strong and independent predictor of severe heart failure, but not in-hospital death. Analysis of the predictive value of each of the five MetS components for severe heart failure showed that hyperglycemia was the major predictor (odds ratio [OR] 3.31; 95% CI 1.86-5.87). These data demonstrate a worse outcome of CVD in patients with MetS.
There are fewer data available concerning MetS and cerebrovascular disease. A 14-year longitudinal cohort study comprising 1131 men (114 [10%] with and 1017 without MetS) has shown that MetS was associated with all types of stroke (OR 2.05 (95% CI, 1.03 to 4.11)); 65 strokes occurred during the monitoring, 47 of which were ischemic.
After a 14-year follow-up in 2097 individuals with initial high prevalence of MetS (men 30.3%, women 24.7%), 75 men and 55 women sustained the first stroke. The age-adjusted relative risk of stroke in individuals with diabetes and MetS was high (OR 3.28; 95% CI 1.82-5.92), higher than that of any other MetS phenotype. In this study, with a high prevalence of MetS, MetS was also an independent risk factor for stroke in individuals without diabetes.
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