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Metabolic syndrome (MetS) is a cluster of metabolic abnormalities including abdominal obesity, impaired fasting glucose, hypertension and dyslipidemia. It seems to affect about one-fourth to one-fifth of the Mediterranean population, and its prevalence increases with age, being similar for both sexes and depending on the region and the definition used, with the National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATPIII) definition being the most effective in the identification of glucose intolerance and cardiovascular risk. Except for these, MetS is associated with fatty liver disease, some forms of cancer, hypogonadism, and vascular dementia. The Mediterranean diet seems to be an ideal diet in patients with MetS, being rich in fibre, monounsaturated and polyunsaturated fats, and low in animal protein; and decreases the prevalence of MetS and cardiovascular disease risk. Except for weight loss, multifactorial intervention including insulin resistance reduction and normoglycemia, management of dyslipidemia, optimizing blood pressure and administration of low-dose aspirin for patients at high or moderately high cardiovascular disease (CVD) risk are additional targets. The present review provides current understanding about MetS in the Mediterranean region, focusing on its prevalence, clinical significance, and therapeutic strategy.
Metabolic syndrome (MetS) represents a constellation of cardiovascular risk factors, such as hyperglycemia, dyslipidemia [involving elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C)], hypertension and abdominal obesity, which predispose the individual to increased risk of developing diabetes mellitus (DM) and cardiovascular disease (CVD).[1,2] It reflects our modern's world sedentary lifestyle, overnutrition, and resultant excess adiposity. It was first described by Reaven in 1988 as “syndrome X” or “insulin resistance syndrome”. Since then, several studies and definitions have been conducted and copious piece of literature has been produced.
Despite its growing prevalence worldwide, there is still lack of a uniformly accepted definition and great controversy with regard to the pathogenesis of MetS. The most widely accepted definition is that proposed by the National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATPIII) criteria, which requires 3 or more of the following parameters: waist circumference (WC) >102 cm in men and >88 cm in women, HDL-C <40 mg/dl (<1.04 mmol/l) in men and <50 mg/dl (< 1.29 mmol/l) in women, TG ≥150 mg/dl (≥1.7 mmol/l), blood pressure (BP) ≥130/85 mmHg and fasting glucose ≥110 mg/dl (≥6.1 mmol/l). There are other two commonly used definitions, one proposed by the International Diabetes Federation (IDF) and one by the American Heart Association (AHA) and the National Heart Lung and Blood Institute (NHLBI). According to the IDF definition, MetS is diagnosed if an individual has abdominal obesity, that is WC ≥94 cm in Europid men and ≥80 cm in Europid women and ≥2 of the remaining 4 criteria of the NCEP-ATP III definition. Cut-off points for hypertension, TG and HDL-C levels are the same but blood glucose levels are considered abnormal at lower levels [≥100 mg/dl (5.6 mmol/L)]. The definition proposed by the AHA/NHLBI in 2005 retained most of the NCEP-ATPIII criteria but adopted the same WC thresholds for some ethnic groups (e.g., Asians) and lower cut-off points for fasting glucose levels [≥100 mg/dL (5.6 mmol/L)] with the IDF definition. Recently, the 2009 Joint Interim Societies (JIS) MetS definition was proposed which tried to unify the above three definitions. This uses the same thresholds for BP, TG, and HDL-C considers WC based on ethnicity [≥94 cm (men) or ≥80 cm (women) for a Mediterranean population, although it is not a mandatory criteria] and fasting glucose levels [≥100 mg/dL (5.6 mmol/L)]. Three or more of these criteria are required for diagnosis. All these criteria are presented in Table 1.
There is no available unifying pathogenetic mechanism for the components of MetS. MetS is closely linked to IR and abdominal obesity, which develop as a result of an atherogenic diet and sedentary lifestyle in a metabolic susceptible individual. Factors predisposing to this phenotype are genetic defects in insulin signalling pathways and mitochondrial function, advancing age and certain drugs, such as corticosteroids. Specific genes, especially those that encode for 11β-hydroxysteroid dehydrogenase type 1, adiponectin, β3-adrenergic receptor, endocannabinoid receptors, may predispose to the development of MetS. Finally, since the clinical features of MetS are shared by Cushing's syndrome it has been proposed that cortisol may contribute to the pathogenesis of both states. Increasing body of evidence has shown higher circulating cortisol levels in patients with MetS compared with healthy subjects despite being within the normal range, increased activity of cortisol in the periphery and dysregulation of the hypothalamic-pituitary-adrenal axis.
The purpose of the present review is to provide knowledge about current status of the MetS in the Mediterranean population, focusing also on optimal therapeutic strategies.
The prevalence of MetS is dependent on the population studied, determined by age, sex, race, or ethnicity, as well as on the definition used. In a large study of the United States (US) population using the NCEP-ATPIII criteria, the unadjusted and age-adjusted prevalence of the MetS was 21.8% and 23.7%, respectively. Lower prevalence has been reported for other populations, such as among Korean adults (15.7% in 1998 and 14.4% in 2001, using the NCEP-ATP III criteria). Data from the National Health and Nutrition Examination Survey (NHANES) III 1988-1994 or NHANES 1999-2000 involving the US population did not indicate any gender difference in prevalence. Nevertheless, in two studies, the Mexico City Diabetes Study and the Korean National Health and Nutrition Survey women had a higher prevalence of the MetS than men. On the other hand, a recent study of the Finnish population demonstrated that the prevalence of the MetS based on both the NCEP-ATPIII and IDF definitions was higher in men than women. The prevalence of MetS is lower in white, non-Hispanic women than men, and higher in African-American women than men.
However, there are also conflicting data regarding the changes in prevalence. The age-adjusted prevalence of the MetS increased from 27% in the NHANES III 1988-1994 to 32.9% in NHANES 1999-2000 (P = 0.014) in U.S. women, although it did not change in U.S. men (from 31.4-31.8%; p=0.866). In the San Antonio Heart Study, an increase in the prevalence of the MetS was also demonstrated in both men and women, as well as Mexican Americans and non-Hispanic whites. Nevertheless, the Mexico City Diabetes Study and the Korean study did not show any increase trend in the prevalence of the MetS, while in the Finnish study the prevalence increased significantly only in women during the years 1992-2002.
Regarding Mediterranean population, in a representative cross-sectional study in Greece, including 4,153 adults older than 18 years, the age-standardized prevalence of the MetS was 23.6%. The prevalence was similar in men (24.2%) and women (22.8%) (P = 0.3), as it was seen in the US population, and increased with age in both sexes, being 4.8% among participants aged 19–29 years and 43% for participants over 70 years old (P for trend < 0.0001). Most of those with MetS had ≥3 components of the syndrome (61%), with abdominal obesity (82%) and arterial hypertension (78%) being the most common of them in both sexes. The prevalence of MetS in Italian adults >18 years seems to be lower, in particular, 18% in women and 15% in men, increasing from 3% among subjects aged 20–29 years to 25% in subjects aged 70 years or older. In another Italian cohort of patients older than 65 years, the prevalence of MetS was 25.9% in non-diabetic men and 55.2% in non-diabetic women.
The prevalence of MetS is much higher in patients with DM (78.2% with NCEP-ATPIII and 89.5% with IDF criteria in a Spanish cohort), being even higher in sedentary diabetic patients (with NCEP-ATPIII definition: 86.2% and with IDF: 93.9%). The prevalence of MetS is also higher in specific patient populations than that reported for the general population, such as those with hypertension (59%), coronary acute syndrome (about 51%),[22,23] hypertriglyceridemia (about 79%), current smokers, subjects with heavy compared with moderate carbohydrate intake, physical inactivity, alcohol intake, lower household income, and those living in an urban area.
As far as the definition criteria are concerned, the prevalence appears to be higher using the IDF criteria in comparison with NCEP-ATPIII.[9,25,26] Analysis of cross-sectional data from nearly 10,000 subjects from the general Greek population comparing the four different definitions (including the JIS one) in terms of the MetS prevalence and predictive value of MetS-related CVD risk, demonstrated much higher prevalence with the IDF and JIS definitions compared with the NCEP-ATPIII and AHA/NHLBI ones. The prevalence of CVD in those with MetS according to IDF and JIS was similar to the whole study population. The age-adjusted prevalence of MetS defined by NCEP-ATPIII and AHA/NHLBI was 24.5% and 26.3%, respectively (P = 0.09), whereas that of IDF and JIS-defined MetS was 43.4% and 45.7% (P < 0.0001, for both comparisons), although the calculated vascular event risk was lower in those with IDF-defined MetS.
Similar data have been conducted by other Mediterranean cohorts. In an Italian cohort of about 3,000 participants, the IDF definition produced a relevant increase in the prevalence of MetS, particularly in older subjects, when compared with NCEP-ATPIII criteria. Moreover, NCEP-ATPIII definition seems to be more effective than IDF in the identification of glucose intolerant subjects. A Spanish cohort showed also a higher overall prevalence with the JIS criteria. In this study of Mediterranean population, the prevalence of MetS using the new definition increased significantly with age, being 4 times higher in individuals over 60 years than those younger than 40 years (P < 0.0001). Interestingly, in a Spanish sample of elderly patients (>65 years) when the IDF definition was applied, the total prevalence was 48.9%, while the prevalence according to NCEP-ATPIII criteria was 46.8%, with a higher prevalence of MS in females than males and a steady decrease as the age of patients increased, both for the ATP III and the IDF definition. These data indicate that IDF and JIS are not useful enough tools in identifying patients at increased CVD risk. Another study from Greece showed that the use of IDF definition results in increased labelling of elderly patients with the diagnosis of MetS, failing, however, to identify more at high risk of stroke. Similar data were reported from a study in a hypertensive Mediterranean population, which indicated a higher prevalence of MetS according to the IDF and JIS definitions compared with that of the NCEP-ATPIII in both genders. Nevertheless, IDF and JIS are more appropriate for Asian populations.
In terms of gender-specific differences in CVD risk factors, a Greek study showed that arterial hypertension and hypertriglyceridemia were more common in men (89.6% vs 84.2% and 86.8% vs 74.2%, respectively; P < 0.001), while women presented with lower HDL-C and higher prevalence of abdominal obesity (58.2% vs 66.2% and 85.8% vs 97.1%, respectively; P < 0.001). The 10-year risk of fatal CVD events using different scores was higher in men (6.3% +/- 4.3% vs 2.7% +/- 2.1%; P < 0.001).
The main utility of diagnosing MetS is the identification of people at high risk of CVD beyond low-density-lipoprotein cholesterol (LDL-C) levels and at high risk of developing DM. Recent data indicate that MetS is a better predictor than glucose intolerance for the development of DM. It is well known that MetS is associated with increased risk of cardiovascular morbidity and mortality.[1,2] In terms of the prevalence of CVD in patients of the Mediterranean region, it is significantly higher in those with MetS than those without (29.4% vs 9.6% in a recent study). Interestingly, subjects with the MetS but no DM have the same CVD prevalence (24.1%) with those with DM without the MetS (25.4%), but lower than those with both the MetS and DM (40.7%). The odds ratio (OR) of prevalent CVD in all patients with MetS was 1.94 in a Greek study (95% CI = 1.35–2.47) and 1.40 (CI = 1.02–1.97) in an Italian cohort. Moreover, patients with both MetS and DM had an OR of 3.04 (95% CI = 1.98–4.11) and in those of MetS but no DM the OR was1.48 (95% CI = 1.12–1.92). Higher OR (4.37, CI: 3.25–5.87) of CVD in individuals with both MetS and DM was shown from another Mediterranean cohort. Nevertheless, this study failed to show an independent association of MetS with CVD in patients with or without DM, after further adjustment for its individual components, arguing against of an additional information provided by diagnosing MetS. In both Mediterranean men and women a significant association of MetS with stroke (OR = 1.67, 95% CI: 1.02–2.75 in men and OR = 1.72, CI: 1.01–2.93 in women) and DM (OR = 4.58, CI, 3.12–6.74 in men and OR = 5.15, CI: 3.23–8.20 in women) has been reported.
A recent Italian study in patients over 65 years old and MetS showed also an increased risk in all-cause [hazard ratio (HR):1.41 (95% CI: 1.16–1.72)], P = 0.001) and cardiovascular mortality [HR: 1.60 (1.17–2.19), P = 0.003]. In this study, high glucose levels in both sexes and low HDL-C in women were independent predictors of mortality. In another study from the Mediterranean region, MetS was associated with carotid intima-media thickness (IMT), an early marker of atherosclerosis. In particular, subjects with MetS had a significantly higher prevalence of a carotid IMT >0.80 mm and of carotid plaques compared with those without MetS. This correlation was evident for TG and fibrinogen levels. Conflicting data have emerged regarding the ability of MetS to predict CVD risk independently of its components. A meta-analysis reported a relative risk (RR) of cardiovascular events and death of 1.78 (95% CI: 1.58–2.00), being stronger in women and remaining significant after adjusting for traditional CVD risk factors (RR: 1.54, 95% CI: 1.32–1.79). On the other hand, others failed to show an independent prediction of CVD with MetS, different from the sum of its components.
Except for CVD and DM, MetS is also associated with as higher urinary albumin excretion, lower glomerular filtration rate (GFR) and a greater prevalence of chronic kidney disease, independently of its individual components (OR:1.33, 95%CI: 1.03–1.71). Other co-morbidities include non-alcoholic fatty liver disease sleep-disordered breathing, and hypogonadism in males, according to the results of a recent meta-analysis. Furthermore, MetS has been associated with increased incidence of some types of cancer. A recent meta-analysis including a case-control study of Mediterranean (Italian) population indicated an increased risk of pancreatic cancer (RR: 1.55, 95% CI: 1.19-2.01), with DM being the key component for this correlation. In another recent study, MetS in postmenopausal women was significantly associated with increased incidence of breast cancer (OR = 1.75, 95% CI: 1.37–2.22) and this risk was higher at older age. One of the proposed mechanisms for this association may be related to increased insulin and insulin-like growth factor-I (IGF-I) activities observed in MetS. Elevated serum insulin concentrations observed in MetS and IR states increase the level and bioavailability of IGF-I, which in turn plays a key role in the development and progression of several cancers. Finally, studies from the Mediterranean region indicated an association of MetS with increased risk of vascular dementia (adjusted HR: 3.82; 95% CI: 1.32–11.06) and, in those with mild cognitive impairment, MetS was linked to increased progression to dementia (HR: 4.40; 95% CI: 1.30–14.82).
Lifestyle modification based on a diet low in saturated and high in unsaturated fats, high in complex unrefined carbohydrates and fibre and low in added sugars and sodium combined with regular moderate to intense physical activity (at a minimum of 30 minutes/day) and smoking cessation, remains the cornerstone of therapeutic approach in patients with MetS. Carbohydrates should constitute 40–65%, protein 10–35% (except those with nephropathy) and fats 20–35% of the total calorie intake. More specifically, saturated fats must be limited to <7%, trans-fatty acids to <1%, and cholesterol to <200 mg/day, while monounsaturated fats should be consumed, as they have beneficial effects on atherogenic dyslipidemia. In addition, n-3-polyunsaturated fatty acids (mainly from fish), which also have cardioprotective effects, should constitute about 10% of calorie intake.[9,46] Both low-glycemic load (LGL) diet and low-fat diet can reduce body weight, but the LGL diet appears to be more suitable for subjects with MetS.
The Mediterranean diet seems to fulfil the aforementioned features of an ideal diet in patients with MetS. It is rich in fibre, monounsaturated and polyunsaturated fats, low in animal protein, and based mainly on fruit, vegetables, fish, nuts, whole grains, and olive oil. The Mediterranean diet seems to be effective in reducing the prevalence of MetS and associated CVD. It is also associated with longer life span and prevention from some forms of cancer. The healthiest components of the Mediterranean vary among the Mediterranean countries. However, fish, olive oil, red wine and vegetables are four essential components of such diet in all the countries. One form of such diet is the “Spanish Ketogenic Mediterranean Diet” (SKMD), which is a protein ketogenic diet including virgin olive oil as the principal source of fat (≥30 ml/day), green vegetables and salads as the main source of carbohydrates, fish as the main source of proteins and moderate red wine intake (200–400 ml/day).[51,52] Recent studies have shown that SKMD is effective in losing weight and safe in ameliorating all the components of the MetS, even in cases of not achieving the optimal body mass index (BMI).[51,52]
Regarding exercise, it may be beneficial beyond its effect on weight loss by selectively removing abdominal fat. It has been shown that aerobic exercise has a dose-response effect on visceral adiposity. Furthermore, an intensive exercise intervention strategy seems to be further beneficial in patients with MetS. Indeed, a study in the Mediterranean population showed that a supervised aerobic and resistance training plus structured exercise counselling was superior to counselling alone as it resulted in significantly greater improvement in all the components of MetS, as well as inflammation, IR and CVD risk scores.
Pharmaceutical intervention for losing weight includes only orlistat at the moment. Orlistat acts by reducing fat absorption via binding to gastric and pancreatic lipases, partially inhibiting the hydrolysis of TG into absorbable free fatty acids and monoacylglycerols. This has been found to result in significant weight loss compared with placebo, but rebound weight gain, if discontinued.[55,56] In association with a hypocaloric diet, orlistat exerts a favourable effect on several CVD risk factors, including BP, fasting glucose, TG, and LDL-C levels in patients with MetS and type 2 DM. Moreover in a large prospective study, orlistat plus lifestyle interventions reduced the incidence of type 2 DM by 37% in high-risk patients compared with placebo and lifestyle changes. Sibutramine has previously been used as an appetite suppressant. A recent study, the Sibutramine Cardiovascular OUTcomes (SCOUT) trial, conducted to assess the drug's cardiovascular safety in high-risk patients, demonstrated a 16% risk increase for the time from randomization to the first occurrence of a primary CVD event. The study also showed a 28% increased risk for nonfatal myocardial infarction (MI), and 36% for nonfatal stroke, although the rates for cardiovascular death and death from any cause were not increased. For these reasons the drug was recently withdrawn from the market in the US, Canada, and Europe. According to the National Institute of Health (NIH) guidelines on obesity, pharmaceutical therapy for weight loss can be considered in patients with a BMI ≥30 kg/m2 or ≥27 kg/m2 in the presence of co-morbidities related to excess adiposity. In more severe cases of BMI ≥40 kg/m2 or ≥35 kg/m2 in the presence of significant co-morbidities, bariatric surgery may be considered.[9,60]
In addition to weight loss, multifactorial intervention including IR reduction and normoglycemia, management of dyslipidemia, lowering BP and administration of low-dose aspirin for patients at high or moderately-high CVD risk (10-year CVD risk ≥10%) is advisable. Although no pharmacologic agent is currently approved to raise insulin sensitivity, metformin has been shown to reduce the progression to type 2 DM in patients with impaired glucose tolerance (IGT). However, there are no cardiovascular end-point studies in patients with MetS treated with metformin. Thiazolidinediones (pioglitazone, rosiglitazone) may be an alternative option for insulin sensitivity. Pioglitazone seems to have a more beneficial effect than rosiglitazone on the plasma lipid profile. In a recent randomized-controlled prospective study in adults with IGT pioglitazone reduced the risk of conversion of IGT to type 2 DM by 72% compared with placebo, although it was associated with significant weight gain and edema. In another prospective trial, pioglitazone significantly reduced the risk of death, nonfatal MI and stroke compared with placebo in patients with type 2 DM. On the other hand, rosiglitazone has been removed from the treatment algorithm of the American Diabetes Association and the European Association for the Study of Diabetes since it significantly increased the risk of MI and death from CVD. Of note, significant concern has risen recently for pioglitazone due to a reported association with bladder cancer.
In terms of dyslipidemia, LDL-C should be the main target of cholesterol-lowering therapy. Each 10% decrease in LDL-C or 10% increase in HDL-C is associated with an 11% risk decrease for CVD. Initiating treatment for LDL-C depends on the absolute CVD risk based on the number of risk factors present and the Framingham score. For lower-risk patients (presence of 0-1 major risk factors and an estimated 10-year CVD risk of <10% according to the Framingham score), the LDL-C goal is <160 mg/dl. For moderate-risk patients (presence of ≥2 risk factors and an estimated 10-year CVD risk of <10%), the LDL-C goal is <130 mg/dl. For moderately high-risk patients (presence of ≥2 risk factors and an estimated 10-year CVD of 10–20%), the LDL-C goal is <130 mg/dl, optionally <100 mg/dl. For high-risk patients [presence of coronary heart disease (CHD) or equivalent co-morbidities such as non-coronary forms of clinical atherosclerotic disease, DM, and multiple (≥2 CVD risk factors with an estimated 10-year risk of >20%], the LDL-C goal is <100 mg/dL, optionally <70 mg/dL when both CHD and DM are present. A secondary target of cholesterol-lowering therapy is non-HDL-C. When TG levels are ≥200 mg/dl and the LDL-C goal has been achieved, the aim should be to decrease non-HDL-cholesterol to 30 mg/dl greater than LDL-C.
Statins are the mainstay of treatment of dyslipidemia in MetS. They are the major LDL-C-lowering agents and reduce LDL-C by 25–45% depending on the dose and specific type of statin used. Statins also increase HDL-C by 5–10% and reduce TG by 7–30%.[4,9] They have several other effects independent of lipid-lowering, which include modulating endothelial function, stabilizing plaque and anti-inflammatory and antithrombotic effects, which further contribute to reducing the CVD risk associated with these drugs. These pleiotropic actions have been shown in patients with impaired fasting glucose or IGT and the MetS. Interestingly a recent Greek study comparing the estimated CVD (e-CVD) risk in patients with MetS when achieving LDL-C <100 mg/dl or <130 mg/dl by atorvastatin, showed greater reductions in e-CVD risk and actual CVD risk when the goal was <100 mg/dl. The reductions at 6 months were >50% in all patients and were even greater during the next 3 years.
If the LDL-C goal is not achieved, other lipid-lowering drugs can be added to statins depending on the lipid profile of the individual patient. Ezetimibe or bile acid sequestrants such as colesevelam are effective in lowering LDL-C by 15–20%. Plant sterols and stanols, which are available as food additives in a variety of dairy products, including margarine and yogurt, have a modest effect on LDL-C in combination with statins. Moreover, fibrates decrease TG levels by 25–50% and LDL-C by up to 30% and increase HDL-C by 5–15%.[4,9] Fibrates, especially gemfibrozil, reduce CVD end points in patients with atherogenic dyslipidemia and MetS. Omega-3 polyunsaturated fatty acids are particularly efficacious in lowering TG, decreasing these by 20–40%, although they raise LDL-C by 5–10% with no effect on HDL-C.[4,9] Finally, niacin is another alternative for reducing TG and non-HDL-C, either as monotherapy or in combination with LDL-C-lowering agents. It is the most potent agent for elevating HDL-C (5–15%), and for increasing the particle size of HDL-C.[4,9,72] It is also the only drug that lowers lipoprotein (a) levels in diabetics.
Additional targets in order to minimize CVD risk in patients with MetS are reducing BP to <130/80 mmHg in patients with coronary heart disease, DM or chronic kidney disease, whereas for patients without these co-morbidities the target is <140/90 mmHg (preferably with angiotensin II converting enzyme inhibitors or angiotensin II receptor antagonists). In addition, low-dose aspirin is advisable for patients at high or moderately-high risk (10-year CHD risk of 10% or more).[4,9] For lower-risk patients, the benefit of aspirin must be weighed against the risk of hemorrhage.
MetS seems to affect about one-fourth to one-fifth of the Mediterranean population, with an increasing prevalence with age, being similar for both sexes and depending on the region and the definition used. The NCEP-ATPIII definition is the most effective in the identification of glucose intolerance and CVD risk. Except for these, MetS is associated with fatty liver disease, some forms of cancer, hypogonadism and vascular dementia. The Mediterranean diet seems to be an ideal diet in patients with MetS, being rich in fibre, monounsaturated and polyunsaturated fats and low in animal protein. It decreases the prevalence of both MetS and CVD risk. In addition to weight loss, multifactorial intervention, including IR reduction and normoglycemia, management of dyslipidemia, optimizing BP and administration of low-dose aspirin for patients at high or moderately-high CVD risk, should be considered.
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Conflict of Interest: None declared.