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Prevention and Treatment of the Metabolic Syndrome

December 5, 2004

The prevalence of the metabolic syndrome is increasing owing to lifestyle changes leading to obesity. This syndrome is a complex association of several interrelated abnormalities that increase the risk for cardiovascular disease and progression to diabetes mellitus (DM). Insulin resistance is the key factor for the clustering of risk factors characterizing the metabolic syndrome. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III defined the criteria for the diagnosis of the metabolic syndrome and established the basic principles for its management. According to these guidelines, treatment involves the improvement of the underlying insulin resistance through lifestyle modification (eg, weight reduction and increased physical activity) and possibly by drugs. The coexistent risk factors (mainly dyslipidemia and hypertension) should also be addressed. Since the main goal of lipid- lowering treatment is to achieve the NCEP low-density lipoprotein cholesterol (LDL-C) target, statins are a good option. However, fibrates (as monotherapy or in combination with statins) are useful for the treatment of the metabolic syndrome that is commonly associated with hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) levels. The blood pressure target is < 140/90 mm Hg. The effect on carbohydrate homeostasis should possibly be taken into account in selecting an antihypertensive drug. Patients with the metabolic syndrome commonly have other less well-defined metabolic abnormalities (eg, hyperuricemia and raised C- reactive protein levels) that may also be associated with an increased cardiovascular risk. It seems appropriate to manage these abnormalities. Drugs that beneficially affect carbohydrate metabolism and delay or even prevent the onset of DM (eg, thiazolidinediones or acarbose) could be useful in patients with the metabolic syndrome. Furthermore, among the more speculative benefits of treatment are improved liver function in nonalcoholic fatty liver disease and a reduction in the risk of acute gout.

Introduction

The metabolic syndrome is essentially a group of interrelated metabolic abnormalities that increase the risk of cardiovascular events and progression to diabetes mellitus (DM). Insulin resistance is believed to be the key factor for the pathogenesis of the metabolic syndrome.1 However, this condition is influenced by a complex interplay between multiple genetic variations interacting with numerous environmental factors.1

A number of definitions of the metabolic syndrome have been proposed. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III defined the diagnostic criteria of the metabolic syndrome (Table I).2 The prevalence of the metabolic syndrome is rapidly increasing.2,3 For example, more than 20% of participants in the Third National Health and Nutrition Examination Survey (NHANES III) had the metabolic syndrome.3

Basic Principles for the Treatment of the Metabolic Syndrome

According to the NCEP ATP III guidelines, the metabolic syndrome is a secondary target for risk reduction therapy.2 The proposed principles for treatment of the metabolic syndrome are shown in Table II. Treatment of the metabolic syndrome involves improvement of the underlying metabolic abnormality (ie, insulin resistance), which can be achieved by lifestyle modification (weight reduction and increased physical activity) and possibly by drugs (eg, thiazolidinediones, which may also improve dyslipidemia and blood pressure). Coexistent risk factors (eg, hypertension and dyslipidemia) should be treated.2 However, the lowdensity lipoprotein cholesterol (LDL-C) level remains the main target of treatment in high-risk patients, including those with the metabolic syndrome. The LDL-C goal varies according to the severity of risk2 (Table II). These patients also commonly have hypertriglyceridemia and low levels of high-density lipoprotein cholesterol (HDL-C); these lipid abnormalities may need to be addressed.2

Table I. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria for the diagnosis of the metabolic syndrome.2

Lifestyle Modification

A priority of treatment is weight reduction and encouraging physical activity. Changes in lifestyle among subjects with impaired glucose tolerance (IGT) were followed by a decrease in the incidence of DM.4,5

In one study,4 522 overweight subjects (body mass index [BMI] = 31 kg/m^sup 2^) with IGT were assigned to either an intervention group (dietary advice, individualized counseling aimed at weight reduction and increasing physical activity) or a control group. The mean follow-up was 3.2 years. The mean ( SD) weight loss between baseline and the end of year 2 was 3.5 5.5 kg in the intervention group and 0.8 4.4 kg in the control group (p < 0.001). The cumulative incidence of DM after 4 years was 11% (95% confidence interval [CI]: 6-15%) in the intervention group and 23% (95% CI: 17- 29%) in the controls. According to the Cox regression analysis of all personyears accumulated, the cumulative incidence of DM was reduced by 58% (p < 0.001) in the intervention group.4 This reduction was directly associated with changes in lifestyle.4

A larger study5 assigned 3,234 nondiabetic persons with elevated fasting and postload plasma glucose concentrations to placebo, metformin (850 mg twice daily), or lifestyle-modification (weight loss and increased physical activity). The mean BMI was 34 kg/m^sup 2^. The average follow-up was 2.8 years. Lifestyle intervention reduced the incidence of DM by 58% (95% CI: 48-66%) and metformin by 31% (95% CI: 17-43%), as compared with placebo. Therefore, lifestyle intervention was more effective than metformin since the incidence of DM differed significantly among the 3 groups (p < 0.001 for each comparison).5

Weight loss is of primary importance for the management of the metabolic syndrome. Studies have shown that even a modest weight reduction (in the range of 5% to 10% of initial body weight) is associated with a significant improvement in several components of the metabolic syndrome (eg, hypertension, dyslipidemia and glycemic status).6-9 Diet is a critical component of treatment since energy- restricted diets can reduce weight and improve the lipid profile, glycemic status, and blood pressure.10 Moreover, high-fat diets are associated with insulin resistance with saturated fatty acids having the most deleterious effect.9 Furthermore, transaturated fatty acids also exhibit adverse effects on insulin action.9 On the other hand, co-3 fatty acids appear to improve insulin sensitivity.11 The importance of the Mediterranean diet has also been emphasized.12 Thus, the Lyon study showed that after 46 months there was a 50-70% lower risk for recurrent heart disease in patients consuming a Mediterranean diet rich in a-linoleic acid as compared to those on a prudent Western-type diet.13 Similarly, another study showed that men following a typical Western diet (rich in red meat, processed meat, French fries, high-fat dairy products, refined grains, and sweets or desserts) were 60% more likely to develop DM than those consuming a diet rich in vegetables, fruits, whole grains, fish and poultry.14

Table II. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines for the management of the metabolic syndrome.2

Some studies suggest that low-fat/high-carbohydrate diets have not been shown to decrease insulin resistance and may even accentuate some of its metabolic manifestations.15,16 An important question is whether the changes observed while on high-carbohydrate/ low-fat diets are beneficial or deleterious with regard to cardiovascular risk. The paradox of improvements with some measures at the same time as worsening with other measures leaves the net effect open to controversy.15 Although there is some debate regarding this issue, it has been proposed that substituting unsaturated fat for saturated fat, without increasing the intake of dietary protein or carbohydrate, may be useful for patients with hypercholesterolemia, metabolic syndrome, or both.16

The nutrient composition of the diet recently proposed by the NCEP ATP III is shown in Table III. In this setting, continuing long- term behavioral therapy with social support strategies could improve achieving and maintaining weight loss.2,17,18

Medications for the treatment of obesity are approved19 for use in adults with a BMI of > 27 kg/m^sup 2^ with overweight-related medical conditions or a BMI > 30 kg/m^sup 2^ without obesity comorbidities. These drugs can be considered as an adjunct to diet and physical activity when these measures are ineffective after 12 weeks. Currently, there are 2 drugs that can be used for longterm weight loss:

1. Sibutramine: A selective inhibitor of the reuptake of both serotonin and epinephrine. It decreases food intake (by inducing a feeling of satiety after eating) and increases thermogenesis. The latter is a useful property because of the decline in the metabolic rate that accompanies weight loss.20

2. Orlistat: an inhibitor of lipase, which decreases intestinal fat absorption.21

Physical activity along with diet modification is of primary importance for the long-term treatment of the metabolic syndrome. However, physical activity requires education and commitment.22 Physical activity is a key factor \in successful weight reduction programs, although the effects of exercise on weight loss are less dramatic than those of caloric restriction.23 Nevertheless, physical activity can beneficially affect qualitative and quantitative lipoprotein abnormalities, carbohydrate intolerance, and hypertension.24,25

Table III. Nutrient composition of the therapeutic lifestyle change (TLC) diet.2

Treatment of the Dyslipidemia Associated with the Metabolic Syndrome

Since the main target of treatment of dyslipidemia is LDL-C lowering, the statins are the firstchoice drugs.2,26 Moreover, an analysis of the 4S study demonstrated that patients with a lipid profile characteristic of the metabolic syndrome (low levels of HDL- C and raised triglycerides [TG]) showed a better response to simvastatin when compared with the other subjects.27

Statins may beneficially affect carbohydrate metabolism. Thus, in WOSCOPS,28 patients on pravastatin had a lower risk of developing DM compared to the placebo group. These results may be related to the lower risk of cardiovascular events in statin-treated patients and subsequently to a lower use of drugs, such as -blockers, that exert an unfavorable effect on carbohydrate tolerance. Furthermore, statins have antiinflammatory effects and they decrease the levels of cytokines that may be implicated in the pathogenesis of insulin resistance (this topic is discussed below). Statins also induce a modest decrease in TGs that could lead to improved carbohydrate tolerance.29 However, the effect of pravastatin on carbohydrate homeostasis in WOSCOPS28 was derived from a post-hoc analysis and is based on a small number (n = 139) of patients. Moreover, in other trials, such as the Heart Protection Study (HPS), there was no significant difference between the treatment groups (4.6% simvastatin vs 4% placebo, p = 0.10) in the number of subjects who developed DM.30

In most cases, statins do not cause major changes in TGs and HDL- C, the main lipid abnormalities associated with the metabolic syndrome.2,31 The NCEP ATP III guidelines2 introduced a secondary target of lipid-lowering treatment in patients with triglyceride (TGs) ranging from 200 mg/dL (2.26 mmol/L) to 499 mg/dL (5.6 mmol/ L). In these cases, some of the TG-rich lipoproteins are as atherogenic as LDL-C and should be lowered. The levels of very low- density lipoprotein cholesterol (VLDL-C) (normal value < 30 mg/dL [0.78 mmol/L]) are a reliable marker of the concentration of these atherogenic particles. Thus, the goal of treatment is based on nonHDL-C levels (VLDL-C + LDL-C = total cholesterol - HDL-C) in each of the 3 categories of coronary heart disease (CHD) risk2,26 (Table II). Studies have shown that the administration of relatively high doses of statins lower not only LDL-C but also TG levels in patients with mixed dyslipidemia.32,33 The TG-lowering effect of statins is related to the drug dose (higher doses evoke greater changes) and the baseline TG value (greater decreases in patients with higher baseline values).32,33 The NCEP ATP III guidelines2 also state that at TG levels = 500 mg/dL (5.6 mmol/L) the priority of treatment shifts away from LDL-C to correcting the hypertriglyceridemia. This is because of the high risk of acute pancreatitis.2

Patients with the metabolic syndrome commonly have low HDL-C levels, an independent risk factor of coronary heart disease (CHD), especially in the presence of other risk factors.34,35 A target value for low HDL-C was not defined in the NCEP ATP III guidelines owing to insufficient data on which to base recommendations. Nevertheless, the NCEP ATP III recommended2 lifestyle changes in patients with low HDL-C levels. However, an International Expert Panel36 concluded that every effort should be made in order to increase HDL-C levels to >40 mg/dL (1.0 mmol/L), especially in patients with DM or the metabolic syndrome. Drugs, such as fibrates and niacin are useful in raising HDL-C levels.2 Primary and secondary prevention trials37-42 also suggest that fibrates induce a substantial decrease in cardiovascular morbidity and mortality in patients with the characteristics of the metabolic syndrome. A post- hoc analysis of the Veterans Affairs High-density lipoprotein Intervention Trial (VAHIT) has shown that the decrease in cardiovascular events may be related to an increase in HDL-C levels (an 11% decrease in events for every 5 mg/dL [0.13 mmol/L] increase in HDL-C).39-41 In VA-HIT,42 in men with CHD and a low HDL-C, gemfibrozil was associated with a reduction of major cardiovascular events, mainly in diabetic patients as well as in nondiabetic patients with a high fasting plasma insulin level. This finding42 suggests that subjects with features of the insulin resistance syndrome may be more likely to benefit from a fibrate. Furthermore, in a post-hoc analysis of the Helsinki Heart Study,38 the effect of gemfibrozil was largely confined to individuals with a BMI > 26 kg/ m^sup 2^, and among these overweight subjects the greatest risk reduction was found in those with increased TGs and low HDL-C levels. In the Bezafibrate Infraction Prevention (BIP) Trial37 even though bezafibrate did not significantly decrease overall cardiovascular events, patients with TGs above 200 mg/dL (2.26 mmol/ L) had a significant relative risk reduction (by 40%).

Monotherapy often cannot lower non-HDL-C levels to established goals.2 Thus, the combination of statins with fibrates may prove particularly effective in this setting.31,43,44 However, combination drug treatment should be administered cautiously since there may be an increased risk of myositis and rhabdomyolysis.44,45 The addition of ezetimibe to statins could be an attractive option in patients with the metabolic syndrome to achieve the LDL-C target. This selective cholesterol transport inhibitor that can be added to statins induces an additional incremental LDL-C reduction (approximately 20%) and also a small decrease in TGs (6-8%) and increase HDL-C (2-3%) levels.31,44,46 Trials combining fibrates and ezetimibe are in progress.44

Although niacin can adversely affect carbohydrate homeostasis, it could be used in patients with the metabolic syndrome.47 Results from the Coronary Drug Project showed that niacin reduced cardiovascular morbidity and mortality in a high-risk population.48

Fish oils can decrease TGs in patients with the metabolic syndrome.31,49 Fish oils have been evaluated in combination with statins.31,49

Treatment of Hypertension Associated with the Metabolic Syndrome

According to the recently published hypertension guidelines, the target of antihypertensive treatment is the reduction of blood pressure to lower than 140/90 mm Hg.50,51 A potentially important aspect of selecting the correct antihypertensive drug in patients with the metabolic syndrome may relate to the effect of these agents on carbohydrate metabolism.52 Thus, diuretics in high doses may stimulate both sympathetic nervous system activity and the renin- angiotensin system, while long-term administration has been associated with dyslipidemia and increased insulin resistance. 53,54 However, diuretics in lower doses (equivalent to 12.5 mg of hydrochlorothiazide) are useful and effective antihypertensive drugs (in monotherapy or in combination with other agents) and are associated with a low incidence and severity of metabolic side effects.55 Thus, in the Prospective Atherosclerosis Risk in Community (ARIC study) the use of thiazides was not associated with an excess risk of subsequent DM in comparison with the risk in patients not receiving antihypertensive therapy (after 3 and 6 years of follow-up).56 Similarly, patients on angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) were not at greater risk than those not taking any medication.56 In contrast, patients who were taking blockers had a 28% higher risk of subsequent DM.56 Moreover, in the Trial of Antihypertensive Intervention and Management (n = 878), the administration of chlorthalidone in mildly hypertensive obese patients was followed by a greater decrease in body weight (6.9 kg) as compared to the administration of atenolol (3.0 kg) or placebo (4.4 kg) at 6 months.57

ß-Blockers reduce cardiac output and renin activity as well as cardiovascular morbidity and mortality in hypertensive patients, including diabetic patients.50,51,58 Moreover, ß-blockers are the drugs of choice in patients with CHD.50-51 However, these drugs may interfere with carbohydrate and lipid metabolism. Thus, in the prospective ARIC study56 the use of -blockers was associated with a 28% greater risk of subsequent DM compared to the risk in those taking no medication. The adverse effects of ß-blockers on carbohydrate tolerance may be related to the decrease in blood flow through muscle leading to reduced glucose uptake.59 Thus, ß- blockers with a simultaneous agonist effect on ß^sub 2^- adrenergic receptors may affect insulin sensitivity to a lesser extent that nonselective ß-adrenergic agonists. For example,60- 62 the new generation of vasodilating ß-blockers, such as nebivolol, celiprolol, and carvedilol, improve peripheral vascular resistance and insulin resistance in nonobese individuals. Moreover, ß-blockers can induce weight gain resulting in a disturbed glucose tolerance.57,63 These drugs64 may also attenuate the ß- receptor-mediated release of insulin from pancreatic ß-cells. This first phase of insulin secretion may play an important role in controlling postload glycemia.65 ß-Blockers also seem to attenuate insulin clearance in insulin-resistant patients, resulting in hyperinsulinemia, which can further down-regulate the insulin receptors inducing decreased insulin sensitivity.66-68

In contrast to ß-blockers, ACEIs can increase insulin- stimulated glucose disposal in diabetic or hypertensive patients.69 Two large trials, the Heart OutcomePrevention Evaluation (HOPE)70 and the Captopril Prevention Project71 showed that ACEI administration was associated with a reduced risk of developing type- 2 DM. These drugs may exert their beneficial effects72-74 on carbohydrate metabolism by improving blood flow through skeletal muscle, thereby increasing the delivery of insulin and glucose or by improving insulin action at the cellular level. ACEIs may be the drugs of choice in obese hypertensive patients with insulin resistance who may exhibit renal hyperfiltration with microalbuminuria, congestive heart failure (CHF) and left ventricular hypertrophy, conditions known to be improved by ACEIs.75,76 For example, in obese hypertensive patients adequate and similar blood pressure control was achieved with perindropril and atenolol.77 However, only perindropril was associated with a more favorable effect on glucose and insulin metabolism; this was associated with a significant regression of left ventricular hypertrophy.77

A number of studies suggested that angiotensin receptor blockers (AIIRBs) also increase insulin sensitivity. Therefore, these drugs are an alternative to ACEIs in hypertensive patients with insulin resistance.78,79 In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, losartan administration was followed by a significantly decreased (by 25% [95% CI: 12-37%] ; p = 0.001) incidence of DM when compared with atenolol.80

Calcium channel blockers (CCBs)81 are effective antihypertensive drugs without adverse metabolic effects. Thus, in the prospective ARIC study56 CCBs were not associated with an excess risk of developing DM. There was also no difference in the incidence of new DM in the NORDIL trial,82 which compared the effect of diltiazem with that of diuretics, ß-blockers, or both. Furthermore, in the Swedish trial in old patients with hypertension (STOP HYPERTENSION-2),83 there was no difference in the rate of DM among the treatment groups. However, in the INSIGHT84 trial, there was a significant difference in the incidence of DM among patients receiving nifedipine compared to those taking coamilozide (4.3% vs 5.6%, respectively, p = 0.023).

The sympathetic nervous system is implicated in the pathogenesis of hypertension in the insulin-resistance syndrome. Thus, centrally acting agents, such as moxonidine, may potentially be useful in these cases. Studies have shown that moxonidine or rilmenidine may improve insulin sensitivity not only in experimental hypertension, but also in patients with the metabolic syndrome.85,86 However, clonidine administration was followed by a marked reduction of both resting metabolic rate and the thermic response to food, effects that may contribute to net positive energy and weight gain in obese patients.87,88

Table IV. Metabolic abnormalities in patients with metabolic syndrome associated with insulin resistance/hyperinsulinemia.

Studies have shown that a-blockers improve carbohydrate and lipid metabolism.8991 However, in the doxazosin arm of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),92 patients treated with doxazosin had a 25% increased risk of developing cardiovascular events compared to those receiving chlorthalidone. Thus, there are some concerns about the use of a-blockers in hypertensive patients.92 Nevertheless, such concerns should be related to the lack of thorough validation of CHF in ALLHAT. Perhaps this explains the markedly greater incidence of CHF in ALLHAT92 when compared with INSIGHT84 and the fact that mortality (9.62% for doxazosin and 9.08% for chlorthalidone) in the diuretic and a-blocker arms of ALLHAT did not differ significantly. It would have been expected that the greater incidence of CHF would have influenced mortality. Also, most of the CHF in ALLHAT occurred early in the trial-perhaps this was an expression of withdrawal of diuretics in some patients when joining the trial.

Management of Other Metabolic Abnormalities Associated with the Metabolic Syndrome

Patients with the metabolic syndrome commonly exhibit other metabolic abnormalities that may be related to an increased cardiovascular risk (Table IV).44,93,94 Thus, it seems reasonable to appropriately treat these abnormalities. Moreover, a number of commonly used drugs may influence specific features of the metabolic syndrome.95

Patients with insulin resistance often also have hyperuricemia,96 which has been proposed as an independent risk factor for CHD. Lifestyle modification can decrease serum uric acid (SUA) concentrations. Furthermore, drugs, such as losartan and fenofibrate, can increase urinary urate excretion, resulting in a fall in SUA levels.97-100 There is also evidence101-107 that statins (atorvastatin, simvastatin) can reduce SUA levels.

The relationship between hyperuricemia and insulin resistance may be indirect and mediated via increased fasting plasma TGs and BMI.108,109 It has been proposed that fasting serum TGs were the most important determinant of SUA levels. Thus, hyperuricemia appears to be an indirect part of the insulin resistance syndrome through its association with fasting hypertriglyceridemia.108 Furthermore, hyperinsulinemia may decrease the urinary excretion of uric acid.109,110 Therefore, it is perhaps expected that drugs that improve insulin sensitivity can lower SUA levels. For example, metformin in some, but not all, studies lowered SUA levels.111-114 However, sulfonylureas do not have a hypouricemic effect.115,116 Some studies showed that troglitazone improves insulin resistance and decreases SUA levels.117,118 However, troglitazone was withdrawn owing to rare but severe hepatotoxicity.119 Therefore, it is surprising that we could not find any studies dealing with SUA levels after the administration of pioglitazone or rosiglitazone, 2 thiazolidinediones in widespread use.

Sibutramine, a drug used for weight loss, can lower SUA levels (p < 0.01), TGs (p < 0.01) and ?GT (p<0.05).120,121 Therefore, this treatment could be useful in patients with the metabolic syndrome.121 Orlistat, another drug used for weight reduction, can also lower SUA levels.111 Raised fibrinogen and plasminogen activator inhibitor-1 (PAI-1, an inhibitor of fibrinolysis) levels are also frequently seen in patients with insulin resistance/ hyperinsulinemia.93,94 Although statins do not seem to consistently affect fibrinogen levels,122 fibrates (with the exception of gemfibrozil) can significantly decrease the circulating levels of this coagulation factor.123-126 However, the effects of both classes of hypolipidemic drugs on PAI-1 levels are not well established.127

Insulin resistance syndrome is also associated with hepatic steatosis (nonalcoholic fatty liver disease, NAFLD).128 Treatment of the metabolic syndrome, which included weight loss and the use of lipid-lowering or hypoglycemic drugs, may be associated with an improvement in liver enzymes.129 The improvement of liver function tests following the use of statins or fibrates suggests that these agents should probably not be avoided in patients with the metabolic syndrome and evidence of nonalcoholic fatty liver disease.130 It is well documented that fibrates can decrease serum alkaline phosphatase (ALP) and ?-GT activity, and this effect may be related to an amelioration of the underlying liver disease.131,132 This topic is discussed further in a dedicated section, below.

Additional Management Options to Prevent the Onset of Diabetes

Thiazolidinediones133 are peroxisome proliferator-activated receptor-gamma (PPAR-?) agonists that are insulin sensitizers used for the treatment of type-2 DM. These drugs may also prevent DM. The Troglitazone in the Prevention of Diabetes (TRIPOD) trial134 showed that in women with gestational DM (approximately 70% with IGT), troglitazone administration resulted in a > 50% reduction in progression to DM. The protective effect of the drug134 was associated with the preservation of pancreatic ß-cell function and appeared to be mediated by a reduction in the secretory demands placed on these cells by chronic insulin resistance. However, troglitazone has been withdrawn from the market. Other thiazolidinediones (eg, rosiglitazone, pioglitazone) in widespread use are not yet recommended for the management of nondiabetic patients with the metabolic syndrome or the prevention of DM. Nevertheless, thiazolidinediones have several useful actions. For example, they can ameliorate the lipid profile (decrease in TGs and small dense LDL and increase in HDL-C), decrease blood pressure, and reduce the expression of inflammatory markers, PAI-1 levels, platelet aggregation, as well as microalbuminuria.135 Thiazolidinediones also partially correct adipocyte production of PAI1 and angiotensin II secretion and improve endothelial function.136,137 It follows that we may eventually see these drugs used in patients with the metabolic syndrome.

Another effective approach to prevent DM in patients with insulin resistance is acarbose. Treatment with this a-glucosidase inhibitor in patients with IGT characterized by moderate post-prandial hyperglycemia resulted in a significant decrease (by 25%) in the incidence of DM.138

In the XENDOS study,139 3,305 patients were followed up for 4 years. They were randomized to lifestyle changes plus either orlistat 120 mg or placebo, 3 times daily. Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction (37.3%, p = 0.0032) in the incidence of type-2 DM over 4 years and produced greater weight loss (5.8 vs 3.0 kg with orlistat and placebo, respectively, p < 0.001) in an obese population. A difference in DM incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT and/or normal glucose tolerance.139 These beneficial effects may relate to the effect of orlistat (combined with dietary measures) on gluco\se, insulin and LDL-C levels.140

The Diabetes Prevention Trial-Type 1 (DPT-1) study141 (using insulin) and the European Nicotinamide Diabetes Intervention Trial (ENDIT)142 (with nicotinamide) failed to prevent or delay type-1 DM in people with a high-risk profile.

The judicious use of antihypertensive drugs may also decrease the risk of developing DM. The comparison of losartan vs atenolol (LIFE study) was already discussed above.80 Moreover, it is possible to speculate that diuretics, such as indapamide sustained release, that do not adversely influence insulin sensitivity are less likely to increase the risk of progression to DM.141 Similarly, antihypertensive treatment with a diuretic, if needed, combined with a ß-blocker, was associated with an aggravated metabolic profile; this was not so for patients treated with an AIIRB, if needed, combined with a CCB.143 There is evidence that the use of ß-blockers is associated with weight gain (of the order of 0.5- 3.4 kg).57,63,144 This weight gain appears to be sustained even after 3 years independently of age, gender, degree of physical activity, and discrepancies in the use of diuretics.144 The mechanisms responsible for this increase in weight are altered metabolism and decreased physical activity.144 The metabolic effects of ß-blockade possibly include a reduction in basal metabolic rate, reduction in the thermogenic response to meals, increased insulin resistance, and inhibited lipolysis.144 The physical activity mechanisms may include diminished exercise tolerance and purposeless movements.144 However, the decision to use a -blocker must be weighed against the established benefits of these drugs. Nevertheless, in obese hypertensive patients, especially if they have the metabolic syndrome, it may be prudent to consider a blood pressure-lowering drug from a different class unless there is a clear indication for a ß-blocker.144

Prediction of Diabetes

In the LIFE study145 the new onset of DM could be strongly predicted by a risk score using BMI, systolic blood pressure, baseline glucose level (nonfasting), HDL-C, and history of prior use of antihypertensive drugs. Patients in the atenolol group had an increasing 5-year risk for DM from the first to the fourth quartile of this risk score, namely, from 1% to 24%, respectively. The corresponding values for patients taking losartan were < 0.5% to 19%.145 The risk was higher in the atenolol group in all quartiles. This difference with losartan was significant (p = 0.02 to 0.04) for all quartiles except for the third.145

Inflammation and the Metabolic Syndrome

Visceral and subcutaneous adipose tissues are major sources of cytokines (adipokines). It follows that obesity is associated with overexpression of tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and PAI-1 and underexpression of adiponectin in adipose tissue.146 Therefore, inflammatory markers like C- reactive protein (CRP), PAI-I, and IL-6 are present in higher concentrations in those with insulin resistance than in healthy subjects.147-149 In turn, TNF-a can cause insulin resistance in obese subjects, and insulin has an antiinflammatory action.147 Thus, the interactions among obesity, insulin resistance, and inflammatory markers are complex.

The NHANES III150 showed that participants with the metabolic syndrome had higher CRP levels when compared with those with no metabolic abnormalities. Furthermore, the higher number of abnormalities of the metabolic syndrome involved, the higher the CRP value.150 This lowgrade inflammation probably contributes to the greater risk for cardiovascular events.150 This interpretation is supported by the evidence that CRP promotes atherogenesis via effects on monocytes and endothelial cells.148,149

In WOSCOPS151 (n = 5,974 men) the mean CRP was higher (p < 0.0001) in the 26% of men with the metabolic syndrome compared with those without. The metabolic syndrome predicted CHD events (HR = 1.30, 95% CI: 1.00-1,67, p = 0.045) in a multivariate analysis. Furthermore, men with 4 or 5 features of the metabolic syndrome had a 3.7-fold increase in risk for CHD and a 24.5-fold increase for DM, respectively, compared with men with none of these features (both p < 0.0001). CRP also enhanced prognostic information for both outcomes (ie, CHD and DM).151

In the Women's Health Study 27,939 US women with no history of cardiovascular disease were followed up for 8 years.152 Overall, 24% of the population had the metabolic syndrome at study entry. High- sensitivity (hs)-CRP levels gradually increased as more features of the metabolic syndrome were present (p<0.0001 for trend). Among those with the metabolic syndrome, ageadjusted event rates were 3.4 vs 5.9 per 1,000 person-years for those with hs-CRP levels < 3 mg/ Lvs > 3 mg/L (p < 0.001).152

The IRAS study also showed a linear increase in CRP levels with an increase in the number of metabolic abnormalities.153 However, the Mexico City Diabetes Study154 showed that inflammation is important in the pathogenesis of DM and metabolic disorders in women while CRP was not a significant predictor of the development of the metabolic syndrome in men.

Drugs that influence insulin sensitivity can alter CRP levels. For example, in well-controlled type-2 diabetics with the metabolic syndrome, those taking metformin had significantly (p = 0.01) lower CRP than those taking glibenclamide (5.56 and 8.3 mg/L, respectively).155 Metformin also improves metabolic disturbances in polycystic ovary syndrome (PCOS). Unlike ethinyl estradiol + cyproterone acetate, metformin significantly (p = 0.006) decreased serum CRP levels from 3.08 0.7 mg/L to 1.52 0.26 mg/L at 6 months in the whole study population and especially in obese subjects.155157 Thiazolidinediones, such as rosiglitazone and pioglitazone have an antiinflammatory and potentially antiatherosclerotic activity.135,147,158-160 Furthermore, troglitazone was more potent in reducing CRP and improving other metabolic abnormalities than metformin.160

A Brief Overview of Adipocyte-Secreted Hormones

A detailed discussion on this topic is beyond the scope of this review. Therefore, we only briefly comment on some hormones that may become therapeutic targets.

Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independently of total adiposity.161,162 Therefore, leptin gene therapy may become a therapeutic option in the future.163

Adiponectin is a protein produced exclusively by adipocytes with putative insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties.162,164 Adiponectin plasma levels are decreased in patients with the metabolic syndrome probably as a result of the accumulation of visceral adipose tissue. This hormone could serve as a convenient marker for identifying subjects with the metabolic syndrome who may progress to IGT.165 It has been proposed that administration of recombinant adiponectin could be a future therapeutic strategy for the metabolic syndrome and type-2 DM.166 There is also evidence demonstrating a relationship between small dense LDL particles and adiponectin.167 Ethnic variations in adiponectin levels have also been reported. For example, adiponectin levels were similar in Caucasian obese (7.0 0.8 mg/mL), African American obese (7.3 3.5 mg/mL), and African American nonobese women (7.1 1.2 mg/mL) but were significantly higher in Caucasian nonobese women (12.2 1.4 mg/mL).168

Resistin, a novel adipocyte-derived hormone, is associated with endothelial activation and it may therefore be linked to cardiovascular risk in the metabolic syndrome.162,169

There may be other neuroendocrine effects and a relative sympathetic predominance in patients with the metabolic syndrome.170 An abnormal regulation of the hypothalamic- pituitary-adrenal axis (eg, Cortisol and growth hormone) may also play a role.171,172 The rise of the cortisol, impaired gonadotropin, and growth hormone secretion may be associated with the metabolic syndrome. Therefore, these hormonal changes represent potential therapeutic targets.171,172

Interactions Between Established and Emerging Risk Factors and the Metabolic Syndrome

Ethnicity and Age

The risk of vascular events may be influenced by ethnicity. Therefore, it is of interest that there is a considerable ethnic variation in the incidence of the metabolic syndrome. For example, compared with Caucasians, Filipinas had a higher prevalence of the metabolic syndrome (34% vs 13%) and type-2 DM (36% vs 9%).173 The metabolic syndrome is common (19.8%) in Greece, a Mediterranean country,174 and it is present in more than 20-25% of the adult U.S. population.175,176 In the United Kingdom the metabolic syndrome has also been increasingly recognized,177 especially in South Asians.178 The metabolic syndrome is relatively common in residents of southwestern France. Specifically, the prevalence of the metabolic syndrome was higher in men than in women (23% vs 12%, respectively, p < 0.001) and increased with age in both sexes (9%, 24%, and 34% for age groups 35-44, 45-54, and 55-64 years for men and 4%, 10%, and 21% for women, respectively).179 In the Japanese population, the influence of lifestyle on serum lipid parameters appeared to be mostly expressed as a function of BMI in younger men, while it appeared to be independent of BMI in older men.180 Among Americans over 60 years old, the prevalence rises to 40% or more compared to 7% among adults aged 20 to 29 years.50,181 Therefore, the prevalence of the metabolic syndrome is age-dependent.

Smoking

Smoking is associated with increased insulin resistance and features of the insulin resistance syndrome.182 Furthermore, in men who smoke, the increased risk of developing DM is about 50%.182 In those who already have DM, it is likely that smoking adversely affects glycemic control and increases the risk of both microvasc\ular and macrovascular complications.182

In an euglycemic hyperinsulinemic clamp study, smokers had lower HDL-C and lipoprotein A-I levels but higher fasting TGs, as well as an increased proportion of small dense LDL-particles. Smokers also had higher levels of fibrinogen and PAI-1.183 The smokers were insulin resistant and lipid intolerant with an impaired TG clearance after a test meal.183 The postprandial lipid intolerance was also seen in individuals with normal fasting TG levels and was related to an increased prevalence of atherogenic small dense LDL.183 Therefore, insulin resistance is likely to be an important contributor to the increased vascular morbidity in smokers.183

Smoking cessation needs to be encouraged in patients with the metabolic syndrome since the benefits override the adverse effect of any accompanying increase in body weight.184 In this context, it is relevant that nicotine replacement therapy (NRT) exerts fewer adverse effects on insulin sensitivity than smoking.185,186

Passive smoking was associated with increased insulin sensitivity in one study.187 However, paradoxically, in the same study, current smoking was not associated with insulin resistance.187 This anomaly may reflect the selection criteria and small numbers of subjects in certain subgroups. In a recent study, secondhand smoke was associated with elevated inflammatory markers (eg, white cell counts, CRP, and fibrinogen) as well as oxidized-LDL and homocysteine (Hey) levels.188 The link between inflammatory markers and the metabolic syndrome was discussed in the section above dealing with inflammation.187,188 The link between smoking and insulin resistance has been reviewed elsewhere.189

Hypertriglyceridemia and Free Fatty Acids

Elevated TG levels are considered as predictors of vascular risk.190 However, in some patient groups the predictive power of raised TG levels may be increased. For example, in the Japanese population, hypertriglyceridemia and DM may be more important CHD risk factors than LDL-C.191 The response to drugs, such as ß- blockers, may differ among normal subjects and patients with the metabolic syndrome. For example, atenolol can induce a significant worsening of insulin resistance in patients with the metabolic syndrome but not in control subjects.192 Furthermore, antihypertensive treatment with a diuretic, if combined with a ß-blocker, was associated with a worsened metabolic profile (including increased TG levels and decreased HDL-C). In contrast, this was not so for patients treated with an AIIRB if combined with a CCB. Therefore, the type of medication can influence TG levels (fasting and postprandially) .143

Postmenopausal women with mixed hyperlipemia show a greater postprandial TG increase and a more pronounced reduction in HDL-C level and LDL size than hypercholesterolemic and normolipemic subjects.193 The presence of the features of insulin resistance syndrome could predict the deterioration of the postprandial lipemic response.193 In turn, postprandial lipemia may be another predictor of vascular risk that is increased in postmenopausal women.193194 Apolipoprotein E polymorphism and familial hypercholesterolemia can also influence fasting and postprandial TG levels.194,195

Among nondiabetic individuals, elevated plasma free fatty acid (FFA) concentrations are associated with an increased risk of CHD. However, a single fasting plasma FFA measurement does not appear to improve the ability to predict CHD onset in men when information on other risk factors is considered.196

Although fenofibrate markedly reduced plasma TG levels in patients with the metabolic syndrome, it did not lower concentrations or turnover rates of FFAs, nor did it change glucose or insulin responses to an oral glucose challenge. These findings indicate that fenofibrate modifies fatty acid metabolism either in the liver or in TGrich lipoproteins but not in adipose tissue.197

Administration of metformin, either as monotherapy or in combination with a sulfonylurea, improved glycemic control and led to a decrease in several vascular risk factors in patients (n = 31) with type-2 DM. These effects include lower fasting plasma glucose, FFA, TG, remnant lipoprotein cholesterol, and soluble vascular cell adhesion molecule-1 (sVCAM-1).198

There is also evidence for a link between fatty acid-induced lipid peroxidation (oxidative stress) and insulin resistance.199

Because statins can produce small changes in HDL-C and TG levels, they may "remove" 2 of the NCEP ATP III criteria for the diagnosis of the metabolic syndrome. In one study, following the use of simvastatin (40-80 mg) or atorvastatin (20-80 mg) for 36 weeks, 47.7% and 48.5%, respectively, of the patients with the metabolic syndrome at baseline no longer met > 3 criteria for this diagnosis.200 The combination of a fibrate with a statin may also exert a similar effect.44,201,202 Fibrinogen and Blood Viscosity

Elevated plasma fibrinogen levels predict an increased risk of vascular events.203 Therefore, it is of interest that patients with the metabolic syndrome had higher plasma fibrinogen concentrations and white blood cell counts than those without this syndrome.203 Fibrinogen level (r = 0.180, p < 0.001), leukocyte count (r = 0.162, p = 0.001), and CRP (r = 0.251, p < 0.001) were all highly significantly correlated to insulin resistance, but not to insulin secretion.203,204 Fibrinogen is also a marker of inflammation, and it is not unexpected that the circulating levels of this coagulation factor are elevated in patients with the metabolic syndrome.122,204 It is, therefore, surprising that statins consistently reduce CRP but not fibrinogen levels.122 The link between inflammation and the metabolic syndrome was discussed above.146-160

If hyperfibrinogenemia can be considered as a component of the metabolic syndrome, it would contribute to the increased cardiovascular risk associated with insulin resistance.205

The metabolic syndrome is also associated with a significant secondary increase of blood, plasma, and serum viscosity and a decrease of whole-blood filterability. There are correlations between hemorheologic variables and some aspects of this syndrome, such as central obesity (waist-to-hip ratio) and insulin resistance.178,206

Stroke, Dementia, and the Metabolic Syndrome

There is evidence showing that hypertension and both hypertriglyceridemia and low levels of HDL-C predict an increased risk of stroke.207 Therefore, it is not surprising that there is evidence of a strong consistent relationship of the metabolic syndrome with prevalent stroke.208 Furthermore, clustering of metabolic cardiovascular risk factors increases the risk of dementia (mainly dementia of vascular origin).209

Carotid Intima-Media Thickness

The metabolic syndrome is associated with increased intima-media thickness (IMT) of the common carotid and the common femoral artery (markers of early atherosclerosis).203,210,212

In patients with manifest vascular disease, the presence of the metabolic syndrome is associated with advanced vascular damage. Moreover, an increase in the number of components of the metabolic syndrome was associated with an increase in mean IMT (p for trend <0.001), lower anklebrachial pressure index (ABPI) (p for trend < 0.01) and higher prevalence of albuminuria (p for trend < 0.01).213

Alcohol Consumption

The relationship between alcohol consumption and insulin sensitivity was assessed in a prospective and cross-sectional study (the Bruneck study, 1990-1995, Italy).214 This study included 820 healthy, nondiabetic women and men aged 40-79 years. Fasting insulin concentrations in those who did not drink alcohol and subjects reporting low, moderate, and heavy alcohol intake were 12.4, 10.0, 8.7, and 7.1 mU/L, respectively (p < 0.001). Postglucose insulin concentrations and estimates for insulin resistance also followed the same pattern. Regular alcohol intake predicted multiple changes in vascular risk factors over a 5-year period including increased concentrations of HDL-C and apolipoprotein A-I, higher blood pressure, and decreased concentration of antithrombin III. These associations were in part attributable to the decrease in insulin concentrations observed among alcohol consumers. The authors concluded that insulin is a potential intermediate component in the association between alcohol consumption and vascular risk factors.214

The cross-sectional population-based Stockholm County study215 recruited 4,232 men and women. In women, the metabolic syndrome was significantly (p<0.05) more common in nondrinkers (20%) and less common among wine drinkers (8%, p<0.01) compared with a group with low alcohol intake. After adjustments, a significant lower odds ratio for the metabolic syndrome was seen in wine drinkers in women (OR = 0.60, p<0.05). The link between alcohol drinking behavior and lifestyle habits also reflects the complex relationship between alcohol and health.215

Light to moderate alcohol consumption is associated with a lower prevalence of type-2 DM and reduced insulin resistance in the severely obese. It follows that light to moderate alcohol consumption need not be discouraged in obese individuals.216

The link between alcohol intake and insulin sensitivity is not well defined. Several mechanisms have been proposed. For example, moderate alcohol consumption may improve insulin sensitivity by increasing plasma adiponectin levels.217 With use of a clamp technique, alcohol consumption was found to be independently and positively associated with insulin-mediated glucose uptake.218 Moderate alcohol consumption, estrogen replacement, and physical activity are associated with increased insulin sensitivity in female twins. The favorable effects of moderate alcohol consumption and physical activity on insulin sensitivity are partly mediated by lower abdominal adiposity.219,220

Lipoprotein(a)

Elevated lipoprotein(a) (Lp[a]) levels maypredict CHD and possibly stroke. Lp(a) levels are elevated in diabetic and nondiabetic android obese subjects.221 Lp(a) is poorly influenced by diet or lipid-lowering drugs.222 Only a few pharmacologie agents (eg, niacin, sex hormones, and the use of thyroxine in hypothyroid patients) can lower serum Lp(a) concentrations.221,222

Homocysteine

The relationship between plasma homocysteine levels and the metabolic syndrome remains controversial.176,223,224

Fibrates can elevate the circulating levels of Hey.225,227 The mechanism responsible for this effect is not defined although it may well be relevant that fibrates (with the possible exception of gemfibrozil) can raise plasma creatinine levels.225,226 It is therefore possible that these drugs reduce the clearance of Hey.225,226 There is also evidence that supplementation with folate and vitamin B^sub 12^ and B^sub 6^ markedly attenuates the Hcy- raising capacity of fibrates.227

Renal Function and Urinary Albumin Excretion

Patients with the metabolic syndrome have higher urinary albumin excretion (urine albumin/creatinine ratio, UACR), a marker of endothelial injury.228 Microalbuminuria is strongly and independently associated with central adiposity.229 It follows that the metabolic syndrome might be an important factor in the pathogenesis of renal disease.230 It is also of interest that the association of hs-CRP with UACR is predominately mediated through its correlation with the metabolic syndrome.223,231

The Menopause, Polycystic Ovary Syndrome, and Hormone Replacement Treatment

Current evidence points toward a lack of protection from vascular events in postmenopausal women receiving hormone replacement treatment (HRT).232 Moreover, HRT has been shown to exert both beneficial and adverse effects on predictors of vascular risk.233,235 It may not be widely appreciated that these effects vary according to which postmenopausal population is evaluated (eg, with and without DM) and which HRT product is used.233,235 Nevertheless, it has been proposed that the metabolic syndrome in postmenopausal women could be partly attributed to estrogen deficiency and may be reversible with HRT.236-239

The polycystic ovary syndrome (PCOS) is associated with a higher incidence of metabolic abnormalities, such as hyperinsulinemia and insulin resistance.239 There is some evidence that long-term estrogen + progestagen treatment improves parameters of the metabolic syndrome in PCOS.239 Similarly, metformin may be beneficial by contributing to weight loss, improving insulin action, and decreasing the CRP levels.155,240 Sibutramine was also effective in patients with PCOS.241

The metabolic syndrome was prevalent among postmenopausal women with CHD enrolled in the WAVE trial.242 Having the metabolic syndrome was not independently associated with changes in minimum lumen diameter or the development of new or progressing coronary lesions but did confer an increased risk of clinical cardiovascular events.242

The postprandial lipemia response in postmenopausal women was discussed in the section dealing with TG and FFAs, above.193

Sleep Apnea

It has been proposed that sleep apnea, which is associated with an increased risk of vascular events, may be a clinical manifestation of the metabolic syndrome.243,244

Psychiatric Drugs and the Metabolic Syndrome

Drugs used to treat psychiatric disorders may cause weight gain (reviewed elsewhere245). This phenomenon involves complex interactions (eg, between drugs and endogenous neurotransmitters).245 Because conditions such as depression are common, the selection of psychiatric drugs should be well informed so as to avoid unnecessary weight gain.245

Erectile Dysfunction and Metabolic Syndrome

The incidence of erectile dysfunction (ED) in diabetic men is high.246,247 However, there is also evidence that there may be a higher risk of developing ED in patients with insulin resistance.246,247 This link is somewhat expected since several vascular risk factors are also predictors of ED.246-248 Furthermore, patients with vascular disease are more likely to have ED.246-248

Human Immunodeficiency Virus and the Metabolic Syndrome

Insulin sensitivity varies widely in human immunodeficiency virus (HIV)-infected patients irrespective of protease inhibitor (PI) use.249 Although PIs can adversely affect insulin sensitivity and insulin secretion, these effects may be modest.249 Obviously, central obesity is not common in these patients.

Cancer and the Metabolic Syndrome

It is relevant to consider the association of obesity with an increased risk of cancer.250 The insulin/insulin-like growth factor (IGF) system may partly explain this effect.250 In addition, the metabolic syndrome is associated with a chronic inflammatory state, and the accompanying cytokine abnormalities may also contribute to tumor progression.250 An association between insulin and the etiology as well as prognosis in colon, prostate, pancreatic, and, particularly, breast cancer has been proposed.250 The potential link with liver cancer is discussed below.

Liver Disease and the Metabolic Syndrome

Elevated aspartate aminotransferase (AST) or alanine amino transferase (ALT) levels predict the presence of nonalcoholic fatty liver disease (NAFLD) if alternative chronic liver diseases are excluded and features of the metabolic syndrome are present.251,252 The prevalence of NAFLD varies from 10% to 40%. NAFLD is increasingly common in developed countries because of the high prevalence of obesity and type-2 DM.253,254 NAFLD includes the spectrum of simple steatosis to nonalcoholic steatohepatitis (NASH).

Steatohepatitis was found in 18.5% of markedly obese vs 2.7% of lean individuals in an autopsy study.253 Furthermore, the risk of steatohepatitis increased by 2.6-fold in those who had a history of type-2 DM.253 Dyslipidemia was found in > 90% of patients with NASH.253 Clark et al254 demonstrated that the majority (69%) of aminotransferase elevations in the U.S. population are unexplained but are strongly associated with central adiposity and various features of the metabolic syndrome. There are also significant associations between ?-GT and the components of the metabolic syndrome.255

The features of insulin resistance, such as obesity and DM, are more frequent in patients with cryptogenic cirrhosis and hepatocellular carcinoma than in age- and sex-matched patients with hepatocellular carcinoma complicating alcoholic or viral liver disease.253 This finding may be attributed to a proportion of patients with NASH progressing to advanced fibrosis, cirrhosis, liver failure, and liver cancer.256,257 In turn, NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role.253

Treatment with the insulin-sensitizing agent (eg, pioglitazone) can improve the biochemical and histologic features of NASH.256,257 These findings support the role of insulin resistance in the pathogenesis of NASH. Similarly, weight loss improved liver function tests in patients with a variety of liver diseases.258 Similarly, the use of lipidlowering drugs (statins or fibrates) can improve liver function tests, presumably by contributing to a decrease in hepatic fat content.130,259,260

Conclusions

The metabolic syndrome is associated with increased cardiovascular disease and all-cause mortality, even in the absence of baseline CHD and DM.1,261 In nondiabetic individuals older than 50 years with the metabolic syndrome176 the CHD risk might approach or even exceed 2% per year, the level that defines a CHD risk equivalent in the NCEP ATP III guidelines.2

The metabolic syndrome may precede the onset of type-2 DM by many years.262 It follows that early treatment of individuals with this syndrome might delay the onset of DM and its complications. Endothelial dysfunction, subclinical inflammation, and impaired fibrinolysis occur in the metabolic syndrome and may contribute to progression of macrovascular as well as microvascular complications.262,263

Because the prevalence of the metabolic syndrome is increasing,2,3 early diagnosis and appropriate management (lifestyle and drugs) should be a priority to reduce the risk of vascular events.264,265 An additional benefit of such treatment could be the prevention of progression to DM. More speculative benefits include improved liver function in patients with NAFLD and a reduction in the risk of acute gout.

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