Cristina Bianchi, M.D., Department of Endocrinology and Metabolism, University of Pisa, Italy, E-mail: c.bianchi[at]ao-pisa.toscana.it

The metabolic syndrome (MS), a cluster of metabolic abnormalities, including abdominal obesity, glucose intolerance, hypertension, and dyslipidemia, carries an increased risk for cardiovascular disease and type 2 diabetes mellitus (T2DM) [1]. Since the main cause for the increase in MS appears to be related to changes in lifestyle, the best strategy to limit MS in the general population and reduce the risk of T2DM and cardiovascular disease should be the treatment of obesity, encouragement of physical activity, and healthier diet [2]. Even modest weight loss can significantly reduce blood pressure, improve lipid profile, and has been demonstrated to prevent T2DM development [3-4]. According to recent evidence-based nutritional recommendations for treatment and prevention of MS [5], protein should contribute for 10-20% of total daily energy; saturated fatty acids and trans unsaturated fatty acids should be ≤ 10% of total energy and further lowered to < 8% if serum LDL-cholesterol level is increased; cholesterol intake should be 300 mg or less per day; carbohydrates should range between 45-60% of total energy. Vegetables, legumes, fruits, and whole-grain cereals represent the most appropriate sources of carbohydrate. Foods rich in dietary fiber are strongly recommended, with a total dietary fiber intake ≥ 40 g/d (or 20 g/1000 kcal/d) with about half in soluble form. Sodium restriction can reduce systolic blood pressure in hypertensive patients. Moreover, 30 minutes of walking a day should be implemented in all overweight subjects.

However, lifestyle modifications, although powerful, is difficult to implement and maintain so that pharmacotherapy may be necessary. In such cases, first-line therapy should be directed toward major cardiovascular risk factors: LDL-cholesterol, hypertension, T2DM, and obesity [2].

In spite of the fact that elevated serum concentration of LDL-cholesterol are not necessarily associated with MS, LDL-cholesterol should be considered the primary target of treatment, because of the high cardiovascular risk of these individuals [2]. Consequently, an intensive control of LDL level by adequate use of statins is mandatory, while in patients with atherogenic dyslipidemia combination therapy is often required [2].

Several options are available for control of hypertension and often a multi-drug treatment is necessary [6]. This treatment should be, whenever possible, neutral with respect to the accompanying disturbances of the MS. The choice of agents that interfere with the renin-angiotensin system (angiotensin-converting enzyme inhibitors ─ ACEIs and angiotensin-II-receptor blockers ─ ARBs) may be recommended because of metabolic neutrality and possible interference of AT1 receptor antagonist with the PPAR-g signaling pathway [7].

Disturbances of glucose metabolism are often present in people with MS and conversely MS is frequent in subjects with abnormal glucose regulation or diabetes [8]. Though many anti-diabetic treatments can be used to improve glycemic control, the strict association between insulin-resistance, T2DM, and MS suggest that insulin sensitizer drugs, such as metformin and thiazolidinediones, may represent a rational first-line treatment of patients with T2DM [9]. Metformin and rosiglitazone can also help to prevent diabetes in people at risk of the disease [10,11]. Within the Diabetes Prevention Program study, metformin reduced the incidence of MS by 17% compared with placebo, though, similar to what was found in terms of T2DM prevention, this effect was lower than that obtained with lifestyle modification [12].

Obesity and visceral obesity in particular, is considered a main driver involved in the growing prevalence of MS all over the world. Though sibutramine and orlistat may be potentially useful in improving the metabolic picture in obese patients with MS [13], much interest has been generated by rimonabant, the first inhibitor of CB1 receptors. Its effects have been assessed in the Rimonabant in Obesity (RIO) trials that evidenced a significant improvement of all metabolic parameters in obese subjects with or without dyslipidemia or diabetes [14]. The importance of effective weight reduction is also supported by initial results obtained in massive obese individuals undergoing bariatric surgery [15].

Even if no specific drug is yet available to reduce the inflammatory state accompanying MS, a number of agents commonly used in these patients, including statins, nicotinic acid, fibrates, ACEIs, and thiazolidinediones, may exert an anti-inflammatory action [16-17]. At the same time, a pro-coagulative state characterizes individuals with MS due to elevation of the circulating levels of fibrinogen, factor VII, PAI-1, as well as increased platelet aggregation. At present, no specific drugs are available for treatment of the prothrombotic state, though a therapeutic option is low-dose aspirin or other anti-platelet agents [18].

Treatment of the MS focuses primarily on therapeutic lifestyle changes supplemented with pharmacotherapy in selected circumstances. As we progress in the understanding of the pathophysiology of the MS, new targets of therapies likely will be identified and new treatments will prove to be even more efficacious than those currently available for the management of this condition.

References

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