The effect of management of the metabolic syndrome
Management of the metabolic syndrome is confounded by several issues. There is on-going debate over the definition, inclusion criteria and clinical status of the syndrome, and continuing questions regarding its etiology and pathogenesis. Presentation is highly heterogeneous, with different features emerging to different extents, often subclinically, challenging the imprecise boundary between ‘collective risk’ and ‘clinical disease’.
Life-style adjustments are acknowledged as fundamental to the management of metabolic syndrome and for prophylactic purposes when earliest features of the syndrome are observed. Present drug therapies are mostly directed against specific components of the syndrome (particularly obesity, Type 2 diabetes, dyslipidemia and raised blood pressure) when these become sufficiently severe to warrant intervention. Drug therapies that address aspects of the etiology and underlying pathogenesis have yet to gain acceptance for the general indication of metabolic syndrome (US ICD code 277.7) by either the regulatory authorities or prescribers. Thus, this short review will consider therapies used for each of the main components of the metabolic syndrome.
Visceral obesity is a common feature of metabolic syndrome that correlates independently with insulin resistance, Type 2 diabetes, low HDL, raised triglyceride, an increased proportion of small dense LDL, raised blood pressure, increased plasma plasminogen activator inhibitor (PAI)-1 antigen and adverse cardiovascular outcomes . Reducing visceral fat mass through diet, exercise, behavioral and healthy-living strategies has been shown to benefit all of these features of the syndrome, and to prevent or reduce progression. A reduction of visceral adipose mass has advantageous effects on several hemostatic and related vascular parameters, including increased blood flow to muscle, decreased plasma PAI-1 antigen and fibrinogen, and possibly decreases in circulating levels of factor (F)VII and factor XII. There is also evidence of improved endothelial function including reduced levels of adhesion molecules and chemoattractant proteins as well as the inflammatory markers, notably C-reactive protein (CRP), in individuals who shed visceral fat.
The antiobesity agents orlistat (gastrointestinal lipase inhibitor) and sibutramine (satiety-inducing serotonin-noraderenaline re-uptake inhibitor), used as adjuncts to dietary measures, can further reduce visceral fat mass as part of an overall reduction in adiposity. Improvements or delayed progression of the metabolic syndrome have been demonstrated with these agents, similarly to diet alone. However, little attention has been given to specific hemostatic parameters, and sibutramine may increase blood pressure. Preliminary accounts of a potential new antiobesity agent, rimonabant (cannabinoid receptor-1 inhibitor), which reduces visceral and other adipose depots, also indicate improvements in several features of the metabolic syndrome.
It is noted that visceral adiposity is by no means an obligatory feature of metabolic syndrome. Moreover, measuring waist circumference as a surrogate for visceral adiposity can sometimes disguise excessive abdominal subcutaneous adipose depots, especially in women.
Drug treatments against insulin resistance, notably metformin and thiazolidinediones, have been studied mostly in the context of impaired glucose tolerance (IGT) and Type 2 diabetes. They act by different mechanisms, resulting in some similar and some varying effects on the metabolic syndrome.
Metformin exerts insulin-dependent and -independent effects that counter insulin resistance, reduce basal hyperinsulinemia, and improve many of the associated cardiovascular risk factors of metabolic syndrome. Body weight is typically unchanged or reduced, facilitating non-pharmacological measures to decrease visceral adiposity. Metformin decreases progression of IGT to Type 2 diabetes, particularly in those who are younger and overweight. Dyslipidemic individuals often show a modestly improved lipid profile with decreased VLDL-triglyceride, sometimes a decrease in LDL and a small increase in HDL. Metformin does not usually affect blood pressure, although decreases have been reported, usually accompanying weight loss.
Metformin can increase endothelial-dependent and -independent vasodilation, and promote fibrinolysis . Plasma PAI-1 and fibrinogen are reduced along with FVII and factor XIII, and there is in vitro evidence that metformin can reduce thrombin activation and polymerization of fibrin. Metformin also reduces platelet aggregation, with reduced platelet factor 4 and β-thromboglobulin. There is a lowering of CRP, reduced production of several cellular adhesion molecules and reduced monocyte adhesion. Within the vascular wall monocyte differentiation into macrophages is reduced by metformin, and animal studies have shown reduced incorporation of lipid into cellular and extracellular components of plaque. Restenosis after stenting is less frequent in diabetic patients receiving metformin, and in vitro studies suggest that high concentrations of metformin can reduce proliferation of vascular smooth muscle. Perhaps the most telling clinical outcome data derive from the United Kingdom Prospective Diabetes Study (UKPDS), which found fewer myocardial events in Type 2 diabetic patients initially randomized to metformin: the effect was independent of the degree of glycemic control.
Thiazolidinediones (pioglitazone and rosiglitazone) improve insulin sensitivity mainly by stimulating the nuclear peroxisome proliferator-activated receptor-gamma (PPARγ). This is expressed mostly in adipose tissue, causing adipogenesis of new small insulin-sensitive adipocytes in subcutaneous depots. There is little apparent effect on the visceral depot but overall weight gain is usually observed . Improved glycemic control with reduced basal hyperinsulinemia is achieved partly through altered lipogenic-antilipolytic activity of the new adipocytes, lowering circulating free fatty acids and improving the glucose-fatty acid (Randle) cycle. Stimulating PPARγ also reduces production of several adipokines that cause insulin resistance (such as tumor necosis factor-α and resistin) while increasing adiponectin, which enhances insulin sensitivity and exerts anti-atherogenic effects. PPARγ is expressed to a small extent in other tissues, and this contributes directly to improved insulin action. Effects on the lipid profile vary: pioglitazone usually reduces triglycerides with little effect on total LDL, whereas rosiglitazone has little effect on triglycerides but may raise total LDL. Both thiazolidinediones reduce the proportion of small dense LDL and often slightly increase HDL. They also tend to produce a small decrease in blood pressure despite some fluid retention and lowered hemoglobin.
Thiazolidinediones improve vascular reactivity by endothelium-dependent and -independent effects, reduce production of angiotensin II and endothelin-1, and increase myocardial blood flow. They favor thrombolysis with reduced PAI-1 and fibrinogen, and exert several effects likely to reduce atherogenesis and plaque rupture. These include reductions of CRP, adhesion molecules and monocyte chemoattractants, vascular smooth muscle proliferation and matrix metalloproteinase-9 production. Intima-media thickness is reduced, as is restenosis after stenting in diabetic patients.
Amongst the multitude of antihypertensive agents, ACE inhibitors and angiotensin II receptor blockers (ARBs) have been tentatively credited with possible fibrinolytic activity. By reducing angiotensin II and bradykinin, ACE inhibitors appear to reduce PAI-1 and tissue-type plasminogen activator (t-PA), but it is unclear whether the ratio is altered. Some ARBs have been reported to decrease PAI-1 in the short term, but long-term data are not available.
Although the metabolic syndrome is associated with an increased proportion of small dense LDL rather than necessarily an increase in total LDL, it is appropriate to include statins here since they are so widely used in individuals with metabolic syndrome. It has been suggested that statins might exert some cardioprotective benefits beyond their cholesterol-lowering effect. Statins decrease expression of cell-bound tissue factor by macrophages in atheroma, but this may be compensated by decreased tissue factor pathway inhibitor. Claims that statins reduce FVII have not been confirmed, so an overall change in activity of the extrinsic pathway is unestablished. There are reports that expression and activity of t-PA are increased while expression of PAI-1 is reduced during statin therapy. Also, statins have been reported to reduce monocyte migration and improve endothelial-dependent vasodilation.
Fibrates stimulate PPARα to increase fatty acid oxidation and lower triglycerides. Triglycerides appear to promote the generation of FVII, but evidence for a reduction of FVII during fibrate therapy is equivocal.
We can conclude that management of the metabolic syndrome is complicated by its highly variable presentations, and current therapies tend to be reserved for individual clinical consequences rather than treating the syndrome as a whole. Nevertheless, in addition to their main effects, most of these therapies have been reported to offer some benefits to hemostasis, providing ‘value-added’ to overall management of the metabolic syndrome.