Metabolic syndrome is a highly prevalent and complex clustering of risk factors for diabetes and cardiovascular disease (CVD).^{1,2, 3} As currently defined the syndrome confers a very high risk of developing type 2 diabetes - a CVD risk equivalent in its own right.¹ To a lesser extent it also predicts the risk of CVD in the medium term.^4,5

The age-adjusted prevalence of metabolic syndrome was approximately 25% of the US adult population in a national survey published in 2002.⁶ In a community-based longitudinal study in the US, the adjusted relative risk of developing diabetes over 11 years among obese patients was increased 10-fold in those with the syndrome, and the risk of developing CVD was increased 2-fold.⁷ Data on the prevalence of the syndrome in adults in the UK are limited but estimates suggest that it is in the order of 15-20%.

The global prevalence of metabolic syndrome seems set to increase in coming years as a consequence of rising rates of obesity.⁸

Rationale for diagnosis

The enhanced probability of developing diabetes and CVD provide the basis for identifying metabolic syndrome in individuals at risk.9 More than 50% of obese subjects have metabolic syndrome. Many more will have one feature, e.g. abnormal lipids. GPs should measure blood pressure (BP), fasting lipids and glucose in all obese individuals, unless of course clinical circumstances render these measurements inappropriate, e.g. they have limited life expectancy from non-vascular disease.

The diagnosis hinges on obesity as a core feature.² In this sense, metabolic syndrome can be regarded as obesity with additional risk factors for CVD. It is important to note that a minority of obese patients remain free of the additional risk factors that define the syndrome.⁷ Protection against the adverse metabolic consequences of obesity may, at least in part, reflect a low level of ectopic fat deposition in the liver.¹⁰ Conversely, some non-obese subjects have features of metabolic syndrome with evidence of insulin resistance.¹¹

Insulin resistance is closely associated with central obesity and may be defined as a reduced biological action of the hormone.^12,13 Insulin resistance is not only closely associated with fatty liver but also with an enhanced vascular risk. It is also a strong predictor of type 2 diabetes. Insulin resistance is closely associated with features of metabolic syndrome even in subjects with normal glucose tolerance.¹⁴ Some ethnic groups, notably South and East Asians, tend to be more insulin resistant and have greater central deposition of adipose tissue for a given BMI compared with Europeans. Adverse metabolic consequences in these groups appear at lower waist circumferences. Cutoffs for this key diagnostic variable are therefore lower.

Diagnosis of metabolic syndrome is relatively straightforward and can be easily carried out in primary care. Indeed, the use of categorical classifications, e.g. for BP, have been consciously used to facilitate the diagnosis. BP and lipids are continuous variables but thresholds are widely used to categorise normality in many risk factors for CVD. Diagnosis should prompt a multifactorial therapeutic strategy to improve risk factor profiles; the aim should always be to accomplish this with non-pharmacological measures.

The clinical usefulness of the diagnosis of metabolic syndrome has been fiercely challenged. Detractors argue that the syndrome is less effective in predicting the risk of CVD than other well established risk scores, each of which has its own limitations. These different approaches to assessing risk are not mutually exclusive and the long-term implications for individuals who have multiple CVD risk factors should be considered, especially in younger subjects.

Recent studies suggest that the diagnosis may have less relevance in terms of predicting CVD events in the elderly;¹⁵ this contrasts with evidence that obesity accompanied by features of the syndrome is deleterious to the vasculature in the young.^16,17 Thus, the rapidly increasing prevalence of metabolic syndrome provides support for the view that diagnosis of the syndrome carries important public health implications.

The second major objection that has been raised is that management revolves around conventional management of risk factors, i.e. there is no specific therapy for metabolic syndrome. This does not negate the value of identifying and treating the relevant risk factors. The literature indicates that a diagnosis of metabolic syndrome provides an early warning of major health problems that lie ahead if appropriate steps are not taken to halt progression.

Management

Effective management of metabolic syndrome hinges on efforts directed at ameliorating each of the metabolic, haemodynamic, and pro-coagulant defects that produce occlusive vascular damage. Among subjects with normal glucose tolerance, metabolic risk factors for CVD become more pronounced as blood glucose rises.¹⁸ Individual components of the syndrome that are readily assessed in clinical practice should therefore be addressed using safe, efficacious, and cost-effective measures.

Lifestyle

Lifestyle modifications such as control of body weight, avoidance of central adiposity through modifications of diet and physical activity are the foundations of management. However, the prevalence and magnitude of the individual components of metabolic syndrome increase over time and such lifestyle measures often prove to be insufficient in the longer term.

Drug treatment

Patients with metabolic syndrome will often require drug treatment for obesity, atherogenic dyslipidaemia and hypertension and will sometimes need antiplatelet therapy. Although no large studies have confirmed benefits of this approach, current views about tackling modifiable risk factors are supported by evidence from subgroup analyses of major clinical trials.¹⁹ Given the likelihood that patients will be on lifelong medication, the risks and benefits of treatment need to be weighed up for each individual.

Patients should be referred to a specialist when treatment goals, based on best practice guidelines for CVD prevention, are not being attained. Reducing polypharmacy is an increasingly important consideration.¹⁹ The polypill concept may assume a more prominent role in the future.

The brief outline of the options presented here does not include newer agents that are directed towards treatment of hyperglycaemia in subjects with diabetes.²⁰ CVD risk increases linearly in patients with type 2 diabetes as the individual diagnostic components of the metabolic syndrome accumulate.²¹ Current evidence supports a multifactorial approach to CVD risk reduction for patients with type 2 diabetes.²²

Anti-obesity drugs: An in-depth discussion of current pharmacological approaches to tackling obesity lies beyond the scope of this article.²³ Avoiding further weight gain may be the only realistic option for many patients. Selective cannabinoid receptor antagonists appear promising since they improve or attenuate several key defects of the syndrome; however, the first agent in this class, rimonabant, was withdrawn because of safety concerns.²⁴

Bariatric surgery is increasingly an option for morbid obesity or when multiple risk factors are present.²⁵

Statins and fibrates: Metabolic syndrome is characterised by a mixed dyslipidaemia, i.e. low levels of high-density lipoprotein (HDL) cholesterol in isolation, or more commonly, in concert with hypertriglyceridaemia. Some subjects with metabolic syndrome will have elevated serum cholesterol levels by chance association; this will accentuate any existing risk. Statins, by lowering levels of low-density lipoprotein (LDL) cholesterol reduce CVD morbidity and mortality in people with impaired fasting glucose levels and metabolic syndrome. Thus statins are first-line therapy even though elevated cholesterol is not a diagnostic feature of metabolic syndrome and they have little impact on the characteristic dyslipidaemia of the syndrome.

Ezetimibe may have a place as an adjunct to, or replacement for, statins in selected cases. Fibrates appear to have a role in the treatment of the dyslipidaemia, albeit less well established: there is evidence of clinical benefits in insulin-resistant patients with low HDL-cholesterol levels.²⁶ No target for HDL-cholesterol has been universally agreed but levels 27

Antihypertensive drugs: As a general principle, avoidance of drugs that may promote weight gain and exacerbate insulin resistance, e.g. conventional ß-blockers for hypertension, is sensible. Incidentally, newer agents in this class with vasodilator properties do not share these disadvantages. The renin-angiotensin system is activated in metabolic syndrome,²⁸ a defect that is amenable to pharmacological intervention. Thus, drugs that block aspects of the renin-angiotensin system are regarded as the drugs of choice by some expert groups.

Such agents should be part of antihypertensive therapy unless there are contraindications to their use.

Drugs from two or three classes are often needed to achieve BP targets. The availability of combination preparations containing two or more metabolically neutral agents, e.g. an ACE inhibitor together with a calcium channel blocker should offer a partial solution to the pill burden. Metabolic syndrome may increase vascular risk by promoting renal damage manifested by reduced glomerular filtration rate and/or (micro)albuminuria.²⁹ Annual monitoring for early renal disease is recommended.

Insulin-sensitisers: A body of evidence suggests a potential role for these drugs in preventing or delaying progression from impaired glucose tolerance to diabetes. This is a controversial issue and no class of anti-diabetic drugs is licensed for this indication, i.e. as a preventative measure in subjects with so-called pre-diabetes, even though metformin is often used off-label in women with polycystic ovary syndrome.

Metformin and thiazolidinediones, by reducing insulin resistance, have the theoretically appealing attribute that multiple aspects of CVD risk may be improved. However, the overall safety profiles and potentially different effects on cardiovascular events between pioglitazone - which has some evidence of protection, and rosiglitazone - which has some evidence suggesting harm - have created new uncertainties about their use.³⁰

Novel insulin-sensitising drugs are under investigation but their role, if any, in the pre-diabetic state will require very careful evaluation in clinical trials. Safety considerations must remain uppermost, as non-pharmacological interventions have clearly demonstrated efficacy in high-risk obese subjects with metabolic syndrome.^{31, 32} However, the difficulty of translating such evidence into daily clinical practice remains formidable.

Conclusions

Fears that the current global explosion of obesity-related insulin resistance³³ will create a tidal wave of diabetes and CVD have led to attention being focused on the clustering of risk factors that defines metabolic syndrome.^34,35,36,37 Younger individuals with the syndrome have a high risk of developing diabetes and face decades of exposure to a multiplicity of inter-related CVD factors. Prevention and management of the syndrome requires a combination of therapeutic lifestyle interventions, i.e. appropriate diet and physical activity, and judicious use of safe and effective antiobesity drugs as required.

Major CVD risk factors such as hypertension and dyslipidaemia should be treated in the context of the high risk of cardiovascular events over the lifetime of the affected individual. More studies are required to address the benefits and risks of this approach in younger subjects when pharmacological interventions become necessary. Efforts to elucidate the molecular basis of metabolic syndrome may provide insights that ultimately generate more specific therapeutic interventions.