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The European Society of Cardiology

The metabolic syndrome – a growing problem

A Tonkin*

Monash University, Melbourne, Vic., Australia

* Andrew Tonkin, MBBS, MD, FRACP, Department of Epidemiology and Preventive Medicine, Monash University, Level 3, 553 St. Kilda Road, Melbourne 3004, Vic., Australia. Tel.: +61-39903-0572; fax: +61-39903-0556
andrew.tonkin{at}med.monash.edu.au

Abstract

The metabolic syndrome is commonly defined as a group of risk factors or abnormalities closely associated with insulin resistance that markedly increase risk for both coronary heart disease and diabetes. Prospective cohort studies should help improve understanding of the relationships among the many risk factors identified as being part of the syndrome and may also improve the definition of the metabolic syndrome. According to the National Cholesterol Education Program definition, metabolic syndrome is estimated to be present in 24% of the US adult population, including 44% of those aged 50 years. With the World Health Organization definition, metabolic syndrome is present in 7–36% of European men and 5–22% of women aged 40–55 years. Abdominal adiposity appears to be a major driving force in metabolic syndrome and its increasing prevalence; adiposity is predictive of metabolic syndrome in population studies and is associated with a variety of metabolic derangements, including insulin resistance, increased systemic inflammation and decreased adiponectin levels. Lifestyle intervention with the goals of weight loss and increased exercise is a critical component of management aimed at preventing progression to diabetes and reducing cardiovascular risk. Lipid disorders in metabolic syndrome require aggressive management, with reduction of low-density lipoprotein cholesterol being a primary aim of lipid-lowering therapy in both metabolic syndrome and diabetes. However, increase in high-density lipoprotein cholesterol is also important. Intervention studies based on additional understanding of risk factors in metabolic syndrome will yield improved approaches to treating patients with the condition.

Key Words: Metabolic syndrome • Diabetes • Diabetes risk factors • Abdominal adiposity • Insulin resistance • Lipid disorders

Introduction

The metabolic syndrome is associated with increased risk for diabetes and coronary heart disease (CHD), and it is widely agreed that it is a growing and pressing problem for society. There is not, however, universal agreement on precisely what this syndrome is and how to define it. Like many ‘syndromes’ in the history of medicine, it is likely a group of disorders that share a common pathway. Identification of patients with features of this syndrome and appropriate and aggressive treatment are necessary to reduce the adverse health consequences associated with metabolic syndrome.

Metabolic syndrome: definitions and prevalence

Metabolic syndrome is recognised to be closely associated with an insulin resistance state. As shown in Fig. 1, recent definitions identify this association, with some explicitly including insulin resistance in the definition. Some of these definitions also include criteria for additional markers other than those shown. The current definitions may imply equal weighting of the different components. An important objective of current and future study of metabolic syndrome should be to obtain prospective longitudinal cohort data that will permit multivariate modeling to determine the relative contributions of different risk factors and markers to development and presence of the syndrome. These may well vary between different populations.



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  		Fig. 1 Recent definitions of metabolic syndrome. ICD-9, International Classification of Diseases–Ninth Revision; WHO, World Health Organization; AHA, American Heart Association; IDF, International Diabetes Federation; ADA, American Diabetes Association; ATP, Adult Treatment Panel.

 
The two most commonly applied definitions of metabolic syndrome are those proposed by the National Cholesterol Education Program Adult Treatment Panel III (ATP III) and the World Health Organization (WHO). In the ATP III definition,1 metabolic syndrome is diagnosed when at least three of the following are present:
  • Fasting plasma glucose >=110 mg/dl (6.1 mmol/l).
  • Abdominal obesity (e.g., waist circumference 102 cm in men, 88 cm in women).
  • Triglyceride level >=150 mg/dl (1.7 mmol/l).
  • High-density lipoprotein cholesterol (HDL-C) level <40 mg/dl (1.0 mmol/l) in men and <50 mg/dl (1.3 mmol/l) in women.
  • Blood pressure >=130/85 mmHg.

According to the WHO definition,2 metabolic syndrome is present in patients with hyperinsulinaemia or fasting plasma glucose >=6.1 mmol/l (110 mg/dl) and at least two of the following:

  • Abdominal obesity (waist:hip ratio 0.90 or body mass index [BMI] >=30 kg/m2).
  • Dyslipidaemia consisting of triglycerides >=1.7 mmol/l (150 mg/dl) or HDL-C <0.9 mmol/l (35 mg/dl).
  • Hypertension (blood pressure >=140/90 mmHg or receiving antihypertensive medication).

It bears noting that owing to the requirement of either impaired fasting glucose or impaired glucose tolerance, the WHO criteria might be expected to capture a greater proportion of individuals en route to development of diabetes compared with the ATP III criteria, indicating a greater focus of the WHO criteria on the syndrome as a pre-diabetic state. Risk of diabetes varies, but epidemiological data indicate annual rates of progression from impaired glucose tolerance to type 2 diabetes of about 2–4% in Caucasian populations, 9–16% in Mongoloid races, 10.0% in Asian Indians and Australian Aborigines and about 6% in Pacific Islanders.

Data from the US NHANES III survey indicate a high prevalence of components of the metabolic syndrome as defined by ATP III. Among 8814 adults, abdominal obesity was present in 38.6%, elevated triglycerides in 30.0%, low HDL-C in 37.1%, elevated blood pressure in 34.0% and hyperglycaemia/diabetes in 12.6%.3 Overall, the prevalence of the metabolic syndrome among adults aged 20 years and older in the NHANES III survey was 24%; prevalence increased with age, with 44% of those aged 50 years meeting the ATP III criteria.4 In other US studies, 24% of subjects met the ATP III criteria and an equal proportion met the WHO criteria in the Framingham Offspring Study; 23% and 21%, respectively, in a non-Hispanic white population in the San Antonio Heart Study; and 31% and 30%, respectively, in a population of Mexican Americans.5 Pooled data from eight studies in Europe in subjects aged 40–55 years indicate that 7–36% of men and 5–22% of women met the WHO criteria.6

Obesity as the driving force?

Many investigators believe that the high and growing prevalence of overweight individuals and obesity in many areas of the world is the driving force behind the high prevalence of the metabolic syndrome. Data from the United States indicate that the prevalence of overweight increased from 45% to 64.5% from 1960–1962 to 1999–2000, with the prevalence of obesity defined as BMI 30 kg/m2 increasing from 13% to 31% over this period.7,8 The problem of obesity is also present in adolescents, as well as adults. According to NHANES III data, 4.2% of subjects aged 12–19 years () met the criteria for the metabolic syndrome. Of those in the 95th BMI percentile, 28.7% had the metabolic syndrome, compared with 6.8% of those in the 85th to <95th percentiles and 0.1% in the <85th percentiles.9 Measurement of waist circumference may prove to be the single most important indicator of the metabolic abnormalities that pose risk for cardiovascular and other diseases. In the Quebec Cardiovascular Study, a waist circumference 90 cm and serum triglyceride level 2.0 mmol/l identified 80% of men with hyperinsulinaemia, increased apolipoprotein B and small, dense low-density lipoprotein (LDL) particles, the key indicators of increased CHD risk in that study.10

Adipose tissue was once generally considered to be a passive storage site for energy that could be accessed in time of need. However, it has become clear that adipose tissue is an endocrine organ and an active source of a variety of inflammatory cytokines and substances that can promote atherosclerosis and modify coagulation and fibrinolysis processes.11 This tissue and its associated abnormalities can predispose to insulin resistance at the levels of both the liver and skeletal muscle owing to alterations of the levels of fatty acids within cells and related changes in fatty acid oxidation; activity of this tissue can also alter endothelial function via an effect on insulin resistance. A number of studies have shown an association of abdominal obesity and increased levels of the inflammatory marker high-sensitivity C-reactive protein (CRP); for example, a cross-sectional analysis in the Insulin Resistance Atherosclerosis Study showed that waist circumference explained 14.5% of the variability in circulating CRP levels on multivariate linear regression (),12 and the highest odds ratio for elevated CRP (2.71, 95% confidence interval, 2.17–3.40, ) was found among NHANES III subjects with abdominal obesity.3 Abdominal obesity is also associated with lower levels of adiponectin, a vascular protective substance that decreases free fatty acid levels and increases insulin sensitivity at the level of the skeletal muscle;13 this association may be stronger in women than in men, a finding that may have important implications regarding assessment of risk of cardiovascular disease in women with metabolic syndrome or diabetes.

Cardiovascular risk and treatment

The metabolic syndrome is an important prognostic factor for CHD. As shown in Fig. 2, risk of CHD was increased nearly 4-fold in men with vs men without the metabolic syndrome over a 12-year period in the Kuopio Ischaemic Heart Disease Risk Factor Study. 14 In a prospective study by Norhammer et al.15 in survivors of acute myocardial infarction with no previous diagnosis of diabetes, it was found that 31% had diabetes and 35% had impaired glucose tolerance at the time of hospital discharge; that this was not an ‘artefact’ of the acute coronary event was indicated by the finding that 25% had diabetes and 40% had impaired glucose tolerance at 3 months after discharge. Such findings suggest a very high prevalence of insulin resistance in patients with CHD events.



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  		Fig. 2 Coronary heart disease mortality in men with and without metabolic syndrome in the Kuopio Ischaemic Heart Disease Risk Factor Study. (Adapted with permission from Lakka et al.14)

 
Lifestyle interventions can have a significant impact on progression to diabetes in individuals with impaired glucose tolerance. Table 1 shows relative risk reductions associated with moderate weight reduction in diet and exercise programs, as well as with metformin and acarbose treatment, in studies in primarily middle-aged and obese individuals. Lifestyle changes can also have beneficial effects on lipid abnormalities, blood pressure, insulin resistance and levels of inflammatory mediators.16 It would be expected that benefits from lifestyle changes would result in decreased cardiovascular events. Lifestyle management cannot be overlooked: much benefit can be achieved by weight loss in obese and overweight individuals, with weight reduction likely significantly improving their risk of disease.


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  		Table 1 Major intervention studies to reduce incidence of type 2 diabetes

 
With regard to dyslipidaemia, there are few data on association of lipid measures with CHD risk specifically in the metabolic syndrome. However, age- and sex-adjusted stepwise selection for variables predicting CHD risk using United Kingdom Prospective Diabetes Study data from 2693 diabetic patients indicates that LDL-C is the most powerful predictor (), followed in order by HDL-C (), HbA1c (), systolic blood pressure () and smoking ().17 Such findings support the emphasis on LDL-C lowering as the primary objective of lipid-lowering therapy to reduce risk in patients with the metabolic syndrome and diabetes. In addition, it is important that analysis of data from the Cholesterol and Recurrent Events (CARE) Trial investigators and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) trials18 indicates that the increased risk gradient associated with low HDL-C remains even after treatment with a statin. Also, the predictive value of HDL-C and triglycerides for CHD events is greater in individuals with lower LDL-C, which is a more common finding in patients with diabetes or metabolic syndrome than in others at risk for CHD; as shown in Fig. 3, there was a clearer association of risk according to quintiles of HDL-C or triglycerides when LDL-C was <3.2 mmol/l (125 mg/dl) than when it was above this level. Such findings support the use of agents that have beneficial effects on HDL-C and triglycerides, even when the focus of therapy is on LDL-C.



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  		Fig. 3 Analysis of data from CARE and LIPID trials showing the relationship of HDL cholesterol (HDL) and triglyceride (TG) quintile (Q) with risk for coronary heart disease (CHD) events according to LDL cholesterol (LDL) above or below 125 mg/dl (3.2 mmol/l). *CHD events include CHD death, myocardial infarction, coronary artery bypass graft and percutaneous transluminal coronary angioplasty. (Adapted with permission from Sacks et al.18)

 
Among statins, which at least at this time are the primary lipid-lowering agents in diabetic patients and patients with the metabolic syndrome who are eligible for such treatment, rosuvastatin produces marked beneficial changes in the lipid profile of patients with metabolic syndrome. In an analysis of 194 hypercholesterolaemic patients with metabolic syndrome according to ATP III criteria, rosuvastatin 10 mg reduced LDL-C by 47%, non-HDL cholesterol by 43% and triglycerides by 23% and increased HDL-C by 10%.19 In an analysis of data from 1342 high-risk patients meeting ATP III criteria for the metabolic syndrome criteria in the comparative MERCURY I trial, the ATP III LDL-C goal of <2.6 mmol/l (100 mg/dl) was achieved by 77% of patients receiving rosuvastatin 10 mg, compared with 62% for atorvastatin 10 mg, 73% for atorvastatin 20 mg, 51% for simvastatin 20 mg and 34% for pravastatin 40 mg.20 Given the effects of fibrates on HDL-C and triglycerides, there is also considerable rationale for combining fenofibrate with statin therapy in patients with metabolic syndrome; studies of such combination therapy in subjects with the metabolic syndrome are needed.

With regard to other potential treatments, there is also considerable interest in the use of thiazolidinediones in patients with the metabolic syndrome. These agents have a number of activities that would be of benefit in the metabolic syndrome, including reduction of visceral adipose tissue mass, reduction of free fatty acids, favourable effects on fibrinolysis and coagulation and favourable effects on systemic inflammation and other atherosclerotic processes.21 Clinical end-point trials of these agents are needed to determine their potential benefits in preventing cardiovascular disease.

Perspective and conclusion

The metabolic syndrome is associated with increased risk of both CHD and diabetes. Management of the metabolic syndrome should reflect the awareness that disease burden is not limited to those patients with the worst values of predictive risk factors. For example, only about 25–30% of cases of ischaemic heart disease, stroke and diabetes occur in the deciles of the population with the most extreme levels of total cholesterol, blood pressure and BMI.22 Although risk associated with the particular risk factor is great in the worst deciles, the majority of disease is distributed throughout the population with lesser abnormalities; thus, management should not be allocated only on the basis of extreme risk factor values. In this regard, it is important to be cognizant of the increased risk carried by the metabolic syndrome and to take appropriate and aggressive measures to prevent development of diabetes and cardiovascular disease in the growing population of individuals with the syndrome.

Better management of metabolic syndrome will also require an improved definition of the syndrome, which would be best derived from prospective longitudinal studies. Much evidence points to abdominal obesity as a central component of metabolic syndrome. The evidence includes population-based data and basic research concerning putative factors released from adipose tissue. Perhaps the simplest approach to improving identification and management of metabolic syndrome based on current knowledge would be to routinely incorporate waist circumference measurement in physical examinations and to initiate appropriate diagnostic and management strategies in patients with abdominal adiposity. In management, lifestyle modification to reduce weight and increase exercise is an important intervention. An aggressive approach to lipid reduction is warranted in metabolic syndrome; at the least, statin therapy should be considered in patients with LDL-C 3.4 mmol/l (130 mg/dl). More data on combination of statin/fibrate treatment are needed. Antihypertensive treatment is also likely to have a role in management in many patients. Additional studies are necessary to determine the potential benefits of thiazolidinedione treatment and to identify other potentially beneficial pharmacologic approaches to treatment of metabolic syndrome.

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