Irish Medical Times | Clinical TImes | The Endocrinology Clinic: the metabolic syndrome

The Endocrinology Clinic: the metabolic syndrome

Prof T Joseph McKenna and Prof Frances Hayes

Concluding their series on ‘Notes from the Endocrinology Clinic’, Prof T Joseph McKenna and Prof Frances Hayes examine the global health threat from the metabolic syndrome

For several decades it has been recognised that a number of clinical disorders tend to cluster in patients who present with cardiovascular disease (CVD). These include all, some or any of the following CVD risk factors: dyslipidaemia, diabetes, hyper-tension and obesity.

While a causal relationship between each of the disorders and CVD was recognised, any relationship between the other disorders was not immediately obvious. The possibilities included that the more of these risk factors that co-existed in a patient, the more likely was CVD to occur.

In addition, it was speculated that the disorders were in some way lifestyle related, particularly with regard to weight gain and obesity. Subsequently the concept of insulin resistance emerged.

Definitions
In 1999 the World Health Organization (WHO) proposed a definition for a condition termed the ‘metabolic syndrome’ to embrace the associations outlined above. The working group which officially recognised the syndrome was established to advise on the definitions of disorders of glucose metabolism and diabetes. It is not surprising therefore that the original definition emphasised insulin and diabetes.

Diabetes or impaired glucose metabolism or insulin resistance demonstrated using the euglycaemic insulin clamp technique was required plus any two of the following: obesity or a high waist:hip ratio; dyslipidaemia; hypertension; microalbuminuria.
In the same year, the European Group for the Study of Insulin Resistance (EGIR) proposed the term ‘Insulin resistance syndrome’ specifically excluding diabetic patients and requiring the measurement of insulin. The term insulin resistance was applied to those subjects whose fasting serum insulin concentration fell in the upper quartile for the general population.

In addition to the presence of insulin resistance as defined in the foregoing, the insulin resistance syndrome required the co-existence of two of the following: central obesity; dys-lipidaemia; hypertension; or, impaired fasting glucose.

The method used to define insulin resistance was chosen because it was not possible to directly compare the results of insulin measurement across assays because of lack of standardisation.

The limitations of this definition of insulin resistance include the assumption that all populations carry the same tendency to resistance, and that no group can have a prevalence greater than 25 per cent.

In 2001, the National Cholesterol Education Programme Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATP III) proposed a definition of the metabolic syndrome that was more immediately applicable in clinical practice.

The ATP III definition required the presence of at least three of the following five clinical features: 1, Central obesity; 2, hypertriglyceridaemia; 3, Low HDL in blood; 4, Hypertension; 5, Impaired fasting glucose or diabetes mellitus.

Associated disorders
It is widely recognised that a further group of conditions, singly or in combination, is frequently associated with the metabolic syndrome. These may occur as a consequence of the syndrome and/or amplify the deleterious consequences of the syndrome and its component disorders.

These include diabetes mellitus, hyperuricaemia, a procoagulant state, endothelial dysfunction, increase in inflammatory markers in blood e.g. C-reactive protein and cytokines (IL-6, TNF), non-alcoholic fatty liver infiltration, sleep apnoea, acanthosis nigricans and polycystic ovary syndrome (PCOS). Directly or indirectly all the components of the metabolic syndrome and the associated disorders are risk factors which significantly predispose to CVD.

Impact
Individuals who have the metabolic syndrome are at least twice as likely to sustain a myocardial infarction or a cerebro-vascular incident than subjects who do not have the syndrome. Each component of the metabolic syndrome independently predicts increased likelihood of developing type 2 diabetes mellitus while subjects with the full-blown syndrome have an approximately a ten- to twentyfold increase in the risk of developing diabetes.

Early recognition of the syndrome is the ideal and its presence should alert clinicians and patients to the opportunity for the adoption of effective preventative measures.
It is for this reason that the entity of the metabolic syndrome should be generally recognized as a common condition with important consequences which are largely preventable or can be greatly modified by timely intervention.

Pathogenesis
Whether the metabolic syndrome represents a discrete entity or is the clustering of disorders noted because of the high incidence of cardiovascular disease in affected subjects, is controversial. It has been argued that the unifying aetiological basis is insulin resistance.

Alternative candidates, none of which are mutually exclusive, are obesity and changes resulting from an increasingly sedentary lifestyle. Indeed, the co-existence of two or all three of these disorders will amplify the effects of all. The concept of insulin resistance is selective or partial. While liver, muscle and fat do not respond normally to insulin other tissues may retain full sensitivity to insulin e.g. ovary, skin.

Thus hyperinsulinaemia develops to maintain normal glucose concentrations in blood. These elevated insulin levels may drive excess androgen production by the ovaries and perturb the process of ovulation in PCOS.

Similarly exposure of dermal cells to high insulin concentrations may be the mechanism underlying the development of acanthosis nigricans. It is only when compensatory hyperinsulinaemia fails that hyperglycaemia and subsequently diabetes occur, although dyslipidaemia frequently precedes this.

PCOS
More than half of PCOS patients are obese and between 10 and 30 per cent demonstrate glucose intolerance (impaired fasting glucose or impaired glucose tolerance), while 5 to 10 per cent have diabetes mellitus with these abnormalities increasing in frequency with age. Although 10 per cent of lean PCOS patients in the US have been reported to have glucose intolerance, this has not generally been observed in European studies.

Screening for glucose intolerance and dyslipidaemia is recommended particularly in overweight or obese PCOS patients. Approximately 10 per cent of PCOS patients have acanthosis nigricans characterised by raised dark skin with a velvet texture and sheen usually occurring over the neck and in the axillae.

The metabolic syndrome is frequently encountered in PCOS. Therefore PCOS is a disorder not only of androgen excess and menstrual irregularity, but is also characterised by the presence of several risk factors for cardiovascular disease.

Screening for the risk factors in this young cohort of patients who typically present in the decade 15-25 years, provides an opportunity to institute preventative measures.

In addition, weight loss and/or metformin treatment are associated with an improved frequency of ovulation presumably due to reduced insulin concentrations in blood.

It should be noted that surrogate markers of cardiovascular disease, e. g. increased carotid intimal thickness and calcification of coronary and carotid arteries, have been identified in excess in PCOS patients.

However, in the small number of relevant long-term studies an excess of cardiovascular events has not been reported in these patients. It is possible that the high oestrogen state in PCOS may provide some long-term protection against cardiovascular disease.

Prevalence
The prevalence of the metabolic syndrome varies widely depending on ethnic group assessed, the age group surveyed and on the definition used. For instance, using similar but not identical definitions, which were modifications of ATP III criteria, two different regions of India give very different results.

In the Jaipur area (2003) the metabolic syndrome was reported to occur in 12.8 per cent (7.9%, male; 17.5%, female) of the population while in the Chennai area (1995) the prevalence was reported to be 41.1 per cent (36.4%, male; 46.5%, female). Of the several US studies, the San Antonio Heart Study and the Framingham Offspring Study are representative covering the period 1988-1996 and report approximate prevalences of 26 per cent in white men, 19 per cent in white women, 29 per cent in Mexican-American men and 33 p;er cent in Mexican-American women.

The prevalence in Europe is also highly variable but possibly slightly lower than in the US. In 2003, a prevalence of approximately 22 per cent in both men and women was reported by Prof O’Halloran’s group at University College Hospital, Cork.

Full-blown metabolic syndrome has been reported in teenage years in 3 to 6 per cent of the US population. The term ‘epidemic’ has been justifiably widely employed to describe the increasing prevalence of diabetes mellitus and the metabolic syndrome world-wide.

This is a major healthcare problem which if not effectively addressed will both reverse the recent decline in cardiovascular disease and over burden global healthcare, not least the Irish system. It is difficult to appreciate the gravity of the cardiovascular disease potential which can be predicted from these data.

Management
At this time the pathogenesis of the metabolic syndrome has not been definitively established. However, whether a discrete entity or the clustering of related conditions, the clinical impact is significant and treatment measures are not specific to the metabolic syndrome.

Management of the metabolic syndrome consists of correcting its individual components, preventing the progression of glucose intolerance to diabetes, and the energetic treatment of those affected by diabetes and the disorders associated with the syndrome.

Lifestyle changes, increased physical activity and dietary adjustments are fundamental to effective management of the metabolic syndrome. These include exercise programmes of increased activity for a minimum of 30 to 45 minutes on five to seven days per week.

Dietary intervention is directed to reduce body weight and address dyslipidaemia characterised by low HDL and elevated triglyceride and LDL lipid fraction concentrations in blood and correct hyperglycaemia. Controversy surrounds which type of diet is most effective in the short and long term and there are safety issues.

Low carbohydrate diets and low fat diets with varying degrees of calorie restriction from very low to moderately low, are the broad categories involved. Several formal studies report the success of these strategies achieving weight loss of approximately 4.2kg over one year that was mostly maintained for the duration of the study, 3.2 years.

Study
In the Finish Diabetes Pre-vention Study (2001) weight loss was associated an impressive 58 per cent reduction in conversion to a diabetic status, from 23 per cent in the control group to 11 per cent in the participants in the exercise-diet arm. Similarly, the Diabetes Prevention Programme (2002) in the US compared the effects of an intense lifestyle modification programme, metformin treatment and a control group on rates of progression to type 2 diabetes in a cohort of patients with impaired glucose tolerance.

The mean weight loss at the end of the study of 2.8 years duration was 5.6, 2.1 and 0.1Kg in the three groups respectively, while the occurrence of diabetes expressed as ‘cases per 100 patient years’ was 4.8, 7.8 and 11, respectively. It is worth emphasizing that the lifestyle modification programmes in the Diabetes Prevention Programme, which included both exercise and diet, were intensive.

Participants randomised to this arm of the study received regular one-to-one counselling and group sessions and a standardised curriculum delivered in 16 lessons over 24 weeks with subsequent monthly one-to-one sessions. It is not appropriate, therefore, to extrapolate the results in these studies to that which is likely to be achieved promoting lifestyle modifications in routine clinical practice.

Effective weight loss
However, it is notable that the most effective weight loss was achieved by those who foll-owed a low-fat diet, monitored their weight and food intake and maintained increased physical activity aimed at achieving a relatively slow weight loss, e.g. 10 per cent over one year.

Drug treatments other than metformin have also been assessed including acarbose (an enteric α-glucosidase inhibitor), thiazolidenediones (troglitazone which was subsequently withdrawn because of hepatic side-effects and pioglitazone), and orlistat (an intestinal lipase inhibitor).

Treatment with acarbose reduced the development of diabetes by 25 to 39 per cent compared to placebo, which was largely sustained after the withdrawal of the drug with a mean follow up of 3.3 years.

At least as noteworthy was a subsequently reported 49 per cent reduction in cardiovascular events (91 per cent in myocardial infarction) and a 34 per cent reduction in the occurrence of hypertension. However, the statistical validity of the cardiovascular data has been challenged.

This year a newer member of this drug family, voglibose, has been reported from Japan to reduce the conversion from impaired glucose tolerance to diabetes by 40 per cent.

Treatment of glucose intolerant patients with rosiglitazone or pioglitazone reduced the progression to diabetes by 60 per cent and 81 per cent respectively.

Obese patients treated with orlistat when compared to placebo-treated patients over approximately 18 months lost more weight (6.7 vs 3.8kg), were less likely to convert from glucose intolerance to diabetes (3.0 vs 7.6%) and were more likely to revert to normal glucose tolerance (72% vs 49%).

The rationale for treating dyslipidaemic patients with the metabolic syndrome with pharmacological agents is extrapolated from evidence of the effectiveness of this approach in patients with diabetes and/or cardiovascular disease.

This may well be the group most likely to derive the greatest benefit when drugs are used for primary prevention. Such drugs include statins, fibrates and nicotinic acid, all of which carry potentially serious side effects.

Patients with the metabolic syndrome are also likely to derive major benefit from treatment with low dose, long-term aspirin. Clearly treatment with aspirin of patients who have a history of gastrointestinal ulcer or bleeding, or those with any bleeding tendency, is to be avoided.

Universally accepted
It is universally accepted that established hypertension should be treated to achieve a target blood pressure. Since glucose intolerance and diabetes are prominent components of the metabolic syndrome and the blood pressure target in patients with diabetes is 130/80 mm/Hg or less, this is the appropriate goal.

To achieve this target it is frequently necessary to use multiple agents, possibly four to five antihypertensive drugs. Central to these are angiotensin converting enzyme inhibitors and angiotensin receptor blockers.

There is some evidence from clinical studies that ramipril or losartan not only significantly reduce cardiovascular events but they may also reduce the progression from impaired glucose tolerance/impaired fasting glucose to diabetes by 25 to 33 per cent over approximately four years.

Conclusion
The metabolic syndrome and its close associations with diabetes and cardiovascular disease pose probably the greatest threat to global health over the next 25 years.

However, diagnosis is simple and treatment is relatively cheap and immediately available. The challenge worldwide, including the 25 per cent of the adult population affected in Ireland and their medical providers, is to recognise the problem and apply corrective measures, mainly lifestyle modification in the first instance, to impact on the development of diabetes and cardiovascular disease.

In 2003, the American Diabetes Association recommended that drugs should not be employed routinely to prevent the development of diabetes until its cost-effectiveness has been established.

Drug treatment should be used as required particularly to achieve therapeutic targets where diabetes or cardiovascular disease has developed. It is unlikely that a generally effective outcome will be achieved without an intensive education programme for the general population and health care workers. A comprehensive public health programme is urgently required.

l Frances Hayes* and
T Joseph McKenna§¶
*Consultant Endocrinologist
§Honorary Consultant,
SVUH, Elm Park, Dublin 4;
¶Specialist in Endocrinology and Diabetes Mellitus,
The Mews, 1 De Vesci Terrace,
Dun Laoghaire, Co. Dublin.

Posted in Cardiovascular on 04 February 2010
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