How to assess and manage the Metabolic Syndrome 

Prevention and treatment of the Metabolic Syndrome

•  References

How to assess and manage the Metabolic Syndrome

The worldwide prevalence of the Metabolic Syndrome has reached epidemic proportions and there is no evidence that this rapid growth will “plateau” in the coming years. Changes in human behaviour and lifestyle observed over the last century, which have promoted a positive energy balance, weight gain, obesity and the progressive development of a dysmetabolic state, have resulted in a dramatic increase in the prevalence of the Metabolic Syndrome worldwide.

Because of its elevated prevalence, the risk associated with the presence of features of the Metabolic Syndrome is receiving considerable attention from the medical community. It has been proposed that a cluster of metabolic complications called the Metabolic Syndrome which includes an atherogenic dyslipidaemia, an insulin resistance state leading to a disturbed plasma glucose/insulin homeostasis, a thrombotic and inflammatory profile, as well as an endothelial dysfunction could substantially increase the risk of coronary heart disease (CHD) and type 2 diabetes. It has also been suggested that the impact of the Metabolic Syndrome on CHD risk of patients with type 2 diabetes could be largely independent from glycaemic control. As the Metabolic Syndrome is largely a consequence of our “toxic” lifestyle, it has been proposed that abdominal obesity, especially visceral obesity, could represent the main correlate of the Metabolic Syndrome in our population. This notion supports the emphasis placed by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) on abdominal obesity and on waist circumference as the best anthropometric correlate of abdominal fat accumulation and related abnormalities in man.

The recognition of the Metabolic Syndrome as a major and prevalent cause of CHD in the recently published NCEP-ATP III has generated considerable interest in the medical community. In addition, NCEP-ATP III has proposed simple clinical variables to identify individuals at risk of having the Metabolic Syndrome. Among the five parameters (waist circumference, triglycerides, HDL-cholesterol, fasting glycaemia, blood pressure) used to identify carriers of the Metabolic Syndrome, the introduction of waist circumference rather than the body mass index has been a major conceptual leap, recognizing the greater role of abdominal rather than overall obesity as the most prevalent cause of the Metabolic Syndrome in our affluent, sedentary population. Furthermore, these new guidelines recognise the importance of elevated triglycerides and of reduced HDLcholesterol concentrations as useful lipid markers of the presence of an atherogenic "dysmetabolic" milieu that is now referred to as the Metabolic Syndrome.

There is also evidence that the increased CHD risk related to the presence of the Metabolic Syndrome could be explained by metabolic abnormalities that are not currently assessed in daily clinical practice. It is therefore suggested that in order to optimally manage CHD risk patients with the Metabolic Syndrome, attention should be given not only to classical risk factors, but also to the improvement of features of the Metabolic Syndrome. For the time being, although we know that the Metabolic Syndrome substantially increases the risk of CHD, we do not know which of its features (insulin resistance/hyperinsulinaemia, small LDL particles, reduced adiponectin levels, increased CRP, etc.) are critical therapeutic targets for the optimal management of CHD risk in type 2 diabetic patients.

Several guidelines have been published for the management of the patient with dyslipidaemia. Although considered high-risk as a group, the level of CHD risk varies considerably among abdominally obese individuals and diabetic patients emphasizing the importance of properly assessing global risk in these patients in order to optimally manage the dyslipidaemic state in this high-risk population. With a high LDL-cholesterol, evidence would support the use of statins as the drug of choice to reduce the risk of a first or recurrent CHD event. In contrast, in the presence of a “normal” LDL-cholesterol in conjunction with a typical dyslipidaemia, a fibrate might reasonably be chosen as the first therapeutic option, particularly among patients with type 2 diabetes or with the features of the Metabolic Syndrome. However, there is also a substantial group of obese patients in whom the concentrations of both LDL-cholesterol and triglycerides are elevated in the presence of relatively low HDL-cholesterol. For this subgroup of high-risk patients, physicians may wish to consider combination therapy with both a statin and a fibrate in order to more aggressively treat patients characterised by such an atherogenic profile. Finally, a more aggressive lifestyle modification approach to help abdominally obese patients characterised by the Metabolic Syndrome achieve long-term changes in nutritional and physical activity habits, is the cornerstone of their management. The use of pharmacotherapy should be envisaged only for patients with medically complicated obesity in whom other approaches have failed.

Prevention and treatment of the Metabolic Syndrome

The Metabolic Syndrome is partly determined by environmental factors and in particular obesity and a sedentary lifestyle. ^1,2 However, there is some evidence suggesting a genetic basis for the Metabolic Syndrome. ³

Interventions aiming at improving insulin sensitivity, especially lifestyle modifications, represent the major basis of the treatment of the Metabolic Syndrome. Weight loss and increased physical activity are the cornerstone of the treatment. Recent evidence from two large prospective trials suggests that lifestyle interventions can substantially decrease the risk to develop diabetes in glucose-intolerant individuals. ^4,5 The Diabetes Prevention Program (DPP) demonstrated that an intensive lifestyle modification with the aim of at least 7% weight loss and at least 150 minutes of moderate-intensity physical activity per week significantly reduced the incidence of type 2 diabetes by 58% compared to placebo. ⁵ These findings are in agreement with those of other trials that showed substantial benefits of lifestyle modification on development of type 2 diabetes. ⁴

In addition to impaired glycaemia, a number of patients included in the DPP study were likely to have other features of the Metabolic Syndrome. Physical activity, weight loss and appropriate diet have a favourable impact on the components of the Metabolic Syndrome, at least in the relatively short term. Men who were engaged in regular moderate or vigorous leisure-time physical activity were less likely to develop the Metabolic Syndrome in a Finnish cohort. ²

However, to date, no randomised controlled trial has demonstrated that lifestyle interventions can prevent the Metabolic Syndrome. Furthermore, the long-term effectiveness of such interventions at the population level needs to be tested. The DPP study also showed that treatment with metformin at a dose of 850 mg twice daily significantly reduced the incidence of type 2 diabetes by 31% compared to placebo. ⁵ This protective effect was mainly observed in obese patients and in subjects younger than 60 years of age. Metformin enhances insulin sensitivity and has been demonstrated to reduce cardiovascular complications in obese type 2 diabetic patients. ⁶ Other drugs have shown their ability to improve metabolic abnormalities. Insulin-sensitising drugs thiazolidinediones may improve insulin-resistance and associated metabolic features. However, there is no direct evidence demonstrating that the currently available thiazolidinediones prevent the development of diabetes or cardiovas-cular disease. Fibrates that act on two important parameters (HDL-cholesterol and triglycerides) may be very useful in the treatment of patients presenting with a cluster of metabolic abnormalities.

References

1. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med 2001; 345: 790-7.
2. Laaksonen DE, Lakka HM, Salonen JT, et al. Low levels of leisure-time physical activity and cardiorespiratory fitness predict development of the metabolic syndrome. Diabetes Care 2002; 25: 1612-8.
3. Liese AD, Mayer-Davis EJ, Tyroler HA, et al. Familial components of the multiple metabolic syndrome: the ARIC study. Diabetologia 1997; 40: 963-70.
4. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343-50.
5. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403
6. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality assoctiated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 2002;25:2244-8.