Abdominal Obesity as a Therapeutic Target: Long-term Benefits of Abdominal Fat Loss and Weight Stabilization in High-risk Abdominally Obese Dyslipidemic Patients With the Features of the Metabolic Syndrome (SYNERGIE Study)

Because of the risk of chronic complications associated with this condition, obesity has become a source of concern for health authorities of countries confronted to the consequences of the affluent and sedentary lifestyle of most of their citizens. It is also finally acknowledged that there is a need to go beyond the study of biological factors promoting obesity and to document approaches, both at the individual and society levels, likely to have an impact on the adiposity of the population of all ages and on related indicators of health and well-being.

In this context, the principal investigator's laboratory has ben studying the metabolic complications of obesity for over thirty years, with a major focus on adipose tissue, lipid metabolism and cardiovascular disease risk factors. It has been particularly involved in studies investigating the seemingly paradoxical and puzzling metabolic heterogeneity of obesity. Imaging studies conducted in the investigator's laboratory have shown that, in both men and women and irrespective of the variation in the amount of total body fat, patients with visceral obesity are characterized by the most severe metabolic abnormalities. Despite these findings, no study has shown that aiming at visceral adipose tissue loss as a therapeutic target would reduce the risk of coronary heart disease (CHD) in patients characterized by this condition. The best available data on the long-term benefits of moderate weight loss come from two landmark trials: the Finnish Prevention of Diabetes study and the American Prevention Program. Despite these trials providing evidence that moderate weight loss produced by an improved diet and a more physically active lifestyle can decrease the risk of developing type 2 diabetes in a high-risk population, several questions remain unanswered. Was the substantial reduction in risk of developing diabetes related to a selective loss of visceral adipose tissue? Was the assumed loss of visceral adipose tissue maintained throughout the two trials? Is the loss of visceral adipose tissue induced by moderate weight loss maintained once a reduced body weight is achieved and maintained over time? Would the assumed improvements in metabolic risk factors produced by these lifestyle modification programs be sustained had the reduced body weight been maintained over time? Most studies have assessed the potential metabolic benefits of weight loss immediately at the end of the weight loss intervention program. Although precautions have often been taken to perform this metabolic assessment once body weight is stabilized (and therefore when patients are presumably in energy balance), whether such improvements in the features of the metabolic syndrome would be maintained over time had patients been able to successfully maintain their reduced body weight over months, if not years, remains unclear. Therefore, there is an urgent need to properly document not only changes in the features of the metabolic syndrome in response to losses of abdominal fat and of total body fat, but also to verify whether the expected metabolic benefits are maintained over time if patients successfully maintain their recommended moderate (5-10%) weight reduction. The investigators consider that this therapeutic objective is realistic and achievable, but the notion that it is enough to generate a sustained and substantial improvement in all markers of the metabolic syndrome modulating CHD risk need to be secured. They hypothesized that under conditions of weight maintenance at a reduced body weight (between 5-10%), there will be a differential deterioration in some features of the metabolic syndrome over the two-year weight maintenance period. However, the investigators propose that such deterioration will be less marked when body weight is reduced by closer to 10% of the initial body weight and maintained as compared to lesser reductions. Finally, the investigators put forward the hypothesis that even in the absence of weight loss, the lifestyle intervention program will prevent visceral adipose tissue accumulation expected to be observed over the two-year follow-up period in the control group maintaining their usual behaviour.

These hypotheses have never been tested, particularly in the population of high-risk viscerally obese patients with the proper measurement of relevant features of the metabolic syndrome. In addition, whether physical activity and an improved diet could have an impact on visceral adipose tissue loss and related metabolic complications even in the absence of weight loss is a question of considerable clinical importance that is still a matter of debate and requires further evidence.

The overall objective of this trial is to verify whether the beneficial effects of weight loss on visceral adipose tissue measured by computed tomography and metabolic risk factors for CHD are maintained once asymptomatic but high-risk patients with abdominal obesity and hypertriglyceridemia are stabilized and maintained for two additional years after a one-year weight loss (5-10%) program. The secondary objectives of the study include:

To document the magnitude of changes of a comprehensive set of atherogenic-prothrombotic-inflammatory risk markers including postprandial lipemia in response to a 5-10% weight loss produced over a period of one year in a sample of asymptomatic but high-risk men with visceral obesity and hypertriglyceridemia.