Long-term Benefits of Abdominal Fat Loss in Abdominally Obese Dyslipidemic Patients (SYNERGIE Study)
Condition: Obesity, Visceral; Diet, Healthy; Cardiometabolic Syndrome; Lifestyle-related Condition
MeSH terms: Obesity; Metabolic Syndrome; Obesity, Abdominal; Syndrome
Study type: Interventional

Summary: 
      The objective of this clinical trial is to verify whether the beneficial effects of weight
      loss on visceral fat measured by computed tomography and metabolic risk factors for coronary
      heart disease are maintained once high-risk patients without symptoms and with visceral
      obesity and dyslipidemia are stabilized and maintained for two additional years after a
      one-year weight loss (5-10%) program.

      Before entering the study, after the one-year intervention program, and after the 2-year
      maintenance period, participants will be asked to take part in multiple assessments: fasting
      lipid profile and apolipoproteins measurements, oral glucose tolerance test, anthropometric
      measurements, computed tomography, dual-energy X-ray absorptiometry, oral lipid tolerance
      test, measurements of inflammatory markers, physical activity and dietary diaries,
      cardiorespiratory fitness assessed by a submaximal treadmill test, and measurements of
      resting and exercise blood pressure.

      During the one-year intervention, participants will be closely monitored by the study's
      dietitians and kinesiologists to achieve the target weight loss. Dieticians will not
      recommend a daily energy deficit greater than 500 calories and will focus on foods rather
      than the nutrient composition of the diet. Participants will have access to the dieticians at
      all time, and appointments every two months will be required during the first year. Regarding
      physical activity, kinesiologists will supervise the exercise prescription which will aim at
      160 minutes per week of moderate-intensity aerobic-exercise. The physical activity
      prescription will be adjusted by the kinesiologist according to the participant's preferences
      and habits.

      The investigators hypothesize that there will be a worsening in some features of the
      metabolic syndrome over the two-year weight maintenance period. However, it is suggested the
      greater the weight loss during the intervention, the less marked the deterioration will be.
      Finally, the investigators put forward that even in the absence of weight loss during the
      intervention, the lifestyle modification program will prevent visceral fat accumulation
      expected to be observed over the two-year maintenance period in the control group maintaining
      their usual behaviour.
    

Detailed description: 
      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.

      To compare the differential response of metabolic risk factors (including potential changes
      in visceral adipose tissue) during the two-year weight maintenance phase after a 5-10%
      reduction in body weight.

      To document the potential deterioration in a comprehensive set of metabolic risk variables in
      a group of asymptomatic but high-risk men with visceral obesity and hypertriglyceridemia
      maintaining their usual behaviour (control group).

      To document the long-term effects of a lifestyle modification program not inducing weight
      loss (non-responders of the lifestyle modification program) on a comprehensive set of
      metabolic risk variables (including visceral adipose tissue) in asymptomatic but high-risk
      men with visceral obesity and hypertriglyceridemia.

      Among patients achieving a 5-10% weight loss over the first year of the study, to quantify
      the proportion of men who will be able to maintain such a reduced body weight over an
      additional period of two years if offered close counselling and monitoring by a team of
      health professionals.

      For this study, 186 asymptomatic high-risk men with features of the metabolic syndrome will
      be assigned to either:

      a control group (n=42) receiving a medical, morphometric and metabolic evaluation at baseline
      as well as usual diet and physical activity recommendations (maintaining their usual
      behaviour) with follow-up measurements at years 1, 2 and 3;

      another group (n=144) subjected to the same baseline and follow-up measurements but who would
      benefit from a monthly individualized dietary counselling combined with a supervised
      exercise/physical activity program expected to generate a 5-10% weight loss over a period of
      one year.

      After the first year, the recommendations provided by the study dieticians and kinesiologist
      will be adjusted to aim at the maintenance of body weight for two additional years. Although
      the objective of the present study is to reshape the lifestyle of sedentary participants with
      abdominal obesity so that significant weight loss is achieved over a year, it is expected
      that some subjects will show a rebound of their body weight during the two-year weight
      maintenance period. These subjects will be kept in the program for ethical reasons, but two
      sets of analyses will be conducted at the end of the study: 1- analyses on subjects that have
      been able to maintain their body weight during the weight maintenance phase within a
      variation below 2.5% and 2- analyses on all subjects on an intent-to-treat basis.

      The investigators expect a 5-10% weight loss to induce a 20-40% loss of visceral adipose
      tissue. The present study has been powered (80% power) to detect a difference of 20% in
      changes in visceral adipose tissue as statistically significant. Two statistical approaches
      will be conducted to analyze data. First, a two-way analysis of variance will be used to
      analyze data at baseline and at one year; one experimental factor being the comparison among
      the two groups (the fixed factor being the various interventions) whereas the other being the
      testing phase (baseline and one year). Time will be analyzed as a repeated-measure factor.
      Different statistical models will be used to obtain the best-fit model and likelihood ratio
      tests will be carried out between models contained in the others. Comparisons of Akaike's
      information criterion (AIC) for the different models will also be performed. Normality will
      be verified with Shapiro-Wilk and Mardia tests. The second approach to analyze the data will
      be similar to the first one except for the definition of the factor time which will have in
      this case three levels: year 1, year 2 and year 3. Values at baseline will be used as
      covariates. This approach will allow us to test the possibility that the non responders were
      different at baseline from other participants assigned in the weight loss group. In addition,
      canonical analysis will be performed to identify relationships between two sets of variables
      to find the linear combination of adiposity variables (BMI, fat mass, subcutaneous and
      visceral adipose tissue) that will be most significantly correlated with the linear
      combination of metabolic risk factors. Posteriori comparisons between means will be obtained
      using Tukey's technique. Significance will be set at p-values ≤ 0.05. Analyses will be
      conducted using SAS (SAS Institute Inc, Cary, NC, USA) under the guidance of the research
      center's statistician.
    

Intervention name(s): Lifestyle modification program
Intervention type(s): Behavioral
Intervention description(s): Participants will take part in a lifestyle modification program focused on physical activity and diet.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Intervention group and control group
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Cardiometabolic health; Physical activity; Diet; Visceral obesity; Lifestyle intervention; Cardiorespiratory fitness