Combined Effects of GLP-1 Analogue and Exercise on Maintenance of Weight Loss and Health After Very-low Calorie Diet

Study Overview
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Brief Summary
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Introduction: The success rate of weight loss maintenance is limited. Therefore, the purpose of this study is to investigate the maintenance of weight loss and immunometabolic health outcomes after diet-induced weight loss followed by one-year treatment with a glucagon-like peptide-1 receptor agonist (liraglutide), physical exercise, or the combination of both treatments as compared with placebo in individuals with obesity. Methods and analysis: This is an investigator-initiated, randomized, placebo-controlled, parallel group trial. The investigators will enroll women and men (age 18 to 65 years) with obesity (body mass index 32 to 43 kg/m2) to adhere to a very low-calorie diet (800 kcal/day) for eight weeks in order to lose at least 5 % of body weight. Subsequently, participants will be randomized in a 1:1:1:1 ratio to one of four study groups for 52 weeks: 1) placebo, 2) exercise 150 min/week + placebo, 3) liraglutide 3.0 mg/day, and 4) exercise 150 min/week + liraglutide 3.0 mg/day. Re-screening is allowed within the recruitment period. The primary endpoint is change in body weight from randomization to end-of-treatment. Ethics and dissemination: The trial has been approved by the ethical committee of the Capital Region of Denmark (H-16027082) and the Danish Medicines Agency (EudraCT 2015-005585-32). The trial will be conducted in agreement with the Declaration of Helsinki and monitored to follow the guidelines for good clinical practice. Results will be submitted for publication in international peer-reviewed scientific journals.

Detailed Description
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Obesity is associated with increased risk of developing cardiovascular disease and type 2 diabetes (T2D), along with increased risk of all-cause mortality [1,2]. Obesity management guidelines recommends weight loss of more than 5 % of initial body weight to improve cardiometabolic risk factors, with greater weight loss producing greater benefits [3,4]. A 5 to 10 % weight loss improves lipid profile ( 20% reduction in triglycerides,  15 % reduction in LDL-cholesterol,  8 % increase in HDL-cholesterol levels) [1,4,5], reduces systolic and diastolic blood pressure ( 5 and  4 mmHg, respectively) [3,6], reduces HbA1c [3,4], and improves insulin sensitivity [7-9]. However, weight regain reverse these health benefits [10,11]. Furthermore, intentional weight loss is typically followed by a 30 to 50 % regain of lost weight within the first year [12-14]. The main biological reasons for the rapid weight regain may be that weight loss causes a decrease in total energy expenditure to a degree that is greater than predicted from the decrease in fat and lean mass [15,16] in combination with increased appetite in the weight-reduced state [17,18]. Increasing energy expenditure by increasing physical activity is the first-line lifestyle modification in the treatment of obesity along with reducing food intake. For exercise interventions targeting general public health recommendations (at least 150 min/week of moderate intensity aerobic exercise), the associated weight loss is often modest (0-3 %) without concomitant calorie restriction [19-21]. However, independent of weight loss, increasing physical activity improves body composition, glycemic control, low grade inflammatory profile, and cardiorespiratory fitness in individuals with overweight and obesity [22-25]. In addition, exercise may preserve lean mass during weight loss [26] and thereby counteract the associated decrease in resting metabolic rate [27], which may explain the observation that individuals performing regular exercise have less body weight regain after weight loss compared to participants that do not exercise [28,29]. Glucagon-like peptide-1 (GLP-1) is an incretin hormone primarily secreted from enteroendocrine L-cells in the gut after food intake. GLP-1 stimulates glucose-dependent insulin secretion thereby lowering blood glucose and reduces appetite and thereby food intake [30,31]. Treatment for 56 weeks with the GLP-1 receptor agonist (GLP-1 RA), liraglutide (3.0 mg), as an adjunct to regular diet and physical activity recommendations has been shown to improve glycemic control and induce moderate weight loss of 4.0 % in patients with T2D [32] and 5.4 % in non-diabetic individuals with overweight or obesity [33] compared to placebo. In addition, liraglutide has been shown to maintain a diet-induced weight loss over 56 weeks [34] and maintain very low-calorie diet-induced improvements of fasting plasma glucose and triglycerides over 52 weeks of weight loss maintenance superior to similar diet-induced weight loss maintenance in obese nondiabetic individuals [18]. Obesity is associated with chronic low-grade inflammation [35,36] which is linked to the development of atherosclerosis and insulin resistance [37-39]. Physically active individuals have lower inflammatory biomarker concentrations than their inactive counterparts [24], possibly explained by antiinflammatory effects of an acute bout of exercise [40] and lower levels of visceral adipose tissue [41]. GLP-1 has also emerged as an immunomodulatory agent [42,43]. In mice, GLP-1 RA administration reduces macrophage accumulation and inflammatory markers in the arterial wall [44], adipose tissue [45], and heart [46]. Similarly, GLP-1 RAs have shown antiinflammatory effects in human coronary artery endothelial cells and aortic endothelial cells [47]. In humans with T2D, short term GLP-1 RA treatment exert antiinflammatory actions, reflected in reduced levels of the macrophage activation molecule sCD163 [48] and reduced production of several proinflammatory markers, such as TNF-α, IL1β, and IL-6 in peripheral blood mononuclear cells [48,49]. Another study showed no improvement of obesity-associated adipose tissue dysfunction in T2D patients after GLP-1RA treatment [50]. One year treatment with GLP-1 RAs reduce the inflammation marker, high-sensitivity C-reactive protein, in overweight and obese individuals [33] and T2D patients [51]. Notably, in patients with T2D and high cardiovascular risk, GLP-1 RAs reduced the rate of occurrence of first major cardiovascular event [52,53]. Thus, both physical activity and GLP-1 RA treatment seem to facilitate weight loss maintenance, improve metabolic health, and reduce systemic inflammation. However, diet-induced weight loss decreases energy expenditure and increases appetite. The investigators hypothesize that the combination of physical activity and liraglutide treatment improves weight loss maintenance and immunometabolic health since the decreased energy expenditure is targeted with exercise and the increased appetite with liraglutide. Objective: The objectives of this study are to investigate the maintenance of weight loss and immunometabolic health outcomes over 52 weeks with liraglutide treatment, physical exercise, and the combination in individuals with obesity, after a very low-calorie diet. Endpoints: Primary endpoint: The primary endpoint is change in body weight from after the initial weight loss phase (baseline/V1) to end of treatment after 52 weeks (end/V3). Secondary endpoints: The secondary endpoints are changes in a) body composition (fat %, lean and fat mass ) and b) metabolic health (glucose tolerance (HOMA-IR, Matsuda, HbA1c), lipid status, waist circumference, blood pressure) from V1 to V3. Other prespecified endpoints: Prespecified endpoints include changes from V0 to V1 to V3 in the following parameters: Physical fitness (measured by VO2 peak test on a bike, strength test, and functional stair test) Fasting and meal-related hormonal response (e.g. GLP-1, PYY, ghrelin, leptin, etc.) Food preferences and subjective appetite sensation (measured by the Leeds Food Preference Questionnaire (LFPQ) and visual analogue scales) Determination of daily physical activity and sleep (measured by triaxial accelerometry (GENEActiv, ActivInsights Ltd, UK) and questionnaires (PSQI and IPAQ)). Endothelial function (e.g. measured by flow-mediated dilation (FMD) and relevant systemic biomarkers) Standard clinical blood samples (e.g. C-reactive protein, vitamin D, and glycated hemoglobin) Electrocardiogram (ECG) Heart rate Health-related questionnaires (self-rated quality of life (The Short Form (36) Health Survey), eating habits (three-factor eating questionnaire), physical activity (International Physical Activity Questionnaire), sleep quality (Pittsburgh Sleep Quality Index), and self-efficacy (General Self-Efficacy Scale). Systemic markers of immunometabolism (e.g. measured by single cell analysis) Immunometabolic changes in the subcutaneous adipose tissue (e.g. measured by single cell analysis) Gene expression profile of circulating inflammatory cells (e.g. in adipose tissue cells in which proinflammatory and antiinflammatory adipocytokines, adipocyte differentiation markers, and markers of macrophages infiltration will be determined by reverse transcription-qPCR). Bone health (measured by DXA scan and relevant systemic bone markers) Faecal bacterial composition Metabolomics and proteomics Epigenetics of spermatozoa Use of medication Proportion of participants with 5,10, 15 and 20% total weight loss Weight loss from V0-V3 Follow-up visit 1 year after end of treatment: Body weight, height, waist and hip circumference, blood pressure and pulse Fasting blood samples (identical to samples obtained for V0) DEXA scan Questionnaires as in V0 Accelerometer device (GENEActiv) worn on wrist for 7 consecutive days and nights after follow-up testing to assess physical activity levels

Official Title
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Synergy Effect of the Appetite Hormone GLP-1 (LiragluTide) and Exercise on Maintenance of Weight Loss and Health After a Low Calorie Diet - the S-LiTE Randomized Trial

Conditions
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Obesity

Intervention / Treatment
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* Drug: Liraglutide
* Behavioral: Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI > 32 and < 43 (kg/m2) Age >18 and <65 years Safe contraceptive method Exclusion Criteria: Patients diagnosed with known serious chronic illness including type 1 or 2 diabetes (or a randomly measured fasting plasma glucose > 7 mmol/l) Angina pectoris, coronary heart disease, congestive heart failure (NYHA III-IV) Severe renal impairment (creatinine clearance (GFR) <30 mL/min) Severe hepatic impairment Inflammatory bowel disease Gastroparesis Cancer Chronic obstructive lung disease Psychiatric disease, a history of major depressive or other severe psychiatric disorders The use of medications that cause clinically significant weight gain or loss Previous bariatric surgery A history of idiopathic acute pancreatitis A family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma Osteoarthritis which is judged to be too severe to manage the exercise programme. As intended per study design the intervention will include a 5% weight loss prior to randomization, thus it is expected that possible participants with mild form of osteoarthritis will be able to manage exercise prescriptions. Pregnancy, expecting pregnancy or breast feeding. If a study participant is in doubt whether she could be pregnant, a urine pregnancy test is performed. Females of childbearing potential who are not using adequate contraceptive methods (as required by local law or practice). Adequate contraception must be used throughout the study period and at least 65 hours after discontinuation of trial medication (65 hours corresponds to 5 times the half-life of Saxenda). Allergy to any of the ingredients/excipients. Allergy to any of the ingredients/excipients of the study medication: liraglutide, disodium phosphate dihydrate, propylene glycol, phenol, hydrochloric acid, sodium hydroxide. Regular exercise training at high intensity (e.g. spinning) >2 hours per week.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: After 8 weeks of weight loss the participants are randomized to receive a) Liraglutide 3mg/day sc or b) placebo sc or c) Exercise + placebo sc or d) Exercise + Liraglutide 3mg/d sc for 52 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liraglutide + exercise<br>Liraglutide: 3 mg/day sc. The GLP-1 RA, liraglutide (3.0 mg), or placebo, will be administrated once daily as subcutaneous injections in the abdomen or thigh. The starting dose is 0.6 mg with weekly increments of 0.6 mg until 3.0 mg is achieved. The titration procedure will be prolonged for participants who do not tolerate fast up-titration. Participants who do not tolerate the 3.0 mg dose may in special circumstances stay at lower dose (2.4 mg). However, the aim is to reach 3.0 mg for all study participants. Exercise: 150 min of moderate intensity, 75 min of vigorous intensity, or an equivalent combination of moderate and vigorous intensity exercise per week in accordance with WHO recommendations. | Drug: Liraglutide<br>* Daily injections (3mg) with weight consultations starting at dose of 0.6 mg injections with 0.6 mg increments weekly until 3.0 mg is achieved. For subjects who do not tolerate the fast weekly up-titration of 0.6 mg study drug until the 3mg, the titration procedure can be prolonged with up to three weeks for each up-titration. Subjects who do not tolerate the 3mg dose may in special circumstances stay at 2.4 mg, however the overall aim is to reach 3 mg for all study subjects. The dosage and up-titration follow the recommendations from the summary of product characteristics.<br>* Other names: Saxenda;Behavioral: Exercise<br>* 150 min of moderate intensity, 75 min of vigorous intensity, or an equivalent combination of moderate and vigorous intensity exercise per week in accordance with WHO recommendations. Exercise prescription will be performed under strict control of the scientific personnel. There will be aerobic exercise and will include 4 sessions per week after the ramp-in period. 2 sessions per week will be performed under supervision of the staff and 2 sessions will be performed individually but monitored by the staff. Supervised sessions include structured exercise with a duration of 45 min. Of this 30 min will comprise of interval-based spinning session and 15 min circuit training program focusing on large muscle groups. Individual exercise includes aerobic exercise and general physical activity (e.g brisk walking and cycling to work). Participants will use heart rate monitors during sessions.<br>|
| Other: Liraglutide + non-exercise<br>Liraglutide: 3 mg/day sc. The GLP-1 RA, liraglutide (3.0 mg), or placebo, will be administrated once daily as subcutaneous injections in the abdomen or thigh. The starting dose is 0.6 mg with weekly increments of 0.6 mg until 3.0 mg is achieved. The titration procedure will be prolonged for participants who do not tolerate fast up-titration. Participants who do not tolerate the 3.0 mg dose may in special circumstances stay at lower dose (2.4 mg). However, the aim is to reach 3.0 mg for all study participants. Non-exercise: Participants should stay at same physical activity level (i.e. max. 2 h of vigorous endurance training/week) as when the participant was included in the study. | Drug: Liraglutide<br>* Daily injections (3mg) with weight consultations starting at dose of 0.6 mg injections with 0.6 mg increments weekly until 3.0 mg is achieved. For subjects who do not tolerate the fast weekly up-titration of 0.6 mg study drug until the 3mg, the titration procedure can be prolonged with up to three weeks for each up-titration. Subjects who do not tolerate the 3mg dose may in special circumstances stay at 2.4 mg, however the overall aim is to reach 3 mg for all study subjects. The dosage and up-titration follow the recommendations from the summary of product characteristics.<br>* Other names: Saxenda;|
| Other: Placebo + exercise<br>Placebo: 3mg/day sc. Exercise: 150 min of moderate intensity, 75 min of vigorous intensity, or an equivalent combination of moderate and vigorous intensity exercise per week in accordance with WHO recommendations. | Behavioral: Exercise<br>* 150 min of moderate intensity, 75 min of vigorous intensity, or an equivalent combination of moderate and vigorous intensity exercise per week in accordance with WHO recommendations. Exercise prescription will be performed under strict control of the scientific personnel. There will be aerobic exercise and will include 4 sessions per week after the ramp-in period. 2 sessions per week will be performed under supervision of the staff and 2 sessions will be performed individually but monitored by the staff. Supervised sessions include structured exercise with a duration of 45 min. Of this 30 min will comprise of interval-based spinning session and 15 min circuit training program focusing on large muscle groups. Individual exercise includes aerobic exercise and general physical activity (e.g brisk walking and cycling to work). Participants will use heart rate monitors during sessions.<br>|
| No Intervention: Placebo + non-exercise<br>Placebo: 3mg/day sc. Non-exercise: Participants should stay at same physical activity level (i.e. max. 2 h of vigorous endurance training/week) as when the participant was included in the study. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body weight change (kg) | Weight will be measured to the nearest 0.1 kg. The same set of scales should ideally be used throughout the trial. Weight should be measured in a fasting state without shoes and wearing light clothes. | Change from baseline to end-of-treatment (52 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body composition (fat percentage) | Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure body fat percentage (%). | Change from baseline to end-of-treatment (52 weeks) | 
| Body composition (fat mass and fat free mass) | Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure fat mass/fat free mass (kg). | Change from baseline to end-of-treatment (52 weeks) | 
| Waist and hip circumference | Waist circumference, the midpoint between lowest rib and iliac crest, and hip circumference, the level of the great trochanters, will be measured in duplicate to the nearest 0.1 cm after gentle expiration. | Change from baseline to end-of-treatment (52 weeks) | 
| HOMA-IR | Fasting insulin (μU/mL) * fasting glucose (mmol/L) / 22.5 | Change from baseline to end-of-treatment (52 weeks) | 
| Matsuda Index | 10000/sqrt(fasting glucose * fasting insulin * mean glucose * mean insulin) | Change from baseline to end-of-treatment (52 weeks) | 
| Hormonal regulation of blood glucose | Measured from blood samples (e.g. glucose tolerance, HbA1c (mmol/mol)) | Change from baseline to end-of-treatment (52 weeks) | 
| Lipids | Measured from blood samples (e.g. cholesterol (HDL, LDL, VLDL) and triglycerides (TG)) (mmol/L) | Change from baseline to end-of-treatment (52 weeks) | 
| Blood pressure | Blood pressure (systolic/diastolic) will be measured in duplicate from the non-dominant arm with a digital blood pressure monitor in sitting position after at least 5 min of rest (mmHg). | Change from baseline to end-of-treatment (52 weeks) | 
| Metabolic Syndrome (yes/no) | Relevant clinical parameters lipids, fasting glucose, waist circumference, and blood pressure will be used to investigate whether the participants have metabolic syndrome (unit: yes/no). | Change from baseline to end-of-treatment (52 weeks) | 
| MetS (z-score) | Relevant clinical parameters lipids, fasting glucose, waist circumference, and blood pressure will be used to calculate a z-score (unit: z-score) | Change from baseline to end-of-treatment (52 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Weight loss maintenance, Immunometabolic health, Exercise intervention, GLP-1 receptor agonist (liraglutide)