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

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

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.

Study Overview

• Status: Unknown
• Conditions: Obesity
• Intervention / Treatment: Drug: Liraglutide; Behavioral: Exercise

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 215
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2200
    • University of Copenhagen, Department of Biomedical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Liraglutide + exercise; 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; 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.; Other Names: Saxenda; Behavioral: 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. 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.
Other: Liraglutide + non-exercise; 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; 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.; Other Names: Saxenda
Other: Placebo + exercise; 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; 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.
No Intervention: Placebo + non-exercise; 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?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physical fitness (ml/min/min)	Measured by VO2 peak test on a bike, strength test, and functional stair test (unit: ml/min/min)	Change from baseline to end-of-treatment (52 weeks)
Quality of life score	The Short Form 36 Health Survey, (units on a scale: 0-100). Higher scores mean a better outocome	Change from baseline to end-of-treatment (52 weeks)
Heart rate	Heart rate (bpm)	Change from screening to baseline to end-of-treatment (52 weeks)
Proportion of participants with % weight loss	Proportion of participants with % weight loss (%)	Change from screening to end-of-treatment (52 weeks)
Total weight loss	Total weight loss (%)	Change from screening to end-of-treatment (52 weeks)
Questionnaires	Scores (units on a scale)	Change from baseline to end-of-treatment (52 weeks)
Fasting and meal-related hormonal response	Blood samples	Change from baseline to end-of-treatment (52 weeks)
Food preferences/subjective appetite sensation	Scores	Change from baseline to end-of-treatment (52 weeks)
Endothelial function	Measured by flow-mediated dilation (%)	Change from screening to baseline to end-of-treatment (52 weeks)
Determination of daily physical activity/sleep	Measured by triaxial accelerometry (GENEActiv, ActivInsights Ltd, UK) (min/day).	Change from screening to baseline to end-of-treatment (52 weeks)
Bone health (Bone mineral density)	Measured by DXA scan (g/cm^2)	Change from baseline to end-of-treatment (52 weeks)
Systemic markers of immunometabolism	Immunometabolic composition (CRP mg/l)	Change from screening to baseline to end-of-treatment (52 weeks)
Immunometabolic changes in the subcutaneous adipose tissue	Immunometabolic composition (gene expression)	Change from screening to baseline to end-of-treatment (52 weeks)
Spermatozoa	Spermatozoa concentration (counts/ml)	Change from screening to baseline to end-of-treatment (52 weeks)
Faecal bacterial composition	Microbiome composition	Change from screening to baseline to end-of-treatment (52 weeks)
Use of medication	n, frequency	Change from screening to baseline to end-of-treatment (52 weeks)
Follow-up visit	one-year follow-up (kg/fat%)	End-of-treatment to 1 year after intervention

Collaborators and Investigators

• Sponsor: Signe Torekov
• Collaborators: Karolinska Institutet; University of Oxford; Hvidovre University Hospital
• Investigators: Study Director: Signe S Torekov, Prof, PhD, University of Copenhagen; Principal Investigator: Sten Madsbad, Prof, MD, Hvidovre University Hospital

Publications and helpful links

General Publications

• Bruce CR, Thrush AB, Mertz VA, Bezaire V, Chabowski A, Heigenhauser GJ, Dyck DJ. Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E99-E107. doi: 10.1152/ajpendo.00587.2005. Epub 2006 Feb 7.
• Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998 Feb 1;101(3):515-20. doi: 10.1172/JCI990.
• Iepsen EW, Lundgren J, Holst JJ, Madsbad S, Torekov SS. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36. Eur J Endocrinol. 2016 Jun;174(6):775-84. doi: 10.1530/EJE-15-1116. Epub 2016 Mar 14.
• Iepsen EW, Lundgren J, Dirksen C, Jensen JE, Pedersen O, Hansen T, Madsbad S, Holst JJ, Torekov SS. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss. Int J Obes (Lond). 2015 May;39(5):834-41. doi: 10.1038/ijo.2014.177. Epub 2014 Oct 7.
• Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003 May;17(8):884-6. doi: 10.1096/fj.02-0670fje. Epub 2003 Mar 5.
• Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894:i-xii, 1-253.
• Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ, Jordan HS, Kendall KA, Lux LJ, Mentor-Marcel R, Morgan LC, Trisolini MG, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014 Jun 24;129(25 Suppl 2):S102-38. doi: 10.1161/01.cir.0000437739.71477.ee. Epub 2013 Nov 12. No abstract available. Erratum In: Circulation. 2014 Jun 24;129(25 Suppl 2):S139-40.
• Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK; American College of Sports Medicine. American College of Sports Medicine Position Stand. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc. 2009 Feb;41(2):459-71. doi: 10.1249/MSS.0b013e3181949333. Erratum In: Med Sci Sports Exerc. 2009 Jul;41(7):1532.
• Abdelaal M, le Roux CW, Docherty NG. Morbidity and mortality associated with obesity. Ann Transl Med. 2017 Apr;5(7):161. doi: 10.21037/atm.2017.03.107.
• Swift DL, Johannsen NM, Lavie CJ, Earnest CP, Church TS. The role of exercise and physical activity in weight loss and maintenance. Prog Cardiovasc Dis. 2014 Jan-Feb;56(4):441-7. doi: 10.1016/j.pcad.2013.09.012. Epub 2013 Oct 11.
• Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, Aronne L; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013 Nov;37(11):1443-51. doi: 10.1038/ijo.2013.120. Epub 2013 Jul 1. Erratum In: Int J Obes (Lond). 2013 Nov;37(11):1514. Int J Obes (Lond). 2015 Jan;39(1):187.
• Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, de Las Fuentes L, He S, Okunade AL, Patterson BW, Klein S. Effects of Moderate and Subsequent Progressive Weight Loss on Metabolic Function and Adipose Tissue Biology in Humans with Obesity. Cell Metab. 2016 Apr 12;23(4):591-601. doi: 10.1016/j.cmet.2016.02.005. Epub 2016 Feb 22.
• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13.
• Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsboll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. doi: 10.1056/NEJMoa1607141. Epub 2016 Sep 15.
• Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr. 2001 Nov;74(5):579-84. doi: 10.1093/ajcn/74.5.579.
• Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011 Aug 5;11(9):607-15. doi: 10.1038/nri3041.
• Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, Nadolsky K, Pessah-Pollack R, Plodkowski R; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocr Pract. 2016 Jul;22 Suppl 3:1-203. doi: 10.4158/EP161365.GL. Epub 2016 May 24.
• Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WS Jr, Brehm BJ, Bucher HC. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Feb 13;166(3):285-93. doi: 10.1001/archinte.166.3.285. Erratum In: Arch Intern Med. 2006 Apr 24;166(8):932.
• Weiss EP, Albert SG, Reeds DN, Kress KS, McDaniel JL, Klein S, Villareal DT. Effects of matched weight loss from calorie restriction, exercise, or both on cardiovascular disease risk factors: a randomized intervention trial. Am J Clin Nutr. 2016 Sep;104(3):576-86. doi: 10.3945/ajcn.116.131391. Epub 2016 Jul 27.
• Weiss EP, Reeds DN, Ezekiel UR, Albert SG, Villareal DT. Circulating cytokines as determinants of weight loss-induced improvements in insulin sensitivity. Endocrine. 2017 Jan;55(1):153-164. doi: 10.1007/s12020-016-1093-4. Epub 2016 Sep 7.
• Trussardi Fayh AP, Lopes AL, Fernandes PR, Reischak-Oliveira A, Friedman R. Impact of weight loss with or without exercise on abdominal fat and insulin resistance in obese individuals: a randomised clinical trial. Br J Nutr. 2013 Aug 28;110(3):486-92. doi: 10.1017/S0007114512005442. Epub 2013 Jan 10.
• Kroeger CM, Hoddy KK, Varady KA. Impact of weight regain on metabolic disease risk: a review of human trials. J Obes. 2014;2014:614519. doi: 10.1155/2014/614519. Epub 2014 Aug 14.
• Thomas TR, Warner SO, Dellsperger KC, Hinton PS, Whaley-Connell AT, Rector RS, Liu Y, Linden MA, Chockalingam A, Thyfault JP, Huyette DR, Wang Z, Cox RH. Exercise and the metabolic syndrome with weight regain. J Appl Physiol (1985). 2010 Jul;109(1):3-10. doi: 10.1152/japplphysiol.01361.2009. Epub 2010 Feb 18.
• Barte JC, ter Bogt NC, Bogers RP, Teixeira PJ, Blissmer B, Mori TA, Bemelmans WJ. Maintenance of weight loss after lifestyle interventions for overweight and obesity, a systematic review. Obes Rev. 2010 Dec;11(12):899-906. doi: 10.1111/j.1467-789X.2010.00740.x.
• Curioni CC, Lourenco PM. Long-term weight loss after diet and exercise: a systematic review. Int J Obes (Lond). 2005 Oct;29(10):1168-74. doi: 10.1038/sj.ijo.0803015.
• Rosenbaum M, Leibel RL. Adaptive thermogenesis in humans. Int J Obes (Lond). 2010 Oct;34 Suppl 1(0 1):S47-55. doi: 10.1038/ijo.2010.184.
• Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med. 1995 Mar 9;332(10):621-8. doi: 10.1056/NEJM199503093321001. Erratum In: N Engl J Med 1995 Aug 10;333(6):399.
• Shaw K, Gennat H, O'Rourke P, Del Mar C. Exercise for overweight or obesity. Cochrane Database Syst Rev. 2006 Oct 18;2006(4):CD003817. doi: 10.1002/14651858.CD003817.pub3.
• Nordby P, Auerbach PL, Rosenkilde M, Kristiansen L, Thomasen JR, Rygaard L, Groth R, Brandt N, Helge JW, Richter EA, Ploug T, Stallknecht B. Endurance training per se increases metabolic health in young, moderately overweight men. Obesity (Silver Spring). 2012 Nov;20(11):2202-12. doi: 10.1038/oby.2012.70. Epub 2012 Mar 22.
• You T, Arsenis NC, Disanzo BL, Lamonte MJ. Effects of exercise training on chronic inflammation in obesity : current evidence and potential mechanisms. Sports Med. 2013 Apr;43(4):243-56. doi: 10.1007/s40279-013-0023-3.
• Lavie CJ, Arena R, Swift DL, Johannsen NM, Sui X, Lee DC, Earnest CP, Church TS, O'Keefe JH, Milani RV, Blair SN. Exercise and the cardiovascular system: clinical science and cardiovascular outcomes. Circ Res. 2015 Jul 3;117(2):207-19. doi: 10.1161/CIRCRESAHA.117.305205.
• Calbet JAL, Ponce-Gonzalez JG, Calle-Herrero J, Perez-Suarez I, Martin-Rincon M, Santana A, Morales-Alamo D, Holmberg HC. Exercise Preserves Lean Mass and Performance during Severe Energy Deficit: The Role of Exercise Volume and Dietary Protein Content. Front Physiol. 2017 Jul 24;8:483. doi: 10.3389/fphys.2017.00483. eCollection 2017.
• Stiegler P, Cunliffe A. The role of diet and exercise for the maintenance of fat-free mass and resting metabolic rate during weight loss. Sports Med. 2006;36(3):239-62. doi: 10.2165/00007256-200636030-00005.
• Jakicic JM, Marcus BH, Lang W, Janney C. Effect of exercise on 24-month weight loss maintenance in overweight women. Arch Intern Med. 2008 Jul 28;168(14):1550-9; discussion 1559-60. doi: 10.1001/archinte.168.14.1550. Erratum In: Arch Intern Med. 2008 Oct 27;168(19):2162.
• Wing RR, Phelan S. Long-term weight loss maintenance. Am J Clin Nutr. 2005 Jul;82(1 Suppl):222S-225S. doi: 10.1093/ajcn/82.1.222S.
• Holst JJ, Deacon CF, Vilsboll T, Krarup T, Madsbad S. Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med. 2008 Apr;14(4):161-8. doi: 10.1016/j.molmed.2008.01.003. Epub 2008 Mar 18.
• Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjoth TV, Andreasen AH, Jensen CB, DeFronzo RA; NN8022-1922 Study Group. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015 Aug 18;314(7):687-99. doi: 10.1001/jama.2015.9676. Erratum In: JAMA. 2016 Jan 5;315(1):90.
• Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, le Roux CW, Violante Ortiz R, Jensen CB, Wilding JP; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015 Jul 2;373(1):11-22. doi: 10.1056/NEJMoa1411892.
• Stepien M, Stepien A, Wlazel RN, Paradowski M, Banach M, Rysz J. Obesity indices and inflammatory markers in obese non-diabetic normo- and hypertensive patients: a comparative pilot study. Lipids Health Dis. 2014 Feb 8;13:29. doi: 10.1186/1476-511X-13-29.
• Panagiotakos DB, Pitsavos C, Yannakoulia M, Chrysohoou C, Stefanadis C. The implication of obesity and central fat on markers of chronic inflammation: The ATTICA study. Atherosclerosis. 2005 Dec;183(2):308-15. doi: 10.1016/j.atherosclerosis.2005.03.010. Epub 2005 Apr 25.
• Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G; Atherosclerosis Risk in Communities Study. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes. 2003 Jul;52(7):1799-805. doi: 10.2337/diabetes.52.7.1799.
• Vozarova B, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA. High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes. 2002 Feb;51(2):455-61. doi: 10.2337/diabetes.51.2.455.
• Torekov SS. Glucagon-like peptide-1 receptor agonists and cardiovascular disease: from LEADER to EXSCEL. Cardiovasc Res. 2018 Aug 1;114(10):e70-e71. doi: 10.1093/cvr/cvy124. No abstract available.
• Insuela DBR, Carvalho VF. Glucagon and glucagon-like peptide-1 as novel anti-inflammatory and immunomodulatory compounds. Eur J Pharmacol. 2017 Oct 5;812:64-72. doi: 10.1016/j.ejphar.2017.07.015. Epub 2017 Jul 6.
• Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010 Apr;59(4):1030-7. doi: 10.2337/db09-1694. Epub 2010 Jan 12.
• Lee YS, Park MS, Choung JS, Kim SS, Oh HH, Choi CS, Ha SY, Kang Y, Kim Y, Jun HS. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia. 2012 Sep;55(9):2456-68. doi: 10.1007/s00125-012-2592-3. Epub 2012 Jun 22.
• Noyan-Ashraf MH, Shikatani EA, Schuiki I, Mukovozov I, Wu J, Li RK, Volchuk A, Robinson LA, Billia F, Drucker DJ, Husain M. A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation. 2013 Jan 1;127(1):74-85. doi: 10.1161/CIRCULATIONAHA.112.091215. Epub 2012 Nov 27.
• Garczorz W, Gallego-Colon E, Kosowska A, Klych-Ratuszny A, Wozniak M, Marcol W, Niesner KJ, Francuz T. Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor alpha-mediated activation. Cardiovasc Ther. 2018 Apr;36(2). doi: 10.1111/1755-5922.12317. Epub 2018 Jan 24.
• Hogan AE, Gaoatswe G, Lynch L, Corrigan MA, Woods C, O'Connell J, O'Shea D. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2014 Apr;57(4):781-4. doi: 10.1007/s00125-013-3145-0. Epub 2013 Dec 21.
• Chaudhuri A, Ghanim H, Vora M, Sia CL, Korzeniewski K, Dhindsa S, Makdissi A, Dandona P. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab. 2012 Jan;97(1):198-207. doi: 10.1210/jc.2011-1508. Epub 2011 Oct 19.
• Pastel E, McCulloch LJ, Ward R, Joshi S, Gooding KM, Shore AC, Kos K. GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction. Clin Sci (Lond). 2017 Mar 1;131(5):343-353. doi: 10.1042/CS20160803. Epub 2017 Jan 3.
• Bunck MC, Diamant M, Eliasson B, Corner A, Shaginian RM, Heine RJ, Taskinen MR, Yki-Jarvinen H, Smith U. Exenatide affects circulating cardiovascular risk biomarkers independently of changes in body composition. Diabetes Care. 2010 Aug;33(8):1734-7. doi: 10.2337/dc09-2361. Epub 2010 Apr 27.
• Jensen SBK, Janus C, Lundgren JR, Juhl CR, Sandsdal RM, Olsen LM, Andresen A, Borg SA, Jacobsen IC, Finlayson G, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment. Nat Commun. 2022 Aug 15;13(1):4770. doi: 10.1038/s41467-022-32307-y.
• Andersen E, Juhl CR, Kjoller ET, Lundgren JR, Janus C, Dehestani Y, Saupstad M, Ingerslev LR, Duun OM, Jensen SBK, Holst JJ, Stallknecht BM, Madsbad S, Torekov SS, Barres R. Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial. Hum Reprod. 2022 Jun 30;37(7):1414-1422. doi: 10.1093/humrep/deac096.
• Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, Svane MS, Bandholm T, Bojsen-Moller KN, Blond MB, Jensen JB, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021 May 6;384(18):1719-1730. doi: 10.1056/NEJMoa2028198.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2016
• Primary Completion (Actual): November 1, 2019
• Study Completion (Anticipated): November 1, 2021

Study Registration Dates

• First Submitted: July 20, 2018
• First Submitted That Met QC Criteria: October 8, 2019
• First Posted (Actual): October 10, 2019

Study Record Updates

• Last Update Posted (Actual): November 2, 2020
• Last Update Submitted That Met QC Criteria: October 28, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Exercise intervention; Weight loss maintenance; Immunometabolic health; GLP-1 receptor agonist (liraglutide)
• Additional Relevant MeSH Terms: Body Weight; Body Weight Changes; Weight Loss; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: U 1111-1173-3104 (UTN); 2015-005585-32 (EudraCT Number); H-16027082 (Other Identifier: The Ethical Committee of the Capital Region of Denmark)

Drug and device information, study documents

• product manufactured in and exported from the U.S.: No