Combined Effects of GLP-1 Analogue and Exercise on Maintenance of Weight Loss and Health After Very-low Calorie Diet
NCT ID: NCT04122716
Last Updated: 2020-11-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
UNKNOWN
PHASE4
215 participants
INTERVENTIONAL
2016-09-30
2021-11-30
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
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
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
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
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Statistical analysis of primary outcome will be blinded to the assessor.
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
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.
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.
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.
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.
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.
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.
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.
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.
No interventions assigned to this group
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
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.
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 Intervention Names
Discover alternative or legacy names that may be used to describe the listed interventions across different sources.
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
* Age \>18 and \<65 years
* Safe contraceptive method
Exclusion Criteria
* 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.
18 Years
65 Years
ALL
Yes
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
Hvidovre University Hospital
OTHER
University of Oxford
OTHER
Karolinska Institutet
OTHER
Signe Torekov
OTHER
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Signe Torekov
Professor
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Signe S Torekov, Prof, PhD
Role: STUDY_DIRECTOR
University of Copenhagen
Sten Madsbad, Prof, MD
Role: PRINCIPAL_INVESTIGATOR
Hvidovre University Hospital
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
University of Copenhagen, Department of Biomedical Sciences
Copenhagen, , Denmark
Countries
Review the countries where the study has at least one active or historical site.
References
Explore related publications, articles, or registry entries linked to this study.
Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894:i-xii, 1-253.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Holt J, Sandsdal RM, Byberg S, Janus C, Juhl CR, Jorgensen JR, Hartmann B, Stallknecht B, Holst JJ, Madsbad S, Jensen SBK, Torekov SS. One Year of Exercise After Weight Loss Increases Postprandial GLP-1 Secretion in Contrast to Usual Activity or GLP-1 Receptor Agonist Treatment. Obesity (Silver Spring). 2025 Sep 25. doi: 10.1002/oby.70043. Online ahead of print.
Holt R, Holt J, Jorsal MJ, Sandsdal RM, Jensen SBK, Byberg S, Juhl CR, Lundgren JR, Janus C, Stallknecht BM, Holst JJ, Juul A, Madsbad S, Jensen MB, Torekov SS. Weight Loss Induces Changes in Vitamin D Status in Women With Obesity But Not in Men: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2025 Jul 15;110(8):2215-2224. doi: 10.1210/clinem/dgae775.
Jensen SBK, Blond MB, Sandsdal RM, Olsen LM, Juhl CR, Lundgren JR, Janus C, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial. EClinicalMedicine. 2024 Feb 19;69:102475. doi: 10.1016/j.eclinm.2024.102475. eCollection 2024 Mar.
Sandsdal RM, Juhl CR, Jensen SBK, Lundgren JR, Janus C, Blond MB, Rosenkilde M, Bogh AF, Gliemann L, Jensen JB, Antoniades C, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial. Cardiovasc Diabetol. 2023 Feb 25;22(1):41. doi: 10.1186/s12933-023-01765-z.
Bogh AF, Jensen SBK, Juhl CR, Janus C, Sandsdal RM, Lundgren JR, Noer MH, Vu NQ, Fiorenza M, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Insufficient sleep predicts poor weight loss maintenance after 1 year. Sleep. 2023 May 10;46(5):zsac295. doi: 10.1093/sleep/zsac295.
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.
Provided Documents
Download supplemental materials such as informed consent forms, study protocols, or participant manuals.
Document Type: Statistical Analysis Plan
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
2015-005585-32
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
H-16027082
Identifier Type: OTHER
Identifier Source: secondary_id
U 1111-1173-3104 (UTN)
Identifier Type: -
Identifier Source: org_study_id