Protocol for a randomised controlled trial of the combined effects of the GLP-1 receptor agonist liraglutide and exercise on maintenance of weight loss and health after a very low-calorie diet

Jensen, Simon B K; Lundgren, Julie; Janus, Charlotte; Juhl, Christian R.; Olsen, Lisa; Rosenkilde, Mads; Holst, Jens J.; Stallknecht, Bente; Madsbad, Sten; Torekov, Signe S.

doi:10.1136/bmjopen-2019-031431

Cited by 16 publications

(33 citation statements)

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“…This study was performed as a substudy of the S-LiTE trial (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 trial protocol with details of the design, a full list of inclusion and exclusion criteria and methods has been published ( Jensen et al , 2019 ) as well as the results of the primary endpoint, weight change ( Lundgren et al , 2021 ). In brief, the S-LiTE trial included 215 women and men (age 18–65 years) with obesity (BMI 32–43 kg/m 2 ) but without diabetes.…”

Section: Methodsmentioning

confidence: 99%

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Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial

et al. 2022

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STUDY QUESTION Does diet-induced weight loss improve semen parameters, and are these possible improvements maintained with sustained weight loss? SUMMARY ANSWER An 8-week low-calorie diet-induced weight loss was associated with improved sperm concentration and sperm count, which were maintained after 1 year in men who maintained weight loss. WHAT IS KNOWN ALREADY Obesity is associated with impaired semen quality. Weight loss improves metabolic health in obesity, but there is a lack of knowledge on the acute and long-term effects of weight loss on semen parameters. STUDY DESIGN, SIZE, DURATION This is a substudy of men with obesity enrolled in a randomized, controlled, double-blinded trial (the S-LITE trial). The trial was conducted between August 2016 and November 2019. A total of 56 men were included in the study and assigned to an initial 8-week low-calorie diet (800 kcal/day) followed by randomization to 52 weeks of either: placebo and habitual activity (placebo), exercise training and placebo (exercise), the Glucagon Like Peptide 1 (GLP-1) analogue liraglutide and habitual activity (liraglutide) or liraglutide in combination with exercise training (combination). PARTICIPANTS/MATERIALS, SETTING, METHODS Inclusion criteria were men who delivered semen samples, 18 to 65 years of age, and a body mass index between 32 and 43 kg/m2, but otherwise healthy. The study was carried out at Hvidovre Hospital and at the University of Copenhagen, and the participants were from the Greater Copenhagen Area. We assessed semen parameters and anthropometrics and collected blood samples before (T0), after the 8-week low-calorie dietary intervention (T1), and after 52 weeks (T2). MAIN RESULTS AND THE ROLE OF CHANCE The men lost on average 16.5 kg (95% CI: 15.2–17.8) body weight during the low-calorie diet, which increased sperm concentration 1.49-fold (95% CI: 1.18–1.88, P < 0.01) and sperm count 1.41-fold (95% CI: 1.07–1.87, P < 0.01). These improvements were maintained for 52 weeks in men who maintained the weight loss, but not in men who regained weight. Semen volume, sperm motility and motile sperm count did not change. LIMITATIONS, REASONS FOR CAUTION The S-LITE trial was a randomized controlled trial of weight loss maintenance. Analysis of semen was preregistered to explore the effects of weight loss and weight loss maintenance on semen parameters, but definite inferences cannot be made. WIDER IMPLICATIONS OF THE FINDINGS This study shows that sperm concentration and sperm count were improved after a diet-induced weight loss in men with obesity. Our findings indicate that either or both liraglutide and exercise as weight maintenance strategies may be used to maintain the improvements in sperm concentration and count. STUDY FUNDING/COMPETING INTEREST(S) This work is supported by an excellence grant from the Novo Nordisk Foundation (NNF16OC0019968), a Challenge Programme Grant from the Novo Nordisk Foundation (NNF18OC0033754) and a grant from Helsefonden. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900). Saxenda (liraglutide) and placebo pens were provided by Novo Nordisk. Cambridge Weight Plan diet products for the 8-week low-calorie diet were provided by Cambridge Weight Plan. E.A.: shareholder, employee of ExSeed Health Ltd. Grant Recipient from ExSeed Health Ltd and listed on Patents planned, issued or pending with ExSeed Health Ltd; J.J.H.: consultant for Eli Lilly A/S and Novo Nordisk A/S. Lecture fees for Novo Nordisk A/S. Listed on Patents planned, issued or pending with the University of Copenhagen, Advocacy group for Antag Therapeutics and Bainan Biotech; S.M.: lecture fees for Novo Nordisk A/S. Recipient of Support for attending meetings from Novo Nordisk A/S. Advisory boards of Novo Nordisk A/S; Sanofi Aventis and Merck Sharp & Dohme. S.S.T.: research grant recipient Novo Nordisk. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER The trial was approved by the Ethical Committee of the Capital Region of Denmark (H-16027082) and the Danish Medicines Agency (EudraCT Number: 2015-005585-32). ClinicalTrials.gov identifier (NCT number): NCT04122716. TRIAL REGISTRATION DATE 11 May 2016. DATE OF FIRST PATIENT’S ENROLMENT August 2016.

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Section: Methodsmentioning

confidence: 99%

“…Three test days were performed before (T0) and after (T1) the 8-week low-calorie diet and at 52 weeks after randomization (T2). Changes in semen parameters were preregistered as explorative endpoints ( Jensen et al , 2019 ) and were the aim of this substudy. The study was reported according to the CONSORT guideline.…”

Section: Methodsmentioning

confidence: 99%

Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial

et al. 2022

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“…After the initial weight loss, participants were randomly assigned to a one-year weight loss maintenance phase with either a moderate-to-vigorous intensity exercise program plus placebo (exercise group), liraglutide 3.0 mg/day (liraglutide group), a combination of exercise and liraglutide (combination group), or placebo (placebo group). Eligible participants were adults (age 18-65 years) with obesity (BMI 32-43 kg/m 2 ) without diabetes (see the full list of eligibility criteria here 27 ). A total of 195 participants completed the eight-week low-calorie diet, of whom 166 participants underwent assessments after one year.…”

Section: Resultsmentioning

confidence: 99%

“…The reported results were part of a randomized placebo-controlled, 2-by-2 factorial trial (EudraCT number, 2015-005585-32; clinicaltrials.gov number, NCT04122716). The study protocol, statistical analysis plan, and primary outcome (body weight) have been published 26 , 27 . The study was approved by the Regional Ethics Committee for the Capital Region of Denmark (H-16027082) and the Danish Medicines Agency and was carried out in accordance with the principles of the Declaration of Helsinki and ICH Good Clinical Practice guidelines.…”

Section: Methodsmentioning

confidence: 99%

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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

et al. 2022

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Weight regain after weight loss remains a major challenge in obesity treatment and may involve alteration of eating and sedentary behavior after weight loss. In this randomized, controlled, double-blind trial, adults with obesity were randomized, in a 1:1:1:1 ratio stratified by sex and age group (<40 years and ≥40 years), to one-year weight loss maintenance with exercise, the GLP-1 receptor agonist liraglutide, or the combination, as compared with placebo, after low-calorie diet-induced weight loss. Primary outcome was change in body weight, which has been published. Here, we investigated the effects of weight loss maintenance with exercise, liraglutide, or the combination on weight loss-induced changes in the pre-specified explorative outcomes, eating and sedentary behavior in 130 participants who completed the trial according to the study protocol (exercise (n = 26), liraglutide (n = 36), combination (n = 29), and placebo (n = 39)). One year after weight loss, the placebo group had decreased postprandial appetite suppression score by 14%, and increased sedentary time by 31 min/day and regained weight. Liraglutide prevented the decrease in postprandial appetite suppression score compared with placebo (0% vs. −14%; P = 0.023) and maintained weight loss. Exercise after weight loss did not increase appetite or sedentary behavior compared with placebo, despite increased exercise energy expenditure and maintained weight loss. The combination of exercise and liraglutide increased cognitive restraint score (13% vs. −9%; P = 0.042), reflecting a conscious restriction of food intake, and decreased sedentary time by 41 min/day (−10 vs. 31 min/day; 95%CI, −82.3 to −0.2; P = 0.049) compared with placebo, which may have facilitated the additional weight loss. Targeting both eating and sedentary behavior could be the most effective for preventing weight regain.Trial registration: EudraCT number, 2015-005585-32; clinicaltrials.gov number, NCT04122716.

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Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment

Jensen,

Sørensen,

Sandsdal

et al. 2024

JAMA Netw Open

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ImportanceA major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss.ObjectiveTo investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined.Design, Setting, and ParticipantsThis study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision.InterventionsAfter an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo.Main Outcomes and MeasuresThe primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population.ResultsIn total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, −0.006 g/cm2; 95% CI, −0.017 to 0.004 g/cm2; P = .24) and lumbar spine (−0.010 g/cm2; 95% CI, −0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, −0.013 g/cm2; 95% CI, −0.024 to −0.001 g/cm2; P = .03) and spine (mean change, −0.016 g/cm2; 95% CI, −0.032 to −0.001 g/cm2; P = .04).Conclusions and RelevanceIn this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss.Trial RegistrationEudraCT: 2015-005585-32

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Protocol for a randomised controlled trial of the combined effects of the GLP-1 receptor agonist liraglutide and exercise on maintenance of weight loss and health after a very low-calorie diet

Cited by 16 publications

References 79 publications

Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial

Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial

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

Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment

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