RESUMO
BACKGROUND: Weight regain after weight loss is a major problem in the treatment of persons with obesity. METHODS: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed. RESULTS: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group. CONCLUSIONS: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).
Assuntos
Fármacos Antiobesidade/uso terapêutico , Terapia por Exercício , Liraglutida/uso terapêutico , Obesidade/terapia , Redução de Peso , Tecido Adiposo , Adulto , Fármacos Antiobesidade/efeitos adversos , Tamanho Corporal , Restrição Calórica , Terapia Combinada , Feminino , Humanos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Identifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss. METHODS: This was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: placebo, moderate-to-vigorous exercise (minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination of both), the GLP-1 RA liraglutide 3.0 mg/day, or a combination (exercise + liraglutide). A total of 166 participants completed the trial. We assessed the prespecified secondary outcome metabolic syndrome severity z-score (MetS-Z), abdominal obesity (estimated as android fat via dual-energy X-ray absorptiometry), and inflammation marker high-sensitivity C-reactive protein (hsCRP). Statistical analysis was performed on 130 participants adherent to the study interventions (per-protocol population) using a mixed linear model. RESULTS: The diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (- 0.37, 95% CI - 0.58 to - 0.16, P < 0.001) and the combination treatment (- 0.48, 95% CI - 0.70 to - 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03). CONCLUSION: The combination of adherent exercise and liraglutide treatment reduced metabolic syndrome severity, abdominal obesity, and inflammation and may therefore reduce cardiometabolic risk more than the individual treatments. Trial registration EudraCT number: 2015-005585-32, ClinicalTrials.gov: NCT04122716.
Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Adulto , Humanos , Liraglutida/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Obesidade Abdominal/complicações , Síndrome Metabólica/tratamento farmacológico , Proteína C-Reativa , Obesidade/epidemiologia , Redução de Peso , Exercício Físico , Inflamação/complicações , Método Duplo-CegoRESUMO
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.
Assuntos
Análise do Sêmen , Motilidade dos Espermatozoides , Dieta Redutora , Exercício Físico , Feminino , Peptídeo 1 Semelhante ao Glucagon , Humanos , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Masculino , Obesidade/complicações , Obesidade/terapia , Sêmen , Contagem de Espermatozoides , Espermatozoides , Redução de PesoRESUMO
BACKGROUND AND AIM: Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD. METHODS: This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex. RESULTS: A greater GLP-1 response was associated with lower central systolic and diastolic BP of - 1.17 mmHg (95% confidence interval (CI) - 2.07 to - 0.27 mmHg, P = 0.011) and - 0.74 mmHg (95% CI - 1.29 to - 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of - 1.27 mmHg (95% CI - 2.20 to - 0.33 mmHg, P = 0.008) and - 1.00 (95% CI - 1.56 to - 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: - 4.94 (95% CI - 8.56 to - 1.31) mmHg, central diastolic BP: - 3.05 (95% CI - 5.29 to - 0.80) mmHg, brachial systolic BP: - 5.18 (95% CI - 8.94 to - 1.42) mmHg, and brachial diastolic BP: - 2.96 (95% CI - 5.26 to - 0.67) mmHg). CONCLUSION: Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005.
Assuntos
Pressão Sanguínea , Artéria Braquial/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/diagnóstico , Peptídeo 1 Semelhante ao Glucagon/sangue , Teste de Tolerância a Glucose , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Estudos Transversais , Dinamarca , Diabetes Mellitus/sangue , Diabetes Mellitus/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Medição de Risco , Fatores de Risco , Rigidez VascularRESUMO
Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.
Assuntos
Adiponectina , Fatores de Crescimento de Fibroblastos , Leptina , Esfingolipídeos , Redução de Peso , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adiponectina/sangue , Adiponectina/metabolismo , Ceramidas/metabolismo , Ceramidas/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/sangue , Fator 15 de Diferenciação de Crescimento/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Leptina/sangue , Leptina/metabolismo , Obesidade/metabolismo , Obesidade/sangue , Esfingolipídeos/metabolismo , Esfingolipídeos/sangueRESUMO
STUDY OBJECTIVES: Insufficient sleep may attenuate weight loss, but the role of sleep in weight loss maintenance is unknown. Since weight regain after weight loss remains a major obstacle in obesity treatment, we investigated whether insufficient sleep predicts weight regain during weight loss maintenance. METHODS: In a randomized, controlled, two-by-two factorial study, 195 adults with obesity completed an 8-week low-calorie diet and were randomly assigned to 1-year weight loss maintenance with or without exercise and liraglutide 3.0 mg/day or placebo. Sleep duration and quality were measured before and after the low-calorie diet and during weight maintenance using wrist-worn accelerometers (GENEActiv) and Pittsburgh Sleep Quality Index (PSQI). To test associations between insufficient sleep and weight regain, participants were stratified at randomization into subgroups according to sleep duration (≥6 h/night) or sleep quality (PSQI score ≤/>5). RESULTS: After a diet-induced 13.1 kg weight loss, participants with short sleep duration at randomization regained 5.3 kg body weight (p = .0008) and had less reduction in body fat percentage compared with participants with normal sleep duration (p = .007) during the 1-year weight maintenance phase. Participants with poor sleep quality before the weight loss regained 3.5 kg body weight compared with good quality sleepers (p = .010). During the weight maintenance phase, participants undergoing liraglutide treatment displayed increased sleep duration compared with placebo after 26 weeks (5 vs. -15 min/night) but not after 1 year. Participants undergoing exercise treatment preserved the sleep quality improvements attained from the initial weight loss. CONCLUSIONS: Short sleep duration or poor sleep quality was associated with weight regain after weight loss in adults with obesity.
Assuntos
Liraglutida , Privação do Sono , Adulto , Humanos , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Privação do Sono/complicações , Obesidade/complicações , Obesidade/tratamento farmacológico , Redução de Peso , Aumento de PesoRESUMO
OBJECTIVE: The aim of this study was to investigate glucose tolerance, glucagon response, and beta cell function during a 1-year maintenance period with either exercise, the glucagon-like peptide-1 receptor agonist liraglutide, or the combination after diet-induced weight loss. METHODS: In this randomized placebo-controlled trial, adults with obesity (BMI: 32-43 kg/m2 ) without diabetes underwent an 8-week low-calorie diet (800 kcal/d) and were randomized to 52 weeks of aerobic exercise, liraglutide 3.0 mg/d, exercise and liraglutide combined, or placebo. Change in glucose and glucagon response to a 3-hour mixed meal test and disposition index, as a measure of beta cell function, were measured. RESULTS: A total of 195 participants were randomized. After 1 year of treatment, the combination group had decreased postprandial glucose response by -9% (95% CI: -14% to -3%; p = 0.002), improved beta cell function by 49% (95% CI: 16% to 93%; p = 0.002), and decreased glucagon response by -18% (95% CI: -34% to -3%; p = 0.024) compared with placebo. Compared with placebo, liraglutide alone improved postprandial glucose response by -7% (95% CI: -12% to -1%; p = 0.018), but not beta cell function or glucagon. Exercise alone had similar postprandial glucose response, beta cell function, and glucagon response as placebo. CONCLUSIONS: Only the combination of exercise and liraglutide improved glucose tolerance, beta cell function, and glucagon responses after weight loss.
Assuntos
Diabetes Mellitus Tipo 2 , Liraglutida , Adulto , Humanos , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Glucagon , Hipoglicemiantes/uso terapêutico , Redução de Peso , Exercício Físico , Glucose , Método Duplo-Cego , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológicoRESUMO
CONTEXT: Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. OBJECTIVE: To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. DESIGN: Randomized control study. SETTING: Outpatient research hospital clinic. PARTICIPANTS: Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m(2) and age 46 ± 2 years. INTERVENTION: After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. MAIN OUTCOME MEASURES: Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. RESULTS: Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5-48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 ± 3 µg/L) vs a 2% (-1 ± 4 µg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase. CONCLUSIONS: Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent.