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Context: Obesity is associated with low vitamin D and recent studies have suggested a difference in vitamin D metabolism between females and males., Objective: The aim of this study was to investigate the effects of weight loss on vitamin D status in individuals with obesity, and secondarily, whether vitamin D metabolism differs between women and men., Methods: Secondary analysis from a randomized placebo-controlled trial, designed to investigate the efficacy of 52 weeks of treatment with either liraglutide, exercise or combined, compared with placebo on weight loss maintenance after an 8-week low-calorie diet-induced weight loss in 195 individuals with obesity (BMI 32-43 kg/m2)., Results: The low-calorie diet-induced weight loss resulted in an increase in serum 25(OH)D in both women and men (12 nmol/L (95%CI 9-15) and 13 nmol/L (95%CI 8-17); p < 0.001 for both). Women who experienced a further weight loss during the 52 weeks of intervention had an increase in serum 25(OH)D compared with women regaining weight (14 nmol/L (95%CI 6-22); p = 0.001). Interestingly, women experiencing further weight loss at week 52 had a lower serum 25(OH)D at baseline compared with women regaining weight (54 nmol/L (SD 19) vs. 70 nmol/L (SD 25); p < 0.001)., Conclusion: Weight loss induced by a low-calorie diet resulted in an increase in serum 25(OH)D in both women and men. Only in women, further weight loss had an additional beneficial impact on vitamin D. Additionally, initial low serum 25(OH)D was associated with successful weight loss maintenance in women, but not men., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

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., Competing Interests: Declaration of interests A family member of R.M.S. holds Novo Nordisk stocks. S.M. is on advisory boards of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi Aventis; receives lecture fees from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, and Sanofi Aventis; and is a research grant recipient from Novo Nordisk and Boehringer Ingelheim. J.J.H. is on the advisory board of Novo Nordisk. S.S.T. is a research grant recipient and receives lecture fees from Novo Nordisk., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: A 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., Objective: To 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 Participants: This 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., Interventions: After 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 Measures: The 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., Results: In 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 Relevance: In 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 Registration: EudraCT: 2015-005585-32.

Background: New obesity medications result in large weight losses. However, long-term adherence in a real-world setting is challenging, and termination of obesity medication results in weight regain towards pre-treatment body weight. Therefore, we investigated whether weight loss and improved body composition are sustained better at 1 year after termination of active treatment with glucagon-like peptide-1 (GLP-1) receptor agonist, supervised exercise program, or both combined for 1 year., Methods: We conducted a post-treatment study in extension of a randomised, controlled trial in Copenhagen. Adults with obesity (aged 18-65 years and initial body mass index 32-43 kg/m 2 ) completed an eight-week low-calorie diet-induced weight loss of 13.1 kg (week -8 to 0) and were randomly allocated (1:1:1:1) to one-year weight loss maintenance (week 0-52) with either supervised exercise, the GLP-1 receptor agonist once-daily subcutaneous liraglutide 3.0 mg, the combination of exercise and liraglutide, or placebo. 166 Participants completed the weight loss maintenance phase. All randomised participants were invited to participate in the post-treatment study with outcome assessments one year after treatment termination, at week 104. The primary outcome of the post-treatment assessment was change in body weight from after the initial weight loss (at randomisation, week 0) to one year after treatment termination (week 104) in the intention-to-treat population. The secondary outcome was change in body-fat percentage (week 0-104). The study is registered with EudraCT, 2015-005585-32, and with ClinicalTrials.gov, NCT04122716., Findings: Between Dec 17, 2018, and Dec 17, 2020, 109 participants attended the post-treatment study. From randomisation to one year after termination of combined exercise and liraglutide treatment (week 0-104), participants had reduced body weight (-5.1 kg [95% CI -10.0; -0.2]; P = 0.040) and body-fat percentage (-2.3%-points [-4.3 to -0.3]; P = 0.026) compared with after termination of liraglutide alone. More participants who had previously received combination treatment maintained a weight loss of at least 10% of initial body weight one year after treatment termination (week -8 to 104) compared with participants who had previously received placebo (odds ratio [OR] 7.2 [2.4; 21.3]) and liraglutide (OR 4.2 [1.6; 10.8]). More participants who had previously received supervised exercise maintained a weight loss of at least 10% compared with placebo (OR 3.7 [1.2; 11.1]). During the year after termination of treatment (week 52-104), weight regain was 6.0 kg [2.1; 10.0] larger after termination of liraglutide compared with after termination of supervised exercise and 2.5 kg [-1.5 to 6.5] compared with after termination of combination treatment., Interpretation: The addition of supervised exercise to obesity pharmacotherapy seems to improve healthy weight maintenance after treatment termination compared with treatment termination of obesity pharmacotherapy alone. Body weight and body composition were maintained one year after termination of supervised exercise, in contrast to weight regain after termination of treatment with obesity pharmacotherapy alone., Funding: Helsefonden and the Novo Nordisk Foundation., Competing Interests: RMS: family member owns Novo Nordisk stocks. S.M.: Advisory boards: AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi Aventis. Lecture fees: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi Aventis. Research Grant Recipient: Novo Nordisk, Boehringer-Ingelheim. S.S.T.: Research Grant and Lecture Fee Recipient: Novo Nordisk. J.J.H.: Advisory board: Novo Nordisk. M.B.B.: Research Grant Novo Nordisk A/S, payment made to institution. B.M.S.: Board member of Steno Diabetes Center Copenhagen. Board member of the Centre for Childhood Health, appointed by the Novo Nordisk Foundation., (© 2024 The Authors.)

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 (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., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

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/m 2 ) 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., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

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., (© 2023. The Author(s).)

Aim: The voltage-gated potassium channel K v 11.1 is important for repolarizing the membrane potential in excitable cells such as myocytes, pancreatic α- and β-cells. Moxifloxacin blocks the K v 11.1 channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin, a drug known to block the K v 11.1 channel., Materials and Methods: The effect of moxifloxacin (800 mg/day for 4 days) or placebo on glucose regulation was assessed in a randomized, double-blind, crossover study of young men and women (age 20-40 years and body mass index 18.5-27.5 kg/m 2 ) without chronic disease, using 6-h oral glucose tolerance tests and continuous glucose monitoring., Results: Thirty-eight participants completed the study. Moxifloxacin prolonged the QTcF interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the 8 days of continuous glucose monitoring and during the oral glucose tolerance tests. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced the early plasma-glucose response (AUC 0-30 min ) by 7% (95% CI: -9% to -4%, p < .01), and overall insulin response (AUC 0-360 min ) decreased by 18% (95% CI: -24% to -11%, p < .01) and plasma glucagon increased by 17% (95% CI: 4%-33%, p = .03). Insulin sensitivity calculated as the Matsuda index increased by 11%, and MISI, an index of muscle insulin sensitivity, increased by 34%., Conclusions: In young men and women, moxifloxacin, a drug known to block the K v 11.1 channel, increased QT interval, decreased glucose levels and was associated with increased muscle insulin sensitivity and more frequent episodes of hypoglycaemia., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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., (© 2022. The Author(s).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Voltage-gated potassium (K v ) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss-of-function (LoF) mutations in KCNQ1, encoding K v 7.1, and KCNH2 (hERG), encoding K v 11.1, were found to exhibit post-prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K + channels in pancreatic beta cell function, with emphasis on K v 7.1 and K v 11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre-clinical, clinical and genome-wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes., (© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

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.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: The voltage-gated potassium channel Kv7.1 encoded by KCNQ1 is located in both cardiac myocytes and insulin producing beta cells. Loss-of-function mutations in KCNQ1 causes long QT syndrome along with glucose-stimulated hyperinsulinemia, increased C-peptide and postprandial hypoglycemia. The KCNE1 protein modulates Kv7.1 in cardiac myocytes, but is not expressed in beta cells. Gain-of-function mutations in KCNQ1 and KCNE1 shorten the action potential duration in cardiac myocytes, but their effect on beta cells and insulin secretion is unknown., Case Presentation: Two patients with atrial fibrillation due to gain-of-function mutations in KCNQ1 (R670K) and KCNE1 (G60D) were BMI-, age-, and sex-matched to six control participants and underwent a 6-h oral glucose tolerance test (OGTT). During the OGTT, the KCNQ1 gain-of-function mutation carrier had 86% lower C-peptide response after glucose stimulation compared with matched control participants (iAUC 360min  = 34 pmol/l*min VS iAUC 360min  = 246 ± 71 pmol/l*min). The KCNE1 gain-of-function mutation carrier had normal C-peptide levels., Conclusions: This case story presents a patient with a gain-of-function mutation KCNQ1 R670K with low glucose-stimulated C-peptide secretion, additionally suggesting involvement of the voltage-gated potassium channel KCNQ1 in glucose-stimulated insulin regulation.

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 1-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, randomised, placebo-controlled, parallel group trial. We will enrol expectedly 200 women and men (age 18-65 years) with obesity (body mass index 32-43 kg/m 2 ) to adhere to a very low-calorie diet (800 kcal/day) for 8 weeks in order to lose at least 5% of body weight. Subsequently, participants will be randomised 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. The primary endpoint is change in body weight from randomisation to end-of-treatment., Ethics and Dissemination: The trial has been approved by the ethical committee of the Capital Region of Denmark and the Danish Medicines Agency. 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., Trial Registration Number: 2015-005585-32., Competing Interests: Competing interests: SST has received research grants from Novo Nordisk. SM has received research grants from Novo Nordisk and Boehringer Ingelheim; lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi Aventis; and is a member of advisory boards of AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi Aventis. JJH has served on advisory panels for GlaxoSmithKline, Novo Nordisk, Zealand Pharma, AstraZeneca, MSD, Intarcia and Hanmi and as a consultant for Novo Nordisk, and has received research support from Merck, Sharp & Dohme., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Semaglutide is a glucagon-like peptide-1 receptor-agonist (GLP-1 RA), which is injected subcutaneously once a week for treatment of Type 2 diabetes. In this review, the present results of semaglutide treatment are presented. Semaglutide has been evaluated in more than 8,000 patients across the spectrum of Type 2 diabetes. Trials with semaglutide have demonstrated superiority with sustained improved glycaemic control and weight loss compared to oral antidiabetic agents, other GLP-1 RAs and basalinsulin. In addition, semaglutide significantly decreased the occurrence of cardiovascular events compared with standard pharmacological diabetic treatment combined with placebo.

The prevalence of obesity and related comorbidities is increasing worldwide. Furthermore, clinically meaningful body weight losses has proven difficult to achieve and especially to maintain through sustained lifestyle change in the form of diet and exercise. Pharmacotherapy against obesity is a non-invasive treatment as an adjunct to lifestyle changes, but approved anti-obesity drugs are currently few. This article reviews the major anti-obesity drugs and the benefit-risk profiles of the long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide (a modified version of liraglutide with longer half-life and tripled receptor affinity). Generally, GLP-1 RAs are well tolerated and induce significant weight loss and lowering of comorbidities. Studies with liraglutide 3.0 mg/day have shown an average placebo-subtracted weight loss of 5.5 kg (range 4.6-5.9) in 1- to 3-year duration trials. One trial using semaglutide 0.4 mg once daily reported an average weight loss of 11.6% (~ 13.1 kg) after 1 year. Furthermore, semaglutide induced a ~ 6 percentage point larger placebo-subtracted body weight loss in a head-to-head comparison with liraglutide (11.6 vs. 5.5% weight loss, respectively). The safety profiles for both drugs were similar, with transient gastrointestinal disorders being the most commonly reported adverse events. The longest running trial and the most recent trials have not raised any new safety concerns. Long-term trials and post-marketing surveillance is warranted to fully assess both long-term efficacy and safety. Future combinational therapies of mimicked gut hormones involved in regulation of energy homeostasis and/or additional lifestyle change in the form of exercise might further improve efficacy.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions., Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population., Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs., Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals., Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A meta-analysis can help inform the debate about the epidemiological evidence on dairy intake and development of acne. A systematic literature search of PubMed from inception to 11 December 2017 was performed to estimate the association of dairy intake and acne in children, adolescents, and young adults in observational studies. We estimated the pooled random effects odds ratio (OR) (95% CI), heterogeneity ( I ²-statistics, Q -statistics), and publication bias. We included 14 studies ( n = 78,529; 23,046 acne-cases/55,483 controls) aged 7⁻30 years. ORs for acne were 1.25 (95% CI: 1.15⁻1.36; p = 6.13 × 10 -8 ) for any dairy, 1.22 (1.08⁻1.38; p = 1.62 × 10 -3 ) for full-fat dairy, 1.28 (1.13⁻1.44; p = 8.23 × 10 -5 ) for any milk, 1.22 (1.06⁻1.41; p = 6.66 × 10 -3 ) for whole milk, 1.32 (1.16⁻1.52; p = 4.33 × 10 -5 ) for low-fat/skim milk, 1.22 (1.00⁻1.50; p = 5.21 × 10 -2 ) for cheese, and 1.36 (1.05⁻1.77; p = 2.21 × 10 -2 ) for yogurt compared to no intake. ORs per frequency of any milk intake were 1.24 (0.95⁻1.62) by 2⁻6 glasses per week, 1.41 (1.05⁻1.90) by 1 glass per day, and 1.43 (1.09⁻1.88) by ≥2 glasses per day compared to intake less than weekly. Adjusted results were attenuated and compared unadjusted. There was publication bias ( p = 4.71 × 10 -3 ), and heterogeneity in the meta-analyses were explained by dairy and study characteristics. In conclusion, any dairy, such as milk, yogurt, and cheese, was associated with an increased OR for acne in individuals aged 7⁻30 years. However, results should be interpreted with caution due to heterogeneity and bias across studies.

Whether there is a causal relationship between milk intake and acne is unknown. We tested the hypothesis that genetically determined milk intake is associated with acne in adults using a Mendelian randomization design. LCT-13910 C/T (rs4988235) is associated with lactase persistence ( TT/TC ) in Northern Europeans. We investigated the association between milk intake, LCT-13910 C/T (rs4988235), and acne in 20,416 adults (age-range: 20⁻96) from The Danish General Suburban Population Study (GESUS). The adjusted observational odds ratio for acne in any milk intake vs. no milk intake was 0.93(95% confidence interval: 0.48⁻1.78) in females and 0.49(0.22⁻1.08) in males aged 20⁻39 years, and 1.15(95% confidence interval: 0.66⁻1.99) in females and 1.02(0.61⁻1.72) in males above 40 years. The unadjusted odds ratio for acne in TT+TC vs. CC was 0.84(0.43⁻1.62) in the age group 20⁻39 years, and 0.99(0.52⁻1.88) above 40 years. We did not find any observational or genetic association between milk intake and acne in our population of adults.

Psoriasis is a chronic inflammatory disease associated with cardiovascular disease, for example, myocardial infarction, stroke, cardiovascular death, and arrhythmias. The resting electrocardiogram may carry prognostic information, but limited evidence is available of electrocardiographic findings in subjects with psoriasis. The electrocardiographic results were compared between 1,131 subjects with self-reported psoriasis and 18,397 controls participating in the Danish General Suburban Population Study (GESUS). The mean heart rate was marginally increased in patients with psoriasis (66 ± 11 vs 65 ± 11 beats/min, p = 0.007), but not after adjustment for smoking and body mass index. All other examined electrocardiographic variables, including QT interval corrected for heart rate with the Fridericia formula, PR interval, QRS duration, R axis, P-wave duration in lead V1, P-terminal force, J point elevation in lead V1, electrocardiographic criteria for left ventricular hypertrophy, electrocardiographic signs of previous myocardial infarction, and premature ventricular or supraventricular complexes, respectively, were comparable between the 2 groups. In conclusion, psoriasis was associated with a marginal increase in resting heart rate, which was driven by smoking and increased body mass index. All other examined electrocardiographic variables were similar between the 2 groups. The results suggest that psoriasis per se is not associated with significant abnormalities of the electrocardiogram., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease, recently associated with metabolic syndrome, subclinical atherosclerosis and increased risk of cardiovascular disease., Objectives: To investigate the hitherto unknown electrocardiographic (ECG) changes associated with HS, which have recently been associated with significant cardiovascular burden., Methods: Data were obtained from the cross-sectional Danish General Population Study (GESUS). HS diagnosis was based on a validated self-reported questionnaire; 404 individuals met the HS diagnosis criteria and 19 001 controls without HS were identified. Severity of HS was staged according to a modified Hurley score. The ECG parameters of heart rate (HR), PR interval, QRS duration, JTc interval and QTc interval were obtained from 12-lead resting ECGs. We investigated the difference in means by unpaired t-test or anova., Results: HR was significantly higher [mean difference 2·3 beats per min (bpm), 95% confidence interval (CI) 1·2-3·4; P < 0·01] when adjusting for age and sex, but when adjusting for multivariates, there was no significant difference (0·3 bpm, 95% CI -0·7 to 1·4; P = 0·52). Severe HS was significantly associated with increased HR across all models (2·9 bpm, 95% CI 0·7-5·1; P = 0·01). Mean QRS duration was significantly shorter in the group with mild HS but not in the groups with moderate and severe HS., Conclusions: Mean resting HR in patients with severe HS was significantly higher compared with controls. Given that resting HR is associated with increased risk of all-cause and cardiovascular mortality, and that patients with HS have increased risk of cardiovascular events, this finding is potentially important, easily testable and intervenable., (© 2017 British Association of Dermatologists.)