Effects of 3 months of 10-h per-day time-restricted eating and 3 months of follow-up on bodyweight and cardiometabolic health in Danish individuals at high risk of type 2 diabetes: the RESET single-centre, parallel, superiority, open-label, randomised controlled trial.

BACKGROUND: Time-restricted eating (TRE) has been suggested to be a simple, feasible, and effective dietary strategy for individuals with overweight or obesity. We aimed to investigate the effects of 3 months of 10-h per-day TRE and 3 months of follow-up on bodyweight and cardiometabolic risk factors in individuals at high risk of type 2 diabetes. METHODS: This was a single-centre, parallel, superiority, open-label randomised controlled clinical trial conducted at Steno Diabetes Center Copenhagen (Denmark). The inclusion criteria were age 30-70 years with either overweight (ie, BMI ≥25 kg/m2) and concomitant prediabetes (ie, glycated haemoglobin [HbA1c] 39-47 mmol/mol) or obesity (ie, BMI ≥30 kg/m2) with or without prediabetes and a habitual self-reported eating window (eating and drinking [except for water]) of 12 h per day or more every day and of 14 h per day or more at least 1 day per week. Individuals were randomly assigned 1:1 to 3 months of habitual living (hereafter referred to as the control group) or TRE, which was a self-selected 10-h per-day eating window placed between 0600 h and 2000 h. Randomisation was done in blocks varying in size and was open for participants and research staff, but outcome assessors were masked during statistical analyses. The randomisation list was generated by an external statistician. The primary outcome was change in bodyweight, assessed after 3 months (12 weeks) of the intervention and after 3 months (13 weeks) of follow-up. Adverse events were reported and registered at study visits or if participants contacted study staff to report events between visits. This trial is registered on ClinicalTrials.gov (NCT03854656). FINDINGS: Between March 12, 2019, and March 2, 2022, 100 participants (66 [66%] were female and 34 [34%] were male; median age 59 years [IQR 52-65]) were enrolled and randomly assigned (50 to each group). Of those 100, 46 (92%) in the TRE group and 46 (92%) in the control group completed the intervention period. After 3 months of the intervention, there was no difference in bodyweight between the TRE group and the control group (-0·8 kg, 95% CI -1·7 to 0·2; p=0·099). Being in the TRE group was not associated with a lower bodyweight compared with the control group after subsequent 3-month follow-up (-0·2 kg, -1·6 to 1·2). In the per-protocol analysis, participants who completed the intervention in the TRE group lost 1·0 kg (-1·9 to -0·0; p=0·040) bodyweight compared with the control group after 3 months of intervention, which was not maintained after the 3-month follow-up period (-0·4 kg, -1·8 to 1·0). During the trial and follow-up period, one participant in the TRE group reported a severe adverse event: development of a subcutaneous nodule and pain when the arm was in use. This side-effect was evaluated to be related to the trial procedures. INTERPRETATION: 3 months of 10-h per-day TRE did not lead to clinically relevant effects on bodyweight in middle-aged to older individuals at high risk of type 2 diabetes. FUNDING: Novo Nordisk Foundation, Aalborg University, Helsefonden, and Innovation Fund Denmark.

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.

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/m2) 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.

Potent incretin-based therapy for obesity: A systematic review and meta-analysis of the efficacy of semaglutide and tirzepatide on body weight and waist circumference, and safety.

Potent incretin-based therapy shows promise for the treatment of obesity along with reduced incidence of cardiovascular events in patients with preexisting cardiovascular disease and obesity. This study assessed the efficacy and safety of the incretin-based obesity treatments, once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg, in people with obesity without diabetes. Of the 744 records identified, seven randomized controlled trials (n = 5140) were included. Five studies (n = 3288) investigated semaglutide and two studies (n = 1852) investigated tirzepatide. The treatment effect, shown as placebo-subtracted difference, on body weight was -15.0% (95% CI, -17.8 to -12.2) with -12.9% (95% CI, -14.7 to -11.1) for semaglutide and -19.2% (95% CI, -22.2 to -16.2) for tirzepatide. The treatment effect on waist circumference was -11.4 cm (95% CI, -13.7 to -9.2) with -9.7 cm (95% CI, -10.8 to -8.5) for semaglutide and -14.6 cm (95% CI, -15.8 to -13.4) for tirzepatide. The adverse events related to semaglutide and tirzepatide were primarily of mild-to-moderate severity and mostly gastrointestinal, which was more frequent during the dose-titration period and leveled off during the treatment period. This emphasizes that once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg induce large reductions in body weight and waist circumference and are generally well-tolerated.

Primary weight loss failure after Roux-en-Y gastric bypass is characterized by impaired gut-hormone mediated regulation of food intake.

BACKGROUND/OBJECTIVES: After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure. SUBJECTS/METHODS: Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting. RESULTS: On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]). CONCLUSIONS: Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.

Increased meal-induced neurotensin response predicts successful maintenance of weight loss - Data from a randomized controlled trial.

BACKGROUND: The gut derived anorexigenic hormone neurotensin (NT) is upregulated after bariatric surgery which may contribute to the sustained weight loss. In contrast, diet-induced weight loss is most often followed by weight regain. We therefore investigated whether diet-induced weight loss impacts levels of circulating NT in mice and humans and whether NT levels predicts body weight change after weight loss in humans. METHODS: In vivo mice study: Obese mice were fed ad-libitum or a restricted diet (40-60 % of average food intake) for 9 days to obtain similar weight loss as observed in the human study. At termination, intestinal segments, the hypothalamus and plasma were collected for histological, real time PCR, and radioimmunoassay (RIA) analysis. CLINICAL TRIAL: Plasma samples from 42 participants with obesity, completing an 8-week low-calorie diet in a randomized controlled trial, were analyzed. Plasma NT was measured by RIA at fasting and during a meal test before and after diet-induced weight loss and after one year of intended weight maintenance. RESULTS: In obese mice, food restriction-induced body weight loss of 14 % was associated with a 64 % reduction in fasting plasma NT (p < 0.0001). In the mouse duodenum (p = 0.07) and jejunum (p < 0.05), NT tissue concentration was decreased without tissue atrophy indicative of a physiological downregulation. In the mouse hypothalamus a downregulation of Pomc (p < 0.01) along with upregulation of Npy (p < 0.001) and Agrp (p < 0.0001) expression was found after restricted feeding in support of increased hunger after diet-induced weight loss. Therefore, we investigated the NT response in humans undergoing weight loss maintenance. In humans, similar to the mice, the low-calorie diet induced weight loss of 13 % body weight was associated with 40 % reduction in fasting plasma NT levels (p < 0.001). Meal-induced NT peak responses were greater in humans who lost additional weight during the 1 year maintenance phase compared to participants who regained weight (p < 0.05). CONCLUSION: Diet-induced weight loss decreased fasting plasma NT levels in both humans and mice with obesity, and regulated hunger-associated hypothalamic gene expression in mice. Meal-induced NT responses were greater in humans who lost additional weight during the 1 year maintenance phase compared to participants who regained weight. This indicates that increased peak secretion of NT after weight loss may contribute to successful maintenance of weight loss. CLINICAL TRIAL REGISTRATION NUMBER: NCT02094183.

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.

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.

Effects of vegan diets on cardiometabolic health: A systematic review and meta-analysis of randomized controlled trials.

In parallel with an increased focus on climate changes and carbon footprint, the interest in plant-based diets and its potential health effects have increased over the past decade. The objective of this systematic review and meta-analysis was to examine the effect of vegan diets (≥12 weeks) on cardiometabolic risk factors in people with overweight or type 2 diabetes. We identified 11 trials (796 participants). In comparison with control diets, vegan diets reduced body weight (-4.1 kg, 95% confidence interval (CI) -5.9 to -2.4, p < 0.001), body mass index (BMI) (-1.38 kg/m2 , 95% CI -1.96 to -0.80, p < 0.001), glycated hemoglobin (HbA1c ) (-0.18% points, 95% CI -0.29 to -0.07, p = 0.002), total cholesterol (-0.30 mmol/L, 95% CI -0.52 to -0.08, p = 0.007), and low-density lipoprotein cholesterol (-0.24 mmol/L, 95% CI -0.40 to -0.07, p = 0.005). We identified no effect on blood pressure, high-density lipoprotein cholesterol, and triglycerides. We found that adhering to vegan diets for at least 12 weeks may be effective in individuals with overweight or type 2 diabetes to induce a meaningful decrease in body weight and improve glycemia. Some of this effect may be contributed to differences in the macronutrient composition and energy intake in the vegan versus control diets. Therefore, more research is needed regarding vegan diets and cardiometabolic health.

Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness.

OBJECTIVE: While existing evidence supports beneficial cardiovascular effects of glucagon-like peptide 1 (GLP-1), emerging studies suggest that glucose-dependent insulinotropic peptide (GIP) and/or signaling via the GIP receptor may have untoward cardiovascular effects. Indeed, recent studies show that fasting physiological GIP levels are associated with total mortality and cardiovascular mortality, and it was suggested that GIP plays a role in pathogenesis of coronary artery disease. We investigated the associations between fasting and postchallenge GIP and GLP-1 concentrations and subclinical atherosclerosis as measured by mean intima-media thickness in the common carotid artery (IMTmeanCCA) and maximal intima-media thickness in the carotid bifurcation (IMTmaxBulb). RESEARCH DESIGN AND METHODS: Participants at reexamination within the Malmö Diet and Cancer-Cardiovascular Cohort study (n = 3,734, mean age 72.5 years, 59.3% women, 10.8% subjects with diabetes, fasting GIP available for 3,342 subjects, fasting GLP-1 available for 3,299 subjects) underwent oral glucose tolerance testing and carotid ultrasound. RESULTS: In linear regression analyses, each 1-SD increment of fasting GIP was associated with increased (per mm) IMTmeanCCA (ß = 0.010, P = 0.010) and IMTmaxBulb (ß = 0.014; P = 0.040) in models adjusted for known risk factors and glucose metabolism. In contrast, each 1-SD increment of fasting GLP-1 was associated with decreased IMTmaxBulb (per mm, ß = -0.016, P = 0.014). These associations remained significant when subjects with diabetes were excluded from analyses. CONCLUSIONS: In a Swedish elderly population, physiologically elevated levels of fasting GIP are associated with increased IMTmeanCCA, while GLP-1 is associated with decreased IMTmaxBulb, further emphasizing diverging cardiovascular effects of these two incretin hormones.

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.

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/m2) 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.

[The glucagon-like peptide-1 receptor-agonist semaglutide].

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.

Instrumentalization of Eating Improves Weight Loss Maintenance in Obesity.

AIM: The purpose of this study was to identify psychosocial determinants for maintaining weight loss. METHODS: 42 obese individuals who achieved a 12% weight loss before entering a 52-week weight maintenance program were interviewed qualitatively. Psychosocial factors related to weight loss maintenance were identified in two contrasting groups: weight reducers and weight regainers. Groups were defined by health-relevant weight maintenance (additional weight loss > 3% at week 52, n = 9 versus weight gain > 3%, at week 52, n = 20). RESULTS: Weight reducers reported structured meal patterns (p = 0.008), no comfort eating (p = 0.016) and less psychosocial stress (p = 0.04) compared to weight regainers. The ability to instrumentalize eating behavior emerged as an important factor (p = 0.007). Nutritional knowledge, motivation or exercise level did not differ between groups (p > 0.05). CONCLUSIONS: Successful weight loss maintenance was associated with an interplay between behavioral, affective and contextual changes. 'Instrumentalization of eating behavior' seems to be an important element in long-term weight maintenance.

Glucagon-Like Peptide 1: A Predictor of Type 2 Diabetes?

BACKGROUND: The incretin effect is impaired in patients with type 2 diabetes. AIM: To assess the relation between the incretin hormone GLP-1 and the prediabetic subtypes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and the combined IFG/IGT to investigate whether a low GLP-1 response may be a predictor of prediabetes in adults. METHOD: 298 articles were found using a broad search phrase on the PubMed database and after the assessment of titles and abstracts 19 articles were included. RESULTS AND DISCUSSION: Studies assessing i-IFG/IFG and i-IGT/IGT found both increased, unaltered, and reduced GLP-1 levels. Studies assessing IFG/IGT found unaltered or reduced GLP-1 levels. When assessing the five studies with the largest sample size, it clearly suggests a decreased GLP-1 response in IFG/IGT subjects. Several other factors (BMI, glucagon, age, and nonesterified fatty acids (NEFA)), including medications (metformin), may also influence the secretion of GLP-1. CONCLUSION: This review suggests that the GLP-1 response is a variable in prediabetes possibly due to a varying GLP-1-secreting profile during the development and progression of type 2 diabetes or difference in the measurement technique. Longitudinal prospective studies are needed to assess whether a reduced GLP-1 response is a predictor of diabetes.

Atrial Natriuretic Peptide in the High Normal Range Is Associated With Lower Prevalence of Insulin Resistance.

In 2243 subjects, MR-proANP was measured at baseline. At follow up, MR-proANP levels in the high normal range were associated with lower prevalence of insulin resistance and higher post challenge GIP secretion.

Liraglutide for Type 2 diabetes and obesity: a 2015 update.

Subcutaneous liraglutide (Victoza(®), Novo Nordisk) was approved for the treatment of Type 2 diabetes mellitus (T2DM) in Europe in 2009 and in the USA in 2010. In December 2014, liraglutide 3.0 mg was approved by the Food and Drug Administration (FDA) and in March 2015 by the European Medicines Agency (EMA) for the treatment of chronic weight management under the brand name Saxenda(®) Novo Nordisk. Liraglutide causes a glucose-dependent increase in insulin secretion, decreases glucagon secretion and promotes weight loss by inhibiting appetite. Liraglutide probably induces satiety through activation of different areas in the hind brain and possibly by preserving free leptin levels. Recently, liraglutide has been suggested to protect against prediabetes and seems to prevent bone loss by increasing bone formation following diet-induced weight loss in obesity. This article not only covers the major clinical trials evaluating the effects of liraglutide in obesity and T2DM but also provides novel insights into the pharmacological mechanisms of liraglutide.