Effect of Semaglutide on Regression and Progression of Glycemia in People With Overweight or Obesity but Without Diabetes in the SELECT Trial.

OBJECTIVE: To determine whether semaglutide slows progression of glycemia in people with cardiovascular disease and overweight or obesity but without diabetes. RESEARCH DESIGN AND METHODS: In a multicenter, double-blind trial, participants aged ≥45 years, with BMI ≥27 kg/m2, and with preexisting cardiovascular disease but without diabetes (HbA1c <6.5%) were randomized to receive subcutaneous semaglutide (2.4 mg weekly) or placebo. Major glycemic outcomes were HbA1c and proportions achieving biochemical normoglycemia (HbA1c <5.7%) and progressing to biochemical diabetes (HbA1c ≥6.5%). RESULTS: Of 17,604 participants, 8,803 were assigned to semaglutide and 8,801 to placebo. Mean ± SD intervention exposure was 152 ± 56 weeks and follow-up 176 ± 40 weeks. In both treatment arms mean nadir HbA1c for participants was at 20 weeks. Thereafter, HbA1c increased similarly in both arms, with a mean difference of -0.32 percentage points (95% CI -0.33 to -0.30; -3.49 mmol/mol [-3.66 to -3.32]) and with the difference favoring semaglutide throughout the study (P < 0.0001). Body weight plateaued at 65 weeks and was 8.9% lower with semaglutide. At week 156, a greater proportion treated with semaglutide were normoglycemic (69.5% vs. 35.8%; P < 0.0001) and a smaller proportion had biochemical diabetes by week 156 (1.5% vs. 6.9%; P < 0.0001). The number needed to treat was 18.5 to prevent a case of diabetes. Both regression and progression were dependent on glycemia at baseline, with the magnitude of weight reduction important in mediating 24.5% of progression and 27.1% of regression. CONCLUSIONS: In people with preexisting cardiovascular disease and overweight or obesity but without diabetes, long-term semaglutide increases regression to biochemical normoglycemia and reduces progression to biochemical diabetes but does not slow glycemic progression over time.

Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m-2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597 .

Healthcare professionals' perceptions and management of obesity & knowledge of glucagon, GLP-1, GIP receptor agonists, and dual agonists.

Background: Anti-obesity medications (AOMs) have historically had limited weight-loss efficacy. However, newer glucagon-like peptide-1 receptor agonist (GLP-1 RA)-based therapies seem to be more effective, including dual agonists of GLP-1R and the glucagon receptor (GCGR) or glucose-dependent insulinotropic polypeptide receptor. Objective: To explore healthcare professionals' (HCPs) experience in obesity treatment and their understanding of agonists of GCGR, glucose-dependent insulinotropic polypeptide (GIP) RA, and GLP-1 RA. Methods: This cross-sectional online survey of HCPs prescribing AOMs was conducted in the United States in 2023 with a questionnaire designed to evaluate prescribing behavior and understanding of GCGR, GIP RA, and GLP-1 RA. Results: The 785 respondents (251 primary-care physicians [PCPs], 263 endocrinologists, and 271 advanced practice providers [APPs]) reported 55% of their patients had obesity (body mass index ≥30 kg/m2 or ≥27 with weight-related complications) and recommended AOMs to 49% overall, significantly more endocrinologists (57% of patients, p < 0.0005) than PCPs (43%) or APPs (46%). The greatest barriers to treatment were medication cost/lack of insurance (mean 4.2 on 1-5 scale [no barrier-extreme barrier]), low patient engagement/adherence (3.3), and inadequate time/staff (3.1). Metformin was the type 2 diabetes (T2D) medication most commonly prescribed to treat obesity in T2D patients (92.5% of respondents). Most HCPs (65%) were very/extremely familiar with GLP-1 RA, but only 30% with GIP RA and 16% with GCGR. Most HCPs expected dual GCGR/GLP-1 RA to benefit many obesity-related conditions; however, only a minority of HCPs perceived that they would benefit non-cardiometabolic complications of obesity. Conclusions: Among HCPs prescribing AOMs, gaps exist in the management of people living with obesity as <50% are prescribed AOMs. Barriers to treatment indicate a need to improve access to AOMs. HCPs were less familiar with GCGR or GIP RA than GLP-1 RA but expect dual GCGR/GLP-1 RA may offer additional benefits, potentially addressing treatment barriers and access. Thus, there is a need for greater education among HCPs regarding the mechanism of action and therapeutic effects of GCGR agonists, and dual GCGR/GLP-1 RA, so that the full range of obesity-related complications can be effectively treated.

Efficacy and safety of semaglutide 2.4 mg according to antidepressant use at baseline: A post hoc subgroup analysis.

OBJECTIVE: To explore the efficacy and safety of semaglutide 2.4 mg in people with overweight/obesity who were also being treated with antidepressants (ADs). METHODS: Across the Semaglutide Treatment Effect for People with obesity (STEP) 1-3 and 5 trials, adults with overweight/obesity and type 2 diabetes (STEP 2 only) were enrolled. People with severe major depressive disorder within 2 years prior to screening or with a patient health questionnaire-9 score ≥15 at screening were excluded. Participants were categorized into subgroups according to baseline AD status (on/off ADs) in this post hoc exploratory analysis of the STEP trials. RESULTS: Of 3683 participants randomized, 539 were on ADs at baseline. Mean body weight change from baseline to week 68 was greater for semaglutide versus placebo, regardless of baseline AD use. In STEP 1, for participants on ADs at baseline, mean change from baseline was -15.7% with semaglutide versus -0.2% with placebo and -14.7% versus -2.8% for those not on ADs at baseline. Similar patterns were seen in STEP 2, 3, and 5. The prevalence of adverse events (AEs) was generally similar between semaglutide and placebo in participants on ADs at baseline. CONCLUSIONS: In adults with overweight/obesity, semaglutide provided clinically meaningful weight loss regardless of baseline AD use, with an AE profile consistent with previous studies.

A scoping review of obesity education interventions for current and prospective medical professionals in Canada.

Background: Obesity is a prevalent chronic disease in Canada. Individuals living with obesity frequently interact with medical professionals who must be prepared to provide evidence-based and person-centred care options. The purpose of this scoping review was to summarize existing educational interventions on obesity in Canada for current and prospective medical professionals and to identify key future directions for practice and research. Methods: A scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. The search strategy was conducted using Medline (via PubMed), Embase, Eric, CBCA, Proquest Education, and Proquest Theses. The inclusion criteria included delivery of an educational intervention on obesity for current medical professionals, medical undergraduate trainees, or residents administered in Canada. Data were extracted from the included studies to thematically summarize the intervention content, and main outcomes assessed. Future directions for research and practice were identified. Results: Eight studies met the inclusion criteria. The interventions ranged in terms of the mode of delivery, including interactive in-person workshops and seminars, online learning modules, webinars, and videos. The main outcomes assessed were attitudes towards patients living with obesity, self-efficacy for having sensitive obesity-related discussions, skills to assess obesity and provision of management options. All studies reported improvements in the outcomes. Future directions identified were the need to develop standardized obesity competencies for inclusion across medical education programs, further research on effective pedagogical approaches to integrating content into existing curricula and the need for broader awareness and assessment of the quality of obesity education resources. Conclusion: Although there have been few obesity-specific educational interventions for current and prospective medical professionals in Canada, existing evidence shows positive learning outcomes. These findings advocate for continued investment in the development of obesity medical training and educational interventions.

Transforming the landscape of obesity education - The Canadian obesity education competencies.

Background: With ongoing gaps in obesity education delivery for health professions in Canada and around the world, a transformative shift is needed to address and mitigate weight bias and stigma, and foster evidence-based approaches to obesity assessment and care in the clinical setting. Obesity Canada has created evidence-based obesity competencies for medical education that can guide curriculum development, assessment and evaluation and be applied to health professionals' education programs in Canada and across the world. Methods: The Obesity Canada Education Action Team has seventeen members in health professions education and research along with students and patient experts. Through an iterative group consensus process using four guiding principles, key and enabling obesity competencies were created using the 2015 CanMEDS competency framework as its foundation. These principles included the representation of all CanMEDS Roles throughout the competencies, minimizing duplication with the original CanMEDS competencies, ensuring obesity focused content was informed by the 2020 Adult Obesity Clinical Practice Guidelines and the 2019 US Obesity Medication Education Collaborative Competencies, and emphasizing patient-focused language throughout. Results: A total of thirteen key competencies and thirty-seven enabling competencies make up the Canadian Obesity Education Competencies (COECs). Conclusion: The COECs embed evidence-based approaches to obesity care into one of the most widely used competency-based frameworks in the world, CanMEDS. Crucially, these competencies outline how to address and mitigate the damaging effects of weight bias and stigma in educational and clinical settings. Next steps include the creation of milestones and nested Entrustable Professional Activities, a national report card on obesity education for undergraduate medical education in Canada, and Free Open Access Medication Education content, including podcasts and infographics, for easier adoption into curriculum around the world and across the health professions spectrum.

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).

Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure.

Obesity is caused by a prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes is debated3,4. Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.

New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics.

Nearly half of Americans are projected to have obesity by 2030, underscoring the pressing need for effective treatments. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represent the first agents in a rapidly evolving, highly promising landscape of nascent hormone-based obesity therapeutics. With the understanding of the neurobiology of obesity rapidly expanding, these emerging entero-endocrine and endo-pancreatic agents combined or coformulated with GLP-1 RAs herald a new era of targeted, mechanism-based treatment of obesity. This article reviews GLP-1 RAs in the treatment of obesity and previews the imminent future of nutrient-stimulated hormone-based anti-obesity therapeutics.

Tirzepatide for the treatment of obesity: Rationale and design of the SURMOUNT clinical development program.

OBJECTIVE: Obesity is a growing global concern compounded by limited availability of effective treatment options. The SURMOUNT development program aims to evaluate the efficacy and safety of tirzepatide as an adjunct to lifestyle intervention compared with placebo on chronic weight management in adults with BMI ≥ 27 kg/m2 with or without type 2 diabetes. METHODS: The SURMOUNT program includes four global phase 3 trials NCT04184622 (SURMOUNT-1), NCT04657003 (SURMOUNT-2), NCT04657016 (SURMOUNT-3), and NCT04660643 (SURMOUNT-4). Participants are randomized to once-weekly subcutaneous tirzepatide versus placebo in a double-blind manner. The primary end point in all trials is the percentage change in body weight from randomization to end of treatment. Results for the primary end point for SURMOUNT-1 were published recently and results for the other trials are expected in 2023. RESULTS: Across trials, participants have a mean age of 44.9 to 54.2 years, are mostly female (50.7% to 69.7%), and have a mean BMI of 36.1 to 38.9. CONCLUSIONS: The extensive assessment of once-weekly tirzepatide in the global SURMOUNT program will detail the clinical effects of this first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist in chronic weight management.

Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): Exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials.

Background: Inflammation is a key driver of atherosclerotic cardiovascular disease. C-reactive protein (CRP), an established biomarker of inflammation, is commonly elevated in people with overweight/obesity. Methods: STEP 1, 2, and 3 were 68-week, placebo-controlled trials of semaglutide for weight management in participants with overweight/obesity, with (STEP 2) or without (STEP 1 and 3) type 2 diabetes. Change in serum CRP from baseline to week 68 was assessed as a prespecified secondary endpoint for semaglutide 2.4 mg versus placebo (STEP 1, 2, and 3) and versus semaglutide 1.0 mg (STEP 2). Post hoc assessments included change in CRP by baseline characteristics (bodyweight, body mass index [BMI], glycaemic status, CRP concentration); change in CRP-defined cardiovascular risk category (<1 [low], 1-3 [intermediate], and >3 mg/L [high]); and correlation between change in CRP and change in bodyweight, waist circumference, fasting serum insulin (STEP 1 and 3), fasting plasma glucose, and homeostatic model assessment of insulin resistance (HOMA-IR). Findings: The trials took place from June through November 2018 (STEP 1 and 2) and from August 2018 to April 2020 (STEP 3). In all trials, semaglutide 2.4 mg reduced CRP at week 68 versus placebo (estimated treatment difference [ETD; 95% CI] -44% [-49 to -39] in STEP 1, -39% [-46 to -30] in STEP 2, and -48% [-55 to -39] in STEP 3; all p < 0.05). In STEP 2, CRP reductions were greater with semaglutide 2.4 mg (-49%) than with 1.0 mg (-42%) but the difference did not reach statistical significance (ETD [95% CI] -12% [-23 to 1]; p = 0.06). Reductions in CRP occurred in parallel with bodyweight loss and were consistent regardless of baseline BMI/bodyweight/glycaemic status. More semaglutide-treated participants had reductions in CRP-defined cardiovascular risk versus those on placebo. Reductions in CRP were positively correlated with reductions in bodyweight, waist circumference, fasting plasma glucose, fasting serum insulin, and HOMA-IR (data not shown). Interpretation: In people with overweight/obesity, once-weekly semaglutide 2.4 mg and 1.0 mg reduced CRP concentration irrespective of baseline BMI/bodyweight/glycaemic status compared with placebo. These data suggest a potential anti-inflammatory role of semaglutide in obesity. Funding: Novo Nordisk.

Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics.

OBJECTIVE: This paper describes the baseline characteristics of the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) study, one of the largest cardiovascular (CV) outcome studies in the field of obesity, which evaluates the effect of semaglutide versus placebo on major CV events. METHODS: SELECT enrolled individuals with overweight or obesity without diabetes, with prior myocardial infarction, stroke, and/or peripheral artery disease. This study reports participants' baseline characteristics in the full study population and subgroups defined by baseline glycated hemoglobin (HbA1c ; <5.7%, ≥5.7 to <6.0%, ≥6.0 to <6.5%), baseline waist to height ratio tertile, and qualifying prior CV event or condition. RESULTS: The study enrolled 17,605 participants (72.5% male) with an average (SD) age of 61.6 (8.9) years and BMI of 33.34 (5.04) kg/m2 . The most common prior CV event was myocardial infarction (76.3% of participants), followed by stroke (23.3%) and peripheral artery disease (8.6%). Furthermore, 24.3% had a heart failure diagnosis. Two-thirds of participants (66%) had HbA1c in the prediabetes range (5.7%-6.4%). Across groups of increasing HbA1c , prevalence of all CV risk factors increased. CONCLUSIONS: The enrolled population in SELECT includes participants across a broad range of relevant risk categories. This will allow the study to garner information about the CV benefits of semaglutide across these relevant clinical subgroups.

Variation in human water turnover associated with environmental and lifestyle factors.

Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lacks access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5604 people from the ages of 8 days to 96 years from 23 countries using isotope-tracking (2H) methods. Age, body size, and composition were significantly associated with WT, as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People who lived in countries with a low human development index (HDI) had higher WT than people in high-HDI countries. On the basis of this extensive dataset, we provide equations to predict human WT in relation to anthropometric, economic, and environmental factors.

Variability in energy expenditure is much greater in males than females.

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction.

Development of a telehealth obesity OSCE and reliable checklist for assessment of resident physicians: a pilot study.

BACKGROUND: Obesity is a major public health problem, yet residents undergo little formal training and assessment in obesity-related care. Given the recent growth of telehealth, physicians must further learn to apply these skills using a virtual platform. Therefore, we aimed to develop an objective structured clinical examination (OSCE) with reliable checklists to assess resident ability to take a patient-centered obesity-focused history that was feasible over telehealth based on published obesity competencies for medical education. METHODS: We developed a 15-minute telehealth OSCE to simulate an obesity-related encounter for residents modified from a script used to assess medical student obesity competencies. We designed three checklists to assess resident skills in history taking, communication and professionalism during the obesity-related encounter. Resident performance was assessed as the percentage of obesity-related history taking questions asked during the encounter and as the mean communication and professionalism scores on a scale of 1 through 5 with 1 representing unacceptable/offensive behavior and 5 representing excellent skills. Encounters and assessments were completed by two commissioned actors (standardized patients) and 26 internal medicine residents over a secure online platform. We assessed the reliability of each checklist by calculating the percent agreement between standardized patients and the kappa (κ) statistic on each checklist overall and by each checklist item. RESULTS: Overall agreement between standardized patients on the history taking, communication and professionalism checklists were 83.2% (κ = 0.63), 99.5% (κ = 0.72) and 97.8% (κ =0.44), respectively. On average, residents asked 64.8% of questions on the history taking checklist and scored 3.8 and 3.9 out of 5 on the communication and professionalism checklists, respectively. CONCLUSIONS: Results from this pilot study suggest that our telehealth obesity OSCE and checklists are moderately reliable for assessing key obesity competencies among residents on a virtual platform. Integrating obesity OSCEs and other educational interventions into residency curricula are needed to improve resident ability to take an obesity-focused history.

Human total, basal and activity energy expenditures are independent of ambient environmental temperature.

Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (-10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p < 0.01) relationships between TEE, BEE and Ta emerged in females but the effect sizes were not biologically meaningful. Temperatures inside buildings are regulated at 18-25°C independent of latitude. Hence, adults in the US modify their environments to keep TEE constant across a wide range of external ambient temperatures.

Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.

AIM: To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension. MATERIALS AND METHODS: STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory. RESULTS: Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables. CONCLUSIONS: One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.

Using psycho-behavioral phenotyping for overweight and obesity: Confirmation of the 6 factor questionnaire.

Objective: Questionnaires that assess dietary habits, eating behaviors, and relevant psychosocial constructs are routinely used in obesity research and clinical practice. The 6 factor questionnaire (6FQ) was previously developed as an assessment tool for psycho-behavioral phenotyping. The primary purpose of this study was to confirm and validate the original findings in a large diverse adult population. Methods: A total of 5399 self-selected participants (mean age of 48 ± 13 years and body mass index of 32 ± 8 kg/m2) completed the 6FQ online. The association between self-reported demographic data and 6FQ responses was assessed using linear regression models. Results: Mean factor score and odds ratio analyses consistently demonstrated a statistically significant relationship between factors and body weight even after adjusting for age, sex, and race/ethnicity. Conclusions: Although the study was correlational in design, the results demonstrate that the 6FQ, an instrument that represents multidimensional unhealthful lifestyle patterns associated with diet, physical activity, cognition, and self-perception worsen with increasing body weight. Psycho-behavioral phenotyping may be a useful approach when assessing and treating patients with obesity.

Total energy expenditure is repeatable in adults but not associated with short-term changes in body composition.

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20-60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested.