OBJECTIVE: Glucagon-like peptide-1 receptor agonists are increasingly prescribed for obesity. Although generally considered safe, marked appetite suppression and persistent gastrointestinal adverse effects may increase t...OBJECTIVE: Glucagon-like peptide-1 receptor agonists are increasingly prescribed for obesity. Although generally considered safe, marked appetite suppression and persistent gastrointestinal adverse effects may increase the risk of nutritional deficiencies. Wernicke's encephalopathy (WE), caused by thiamine deficiency, is a rare but potentially fatal neurological disorder that may result in irreversible cognitive impairment if not promptly recognized and treated. Recently, cases of WE associated with semaglutide use have been reported. This study aimed to systematically review published case reports of WE occurring after semaglutide treatment for obesity from an endocrinological drug safety perspective. METHODS: A systematic literature search was conducted in PubMed, Embase, CINAHL, and Scopus according to PRISMA guidelines. Case reports were included when semaglutide was prescribed for obesity and the presentation was consistent with WE. RESULTS: Six cases were identified. All patients experienced prolonged gastrointestinal symptoms and substantial weight loss before neurological deterioration. Common manifestations included altered mental status and oculomotor abnormalities. Outcomes were poor in several cases, including progression to Korsakoff syndrome or death. CONCLUSIONS: Clinicians should remain vigilant for thiamine deficiency in patients with persistent gastrointestinal intolerance or rapid weight loss during GLP-1 treatment, as early parenteral thiamine administration is essential to prevent irreversible neurological sequelae.
OBJECTIVE: This study aimed to evaluate relationships between delayed gastric emptying and appetite suppression during treatment with liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA). METHODS: We conduct...OBJECTIVE: This study aimed to evaluate relationships between delayed gastric emptying and appetite suppression during treatment with liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA). METHODS: We conducted a secondary data analysis from a 16-week randomized, placebo-controlled liraglutide trial in patients with obesity. We examined correlations between solid food gastric emptying and measurements of satiation and energy intake in the entire cohorts at baseline and end of treatment and separately in placebo- and liraglutide-treated patients who completed the trial. We also compared appetitive measures among liraglutide-treated participants who displayed either normal, persistently delayed, or transiently delayed emptying during treatment. RESULTS: In the entire cohorts at baseline and completion, gastric emptying correlated significantly with energy intake and, at baseline, with one parameter of satiation. Gastric emptying accounted for only 4%-6% of the variance in these appetitive measures. No such correlations were found in the placebo- or liraglutide-treated groups alone. There were no differences in appetitive measures among the subgroups that displayed different gastric emptying patterns during liraglutide treatment. CONCLUSIONS: Delayed gastric emptying appears to play little direct role in appetite suppression induced by liraglutide. Further research should explore whether delayed emptying or other gastrointestinal effects of other GLP-1RAs affect appetite directly or indirectly. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02647944.
OBJECTIVE: Obesity, particularly excess visceral adipose tissue (VAT), may accelerate biological aging; however, few studies have examined this in middle-aged adults. We investigated associations between dual-energy X-ra...OBJECTIVE: Obesity, particularly excess visceral adipose tissue (VAT), may accelerate biological aging; however, few studies have examined this in middle-aged adults. We investigated associations between dual-energy X-ray absorptiometry (DXA)-derived VAT and two biomarkers of biological aging-phenotypic age acceleration (PhenoAgeAccel) and leukocyte telomere length (LTL)-in 4799 participants (2614 females, aged 45-69 years) from the Busselton Healthy Ageing Study. METHODS: Whole-body DXA (GE Lunar) quantified VAT mass. Phenotypic age was estimated from chronological age and nine biomarkers. In a subsample of 1221 participants, LTL was measured as the telomeric DNA to single-copy gene (T/S) ratio. Sex-stratified linear regressions assessed associations, adjusting for chronological age and lifestyle factors. RESULTS: Mean ± SD VAT mass was 1677 ± 873 g in males and 882 ± 598 g in females. Higher VAT was associated with greater PhenoAgeAccel in both sexes; each 1-SD increase in VAT corresponds to 1.397 (95% CI 1.197, 1.596) and 1.919 (1.738, 2.099) years higher PhenoAgeAccel in males and females, respectively. In females only, higher VAT was associated with shorter LTL (-0.041 [-0.069, -0.013] per 1 SD). Associations mostly remained significant after adjustment for anthropometric and other DXA-derived adiposity measures. CONCLUSIONS: VAT may represent a specific marker of accelerated biological aging, independent of lifestyle and adiposity measures.
Brown A, Patel SS, Kozato A
… +12 more, Orandi BJ, Massie A, Vu AH, Somoza E, Mei T, Desai S, Zhang DS, Segev D, Welcome AU, Ren-Fielding C, Parikh M, Chhabra KR
OBJECTIVE: Directly compare the real-world effectiveness of semaglutide and tirzepatide to bariatric operations: sleeve gastrectomy and gastric bypass. METHODS: This study included adults with BMI ≥ 35 who received injec...OBJECTIVE: Directly compare the real-world effectiveness of semaglutide and tirzepatide to bariatric operations: sleeve gastrectomy and gastric bypass. METHODS: This study included adults with BMI ≥ 35 who received injectable semaglutide or tirzepatide (GLP-1RAs) or sleeve gastrectomy or gastric bypass (bariatric surgery) at two urban health systems from 2018 to 2024. Total weight loss (TWL) was compared up to 3 years post treatment with inverse probability weighting and mixed linear models. Intention-to-treat (any GLP-1RA) and per-protocol (1 year of continuous GLP-1RA orders) analyses were performed. RESULTS: Of 44,025 patients studied, bariatric surgery was associated with greater weight loss at 1, 2, and 3 years post treatment: semaglutide (n = 25,804) TWL (95% CI): 5.4% (5.3%-5.6%), 6.5% (6.4%-6.7%), and 7.4% (7.3%-7.6%); tirzepatide (n = 7308): 9.1% (8.9%-9.4%) and 10.8% (10.2%-11.3%); sleeve gastrectomy (n = 8728): 24.4% (24.3%-24.6%), 22.4% (22.3%-22.5%), and 22.0% (21.8%-22.1%); gastric bypass (n = 2185): 29.8% (29.7%-29.9%), 28.1% (28.0%-28.2%), and 28.4% (28.3%-28.5%). With 1 year of continuous GLP-1RA, findings were: semaglutide TWL: 7.2% (7.0%-7.4%), 8.0% (7.8%-8.2%), and 8.8% (8.6%-9.0%); tirzepatide TWL: 11.7% (11.4%-11.9%) and 11.9% (11.5%-12.3%). CONCLUSIONS: In this retrospective two-center study, bariatric surgery was associated with greater weight loss than GLP-1RAs among patients eligible for both options.
Jovanovic B, Singh S, Zhang F
… +3 more, Williams EA, Roberts SB, Lowe MR
Obesity (Silver Spring)
· 2026 Jul · PMID 42316515
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OBJECTIVE: Higher short-term weight variability (WV) predicts greater subsequent weight gain in weight-stable adults and toddlers and lower long-term weight loss among adults with overweight or obesity who previously los...OBJECTIVE: Higher short-term weight variability (WV) predicts greater subsequent weight gain in weight-stable adults and toddlers and lower long-term weight loss among adults with overweight or obesity who previously lost weight. We extend prior work by examining the impact of naturally occurring WV on subsequent weight loss (weight at month 3 minus later weights) in individuals without obesity enrolled in the Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy (CALERIE) study. METHODS: Participants (N = 143) followed a 25% caloric restriction diet over 2 years. WV was calculated as the root-mean-squared-error of individuals' weights over the first 12 weeks. Multilevel models examined WV's prediction of subsequent weight loss at 6, 12, 18, and 24 months relative to month 3, adjusting for baseline BMI, 12-week weight change, and demographic variables. Sensitivity analyses further included time-varying adherence and eating behaviors (disinhibition, restraint, craving). RESULTS: Higher WV was associated with less subsequent weight loss at 6 months (B = -0.38, 95% CI [-0.63, -0.13], β = -0.16, p = 0.003). The interaction between time and WV was not significant; analyses suggested the association extends through year 1. CONCLUSIONS: Short-term WV predicted lower subsequent weight loss in adults without obesity. Once its biobehavioral mechanisms are understood, WV might provide insight into humans' innate capacity for long-term weight stability and inform future mechanistic research and clinical interventions. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT00427193.
OBJECTIVE: Dietary protein reduction increases plasma fibroblast growth factor 21 (FGF21) and energy requirements in lean men under eucaloric conditions. Whether these metabolic effects translate to weight loss during is...OBJECTIVE: Dietary protein reduction increases plasma fibroblast growth factor 21 (FGF21) and energy requirements in lean men under eucaloric conditions. Whether these metabolic effects translate to weight loss during isocaloric conditions in men with overweight or obesity remains unclear. METHODS: Seventeen men with overweight or obesity were randomly allocated to two different highly controlled, isocaloric diets for 5 weeks, receiving either a protein-reduced diet (0.9 g kg BW day) substituted with increased carbohydrates or a habitual diet (1.8 g kg BW day). RESULTS: Protein reduction induced a 2.0 ± 0.6 kg weight loss and increased plasma FGF21 concentration compared with higher protein intake, without caloric restriction. Changes in plasma FGF21 concentration were inversely associated with changes in body weight (r = -0.59, p = 0.02). Expression of key components in the FGF21 receptor complex, FGFR1 and β-klotho, and downstream targets in subcutaneous adipose tissue remained unchanged. Markers of skeletal muscle mitochondrial oxidative phosphorylation were also unaltered. Fat mass decreased significantly, whereas this level of protein reduction only tended to lower lean body mass. CONCLUSIONS: These findings suggest that reducing protein intake (0.9 g kg BW day), substituted with increased carbohydrates, compared with a habitual protein intake (1.8 g kg BW day), can induce weight loss without restricting total energy intake in men with overweight or obesity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06263725.
OBJECTIVE: This study assessed changes in body composition and 24-h energy metabolism at 6 and 12 months after initiation of a 1-month very low-calorie ketogenic diet (VLCKD) in women with obesity. METHODS: Seventeen wom...OBJECTIVE: This study assessed changes in body composition and 24-h energy metabolism at 6 and 12 months after initiation of a 1-month very low-calorie ketogenic diet (VLCKD) in women with obesity. METHODS: Seventeen women with obesity who completed a 1-month VLCKD underwent a 4-week transition phase with carbohydrate reintroduction, followed by a hypocaloric balanced diet. Assessments of body composition by dual-energy X-ray absorptiometry (DXA) and 24-h energy expenditure (24hEE) by a whole-room indirect calorimeter were performed. RESULTS: Following the initial 7% weight loss, body weight further decreased at 6 months (-3.9%, p < 0.05), primarily driven by a significant decrease in fat mass (-10%, p < 0.05). From 6 to 12 months, three participants continued to lose weight, whereas most remained stable or partially regained. Lean soft tissue, decreased during the VLCKD phase, remained stable throughout follow-up. Both 24hEE and 24-h sleeping metabolic rate exhibited a progressive trend toward increase. Minute-by-minute 24hEE trajectories revealed a significant increase in metabolic rate from 1 to 6 months (p < 0.001). The metabolic adaptation observed after 1 month of VLCKD was no longer detectable at either 6 or 12 months. CONCLUSIONS: These findings provide novel insight into the physiological adaptations following VLCKD, supporting its role in supervised weight loss programs for selected patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT07418281.
Rutter MK, Mount J, Gibson JM
… +12 more, Webb J, Marler C, Reed C, Gore M, Ye W, Gomez Valderas E, Wilding J, Sattar N, Davies MJ, Khunti K, Haynes R, Batterham RL
OBJECTIVE: SURMOUNT-REAL UK will evaluate the effectiveness of tirzepatide when offered in addition to standard-of-care (SoC) in adults with Class I obesity (BMI ≥ 30 and ≤ 34.9 kg/m) and without diabetes in a UK primary...OBJECTIVE: SURMOUNT-REAL UK will evaluate the effectiveness of tirzepatide when offered in addition to standard-of-care (SoC) in adults with Class I obesity (BMI ≥ 30 and ≤ 34.9 kg/m) and without diabetes in a UK primary care setting. METHODS: A 5-year, phase 4, multicenter, open-label, pragmatic randomized clinical trial is enabled through access to participants' integrated electronic healthcare record data. The study will enroll approximately 3000 participants from Greater Manchester, UK, who are randomly assigned in a 1:1 ratio to receive either tirzepatide and SoC or SoC alone. RESULTS: The primary endpoint is the percent change in body weight from baseline to Month 24, with the time to onset of type 2 diabetes to Month 60 being the key secondary endpoint. Additional endpoints include the impact of tirzepatide versus SoC on obesity-related complications, health-related quality of life, healthcare resource utilization, productivity, employment, and sickness-related absences. CONCLUSIONS: SURMOUNT-REAL UK employs a novel study design to evaluate real-world health outcomes and potential long-term benefits for both participants and the healthcare system associated with the delivery of pharmacological obesity treatment at a population level. The study is intended to generate critical evidence to support informed decision-making in obesity management, clinical guideline development, and healthcare policy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT07247084.
OBJECTIVE: This study assessed the impact of sex and age on weight loss outcomes in patients receiving tirzepatide in real-world clinical practice. METHODS: We conducted a retrospective cohort study of adults with overwe...OBJECTIVE: This study assessed the impact of sex and age on weight loss outcomes in patients receiving tirzepatide in real-world clinical practice. METHODS: We conducted a retrospective cohort study of adults with overweight or obesity who initiated tirzepatide at Mayo Clinic between June 2022 and May 2024 and completed ≥ 12 months of continuous therapy. Primary outcome was total body weight loss percentage (TBWL%) at 15 months, stratified by sex and age groups (≤ 45, 46-59, ≥ 60 years). RESULTS: Among 1039 patients (57% women; mean age 56 ± 11 years), women achieved significantly greater TBWL% than men after 15 months of treatment (15.1% vs. 10.7%, p < 0.001). Patients aged ≤ 45 years had greater weight loss than those ≥ 60 years (15.1% vs. 12.3%, p = 0.024). In multivariable analyses, greater weight loss was independently associated with female sex, absence of type 2 diabetes, no prior obesity medication use, no concomitant weight gain-promoting medications, and higher tirzepatide dosage. Age was not an independent predictor. CONCLUSIONS: Sex, but not age, predicted weight loss with tirzepatide among individuals using the medication continuously for ≥ 12 months. These findings underscore the importance of incorporating sex-specific considerations into personalized obesity treatment strategies.
Wu Z, Wang M, Guo L
… +6 more, Zheng H, Huang L, Xu T, Li Q, Di J, Han X
Obesity (Silver Spring)
· 2026 Jul · PMID 42289309
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OBJECTIVE: Obesity, a critical public health challenge, involves dysregulated food stimuli responses central to its pathophysiology. Aversion to harmful food is protective, but dynamic brain network reorganization during...OBJECTIVE: Obesity, a critical public health challenge, involves dysregulated food stimuli responses central to its pathophysiology. Aversion to harmful food is protective, but dynamic brain network reorganization during aversion processing in obesity and its clinical implications remain inadequately understood. METHODS: Brain activity was recorded from 30 participants with obesity and 35 healthy participants during exposure to spoiled food videos in an MRI scanner. We applied dynamic network analysis to assess obesity-related alterations in neural circuits and their links to eating disorders. RESULTS: The group with obesity showed significantly lower integration between the visual (VN), dorsal attention (DAN), and subcortical (SUB) networks than the healthy control group while viewing spoiled food videos. Critically, this DAN-SUB integration correlated positively with body image distress and negatively with craving ratings, and it moderated the predictive link between cognitive impulsivity and eating disorders. Granger causality analysis confirmed a dominant indirect pathway with stronger effective connectivity, showing differential spatial associations with neurotransmitter receptors (α4β2, mGluR5, NMDA, and CB1). CONCLUSIONS: This study reveals VN-DAN-SUB dynamic interactions in aversion processing, emphasizing the indirect pathway's key role. Inefficient VN-DAN-SUB coordination in obesity may impair aversive food stimuli regulation, supporting the emotion regulation deficit hypothesis and offering a neurobiological basis for future interventions.
OBJECTIVE: Approximately 41% of the US population has obesity, though the prevalence of the highest BMI populations (e.g., ≥ 60 kg/m) is increasing most rapidly. Given the association between obesity and surgical disease...OBJECTIVE: Approximately 41% of the US population has obesity, though the prevalence of the highest BMI populations (e.g., ≥ 60 kg/m) is increasing most rapidly. Given the association between obesity and surgical disease burden, we hypothesized that higher BMI groups would account for a growing proportion of operative volume over time. This study examined whether individuals with higher BMI have been receiving proportionally more surgical care over time. METHODS: All multispecialty National Surgical Quality Improvement Program (NSQIP) cases from 2005 to 2022 were analyzed (n = 11,634,075). Multinomial logistic regression was performed to analyze trends among BMI categories (< 30.0, 30.0-39.9, 40.0-49.9, 50.0-59.9, 60.0-69.9, and ≥ 70 kg/m), while adjusting for demographics and comorbidities. RESULTS: Regression models demonstrated decreased odds of patients with BMI ≥ 50 kg/m undergoing surgery over consecutive years, with increasingly higher BMI groups representing greater declines. Patients with BMI 30.0-39.9 kg/m demonstrated increased proportional operative volume. CONCLUSIONS: Despite increased growth in higher BMI populations, individuals in these categories undergo fewer surgical operations annually. These findings demonstrate a critical need to understand these inequalities, which are underscored by rising obesity prevalence that may be contributing to poor access to surgical care as well as increased morbidity/mortality of presentation with more advanced disease.
OBJECTIVE: Use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has increased rapidly following approval for obesity treatment, but data on their use in younger populations remain limited. We examined trends in GL...OBJECTIVE: Use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has increased rapidly following approval for obesity treatment, but data on their use in younger populations remain limited. We examined trends in GLP-1RA use among 12- to 24-year-olds in Denmark during 2018-2025. METHODS: Using nationwide prescription, hospital, and laboratory registries, we conducted a drug utilization study including all 12- to 24-year-olds who filled a GLP-1RA prescription between January 2018 and December 2025. We described incidence of use, baseline characteristics, prescribing patterns, and treatment persistence. RESULTS: GLP-1RA use rose more than 50-fold across the study period, reaching 418 new users per 100,000 by 2025, driven by semaglutide for weight management. Uptake was steepest among individuals aged 18-24 years (from 13 to 686 per 100,000) and more modest among adolescents aged 12-17 years (from 1.7 to 72 per 100,000). Most users were female, few had diabetes, and 33% had psychiatric comorbidity, particularly emotional and neurodevelopmental disorders. By 2025, 78% of new treatments were initiated in general practice. Only 38% were covered by a prescription after 1 year. CONCLUSIONS: Findings demonstrate rapid uptake of GLP-1RAs in youth and the need for specialist involvement, long-term safety data, and careful evaluation of mental health in this population.
Obesity (Silver Spring)
· 2026 Jul · PMID 42249608
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OBJECTIVE: This study evaluated changes in weight status and cardiometabolic parameters following bariatric surgery (BS) among adolescents with obesity using population-based real-world data. METHODS: This retrospective...OBJECTIVE: This study evaluated changes in weight status and cardiometabolic parameters following bariatric surgery (BS) among adolescents with obesity using population-based real-world data. METHODS: This retrospective cohort study used electronic health records from Clalit Health Services, Israel. Adolescents aged 12-20 years who underwent BS between 2010 and 2024 were included. Demographic characteristics, socioeconomic position (SEP), anthropometry, blood pressure, and laboratory parameters were extracted. Longitudinal changes in BMI and cardiometabolic outcomes were analyzed using mixed-effects models adjusted for sex, ethnicity, SEP, age at BS, and baseline BMI. Median follow-up was 5.8 years. RESULTS: The cohort included 1035 adolescents (69.7% female; median age at surgery ~18.6 years), with sleeve gastrectomy as the predominant procedure. BMI declined significantly over time (p < 0.001), with maximal reduction at 1-3 years and sustained improvement thereafter. Males experienced greater BMI reduction than females (p < 0.001). BMI trajectories were similar across SEP and ethnic groups, while individuals with higher baseline BMI maintained higher BMI throughout follow-up (p < 0.001). Blood pressure and multiple metabolic parameters improved substantially, with durable long-term benefits and some sex-specific differences. CONCLUSIONS: Adolescent BS was associated with sustained improvements in BMI and cardiometabolic risk factors in a large real-world cohort, supporting its long-term effectiveness across population subgroups.
Fleming-Batayneh VL, Helsel BC, Ptomey LT
… +24 more, Handen BL, Mapstone M, Petersen M, Krinsky-McHale SJ, Hom CL, Minhas D, Luo W, Laymon C, Lee JH, Cohen A, Ances BM, Brickman AM, Pulsifer M, Rosas HD, Lai F, Zaman SH, Head E, Tudorascu D, Price J, Schmitt F, Christian BT, Okonkwo O, Hartley SL, Alzheimer Biomarkers Consortium‐Down Syndrome (ABC‐DS) Investigators
Obesity (Silver Spring)
· 2026 Jul · PMID 42244445
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OBJECTIVE: Adults with Down syndrome (DS) often show elevated systemic inflammation, but the association with obesity, aging, and Alzheimer's disease (AD) pathology is not well understood. METHODS: Data were drawn from 1...OBJECTIVE: Adults with Down syndrome (DS) often show elevated systemic inflammation, but the association with obesity, aging, and Alzheimer's disease (AD) pathology is not well understood. METHODS: Data were drawn from 188 nondemented adults with DS participating in the Alzheimer Biomarkers Consortium-DS (ABC-DS). Participants completed clinical assessments, blood draws, and neuroimaging. Plasma biomarkers included indicators of general, pro-, and anti-inflammation. Mixed linear models tested associations between BMI, age, PET-measured amyloid burden, and inflammatory biomarkers, adjusting for sex, trisomy type, and collection site. False discovery rate correction was applied. RESULTS: The majority of the participants met criteria for obesity. Higher BMI was significantly associated with elevated levels of CRP, IL-6, TNF-α, B2M, IL-18, and slCAM-1 (p < 0.05). Older age was significantly associated with higher B2M (β = 1.22e + 05, p < 0.001). Amyloid burden was positively associated with IL-6 (β = 0.005, p = 0.037). CONCLUSIONS: Obesity, aging, and amyloid burden relate to systemic inflammation in adults with DS. Obesity showed the strongest and most consistent associations, emphasizing the value of regular monitoring and weight management strategies to help reduce inflammation. Aging and early amyloid accumulation showed more limited links with systemic inflammation; future work should examine whether these processes are more closely related to biomarkers of neuroinflammation as AD progresses.