Obesity

Background and aimsThe optimal eating window for time-restricted eating (TRE) remains unclear. We investigated the effects of 8-hour TRE combined with usual care (UC, a Mediterranean diet-based education program), versus UC alone over 12 weeks on hepatic fat fraction, liver health markers, and fecal microbiota in adults with overweight or obesity. MethodsIn this multicenter randomized trial, participants (50% women) were assigned to UC (n=49), early TRE (n=49), late TRE (n=52), or self-selected TRE (n=47). Hepatic fat fraction was assessed by MRI; liver markers included elastography-based parameters, liver enzymes, and circulating biomarkers. Fecal microbiota was analyzed by 16S rRNA gene sequencing. ResultsHepatic fat fraction decreased significantly within the three TRE groups (all P[&le;]0.02), but no between-group differences were observed when comparing early TRE (mean difference [MD]: -0.4%; P=0.95), late TRE (MD: -1.5%; P=0.15), and self-selected TRE groups (MD: -0.7%; P=0.77) with the UC group, or among the TRE groups themselves (all P[&ge;]0.41). Similarly, no between-group differences were found in liver health markers and fecal microbiota. Participants with metabolic dysfunction-associated steatotic liver disease at baseline as well as those achieving [&ge;]5% weight loss had greater reductions in hepatic fat fraction than those who did not (MD: -2.7 and -2.6%; respectively, both P<0.001). A higher proportion of participants in the TRE groups achieved [&ge;]5% weight loss compared with UC (41-44% vs 16%; P=0.001). ConclusionThese findings suggest that the timing of the eating window in TRE may not impact liver fat or microbiota composition beyond the effects of weight loss, though the study was not powered for secondary outcomes. The study was registered on ClinicalTrials.gov (identifier: NCT05310721)

BackgroundObesity is associated with increased risk of morbidity, reduced quality of life, and pervasive weight stigma. For patients with severe obesity and multimorbidity who are ineligible for bariatric surgery, effective treatment options remain limited. Recently, glucagon-like peptide 1 receptor agonist-based weight loss medications have shown promise in weight management, but their effects in highly complex patient populations are not well described. ObjectiveThis protocol outlines a prospective observational study designed to explore and describe changes in cardiometabolic health, physical activity, physical capacity, and wellbeing among patients with obesity and multimorbidity enrolled in a two-year intensive weight loss program with GLP-1RA medication. MethodsThe study uses an exploratory prospective longitudinal cohort design and is based on an intensive weight loss program for patients with obesity and multimorbidity at Copenhagen University Hospital - Hvidovre. Approximately 35 patients will be enrolled over a six-month period. Data are collected at baseline, four months, and 24 months. Key outcomes include objectively measured physical activity, health-related quality of life, and 10-year cardiovascular risk. Additional outcomes include anthropometrics, mental health-related quality of life, weight bias internalization, cardiorespiratory fitness, lower body strength, and walking capacity. Data will be analyzed descriptively, and changes will be reported as mean differences with 95% confidence intervals. The study was registered at clinicaltrials.gov prior to recruitment (NCT06234111). PerspectiveThis study will provide novel insights into the health effects of intensive GLP-1RA-based weight loss program for patients with severe obesity and multimorbidity ineligible for bariatric surgery, thereby addressing an important knowledge gap in obesity management. Trial RegistrationThe study has been pre-registered with clinicaltrials.gov prior to inclusion of the first participant (NCT06234111). Project groupO_ST_ABSSemPAct project groupC_ST_ABSRasmus H. Brodsgaard (principal investigator), Thomas Bandholm, Kirstine N. Bojsen-Moller, Carsten Dirksen, Jeanette W. Kirk, Mette M. Pedersen, Sara O. Hofmann, Emilie S. Larsen, Minna Titika Finken, and Olivia M. Duun.

IntroductionSemaglutide is an effective intervention for weight loss, but the relative contributions of fat and fat-free mass (FFM) to total weight loss remain unclear. MethodsThis was a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating semaglutide use in adults living with overweight or obesity. Searches were performed in PubMed, Web of Science, Embase, and Scopus through April 2025. Eligible trials reported baseline and post-treatment measures of body mass, fat mass, and FFM. Data extraction followed PRISMA guidelines, and risk of bias and certainty of evidence were assessed. Random-effects models were applied, with linear or quadratic functions fitted as appropriate. ResultsSeven RCTs involving 452 participants (259 semaglutide, 193 placebo) met the inclusion criteria. Semaglutide produced significant non-linear weight loss (0.04 kg/day; 95% CI 0.03-0.05; p<0.0001), primarily due to fat mass reduction (0.03 kg/day; 95% CI 0.01-0.05; p=0.007). FFM declined linearly at a smaller rate (0.007 kg/day; 95% CI 0.003-0.010; p=0.0001). Certainty of evidence was moderate. ConclusionSemaglutide induces substantial reductions in body and fat mass, with modest FFM loss. Clinical strategies combining semaglutide with resistance exercise and nutritional support may help preserve lean mass and optimize long-term outcomes.

BackgroundGlucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as breakthrough weight loss agents. However, discontinuation is common, and clinical trials have demonstrated significant weight regain following cessation. In this systematic review, we aimed to characterise the trajectory of weight regain after GLP-1RA cessation. MethodsThis systematic review and meta-regression analysis followed Cochrane and PRISMA guidelines. We searched MEDLINE, Embase, Cochrane Library, Scopus and Web of Science from inception to December 26, 2024 for randomised controlled trials and observational studies reporting weight outcomes after cessation of GLP-1RAs in adults with overweight or obesity. Weight regain was the primary outcome and was modelled using nonlinear regression. Secondary outcomes included HbA1c and systolic blood pressure. The study protocol is registered with PROSPERO (CRD420250631751). FindingsWe identified 44 relevant studies. Weight, HbA1c and systolic blood pressure consistently rebounded after cessation of GLP-1RAs. Six trials with 3,236 participants were included in the exponential recovery model. Weight regain was estimated to plateau at 75.6% (95% CI 68.5-82.7) of the weight lost on treatment. The rate constant was 0.0302 per week (95% CI 0.0204-0.0399), corresponding to a half-life of 23.0 weeks. At 1 year after cessation, an estimated 40.2% of the on-treatment weight loss remained. Most studies were assessed to have moderate risk of bias. InterpretationGLP-1RA cessation is associated with a predictable and decelerating pattern of weight regain, which appears to plateau below pre-treatment levels, suggesting that partial weight-loss benefit may persist long-term but is substantially attenuated. FundingNone.

IntroductionObesity is a chronic, prevalent, multifactorial disease, stigmatized and linked to multiple long-term complications, which makes the treatment currently available below of the expectations from what is necessary to combat it. Because of this limitation, off-label medications for the treatment of obesity, such as topiramate, have been widely used, in association with on-label medications, such as sibutramine, in order to achieve more effective weight loss. ObjectiveCompare the effectiveness of the combination of sibutramine and topiramate with sibutramine monotherapy in weight loss in obese adults in regular follow-up. An effective weight loss is expected in the association group, due to complementary mechanisms of act, and antagonistic side effects of drugs, leading to greater weight loss and therapeutic adherence. Materials and MethodsRetrospective cohort study with analysis of 66 medical records, distributed equally between groups. A weight loss of [&ge;] 5% was considered as an effectiveness criterion. ResultsThe group treated with the association, after a mean follow-up period of 52 weeks, had a mean weight loss of 9.0%{+/-}8.2, against 5.3% {+/-} 4.7 for the monotherapy group (p= 0.011). In the analysis of subgroups by weight loss categories, patients treated with the combination had an odds ratio of 6,7, to achieve [&ge;]15% weight loss than the monotherapy group (OR=6.7, 95%CI=[1, 3; 33.7]). ConclusionA more effective weight loss was observed in the group treated with the combination of sibutramine and topiramate, when compared to the monotherapy group, after 52 weeks.

BackgroundAccording to World Health Organization (WHO), United Arab Emirates (UAE) has one of the highest prevalence rates of obesity in the Middle East at 34%. There is a paralleled rise in the incidence of related metabolic conditions, particularly type 2 diabetes, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Body mass index (BMI) alone is an insufficient marker of abdominal adiposity and addition of waist circumference (WC) can help to assess the cardiometabolic risk. AimTo study the prevalence of obesity related diseases in a multidisciplinary weight management program and determine the relationship to obesity anthropometric indices. MethodsThis is a cross-sectional study conducted at Mediclinic Parkview Hospital in Dubai, UAE. 308 patients have been evaluated from January 2019 until September 2019 as part of a multi-disciplinary weight management program. Key demographics, anthropometrics, and clinical data was analyzed using Statistical Package for Social Sciences software version 25 (SPSS Inc., Chicago, IL). ResultsThree hundred and eight patients taking part in the weight management program were studied. The population was constituted of 103 (33%) males and 205 (67%) females. The mean age was 41 years ({+/-}9.6) with a median BMI of 34.5 ({+/-}6.7) and 33.7 ({+/-}7.8) for males and females respectively. Mean waist circumference was 113.4 cm ({+/-}23.3) and 103.5 cm ({+/-}16.2), fat percent was 33.7% ({+/-}11.6) and 45 ({+/-}6.8), fat mass was 41 kg ({+/-}15.2) and 41.1 ({+/-}14.1), and visceral fat was 6.5 kg ({+/-}3.2) and 3.1 ({+/-}1.8), for males and females respectively. The population was heterogeneous with 38 nationalities. BMI strongly correlated with waist circumference (male; female, r=0.67; r=0.72) and visceral fat (male; female, r=0.89; r=0.78). Further, waist circumference was significantly associated with risk of diabetes, hypertension, and NAFLD. ConclusionThe study has confirmed the high prevalence rates of obesity related diseases in a private hospital setting in a multinational cohort of obese patients. BMI and waist circumference are the most representative measures of obesity in our population and correlate with abdominal adiposity and obesity related diseases. Further studies will play a part in assessing the benefit of these measures during weight reduction interventions.

Anti-obesity medications (AOMs) are used with lifestyle change support for weight management for adults with obesity. We investigated whether initiation of AOMs appeared to reduce attempted lifestyle changes. We searched for orlistat, liraglutide, semaglutide, and low-fat reducing diet (LFRD) trials in a trial register, Medline, Embase and systematic reviews from 1990 to June 2023. Weight changes in placebo groups of AOM trials with lifestyle interventions were compared to weight changes in LFRD trials. 16 orlistat, 7 liraglutide, 5 semaglutide, and 7 LFRD trials were included. Weight loss in orlistat placebo groups was 1.1kg less than LFRDs, a statistically non-significant difference, where last observation carried forward values were used for missing data in trials. Adjustment with baseline observation carried forward found 2.6kg less weight lost, a significant difference. Last observation carried forward data for orlistat trials providing completer data found a 0.2kg difference. Liraglutide placebo groups had 2.1kg less weight lost than predicted from LFRD trials. Semaglutide placebo groups had 2.0kg less weight loss. Compensatory reductions in changes to lifestyle behaviours may result following AOM initiation, but this needs to be explored further. Variability in trial design and study populations may contribute to the differences in weight change found.

AimsTo characterize trends in the initiation of newer anti-obesity medications (AOMs) and determine factors associated with their use among obese/overweight populations. Materials and methodsThis retrospective study utilized electronic health record data from OneFlorida+ (2015-2024). Adults eligible for AOMs were included, defined as having a BMI [&ge;]30 kg/m{superscript 2} or a BMI of 27-29.9 kg/m{superscript 2} with at least one obesity-related comorbidity. The primary outcome was the initiation of newer AOMs, specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) including liraglutide, semaglutide, and tirzepatide. Trends across years were examined, and a multivariable logistic regression identified sociodemographic, clinical, and healthcare utilization factors associated with AOM initiation. ResultsOf 319,949 adults, 1.8% initiated newer AOMs. Semaglutide accounted for 77.9% of initiations, tirzepatide 19.7%, and liraglutide 17.8%. Initiation trends showed liraglutide uptake peaked at 5% in 2018 but declined afterward, while semaglutide and tirzepatide uptake increased exponentially since 2022. Odds of initiation were lower for Black (aOR (95% CI): 0.87 [0.80- 0.94]) and Hispanic (0.84 [0.78-0.91]) groups vs. Whites, and for Medicaid (0.69 [0.63-0.76]) and uninsured (0.81 [0.74-0.87]) patients vs. privately insured. Higher odds were associated with being female, middle-aged, having more outpatient visits, and visiting endocrinologists. ConclusionsThe initiation of newer AOMs among overweight and obese populations remains low, but uptake has increased exponentially since 2022. Our findings reveal significant disparities in obesity care, highlighting the importance of addressing inequities in AOM access to improve obesity outcomes.

Obesity is a widespread health issue worldwide. Therefore, evaluating existing pharmaceuticals and developing new effective strategies to mitigate the problem is essential. Although literature reviews of a broad range of interventions for managing obesity exist, a recent evaluation of the efficacy of orlistat is lacking. This meta-analysis aims to quantify the efficacy of orlistat on body mass index (BMI) and the impact of age, dose, duration, and comorbidities. A literature search of orlistat on PubMed was carried out, and 177 placebo-controlled randomized clinical trials published in the last twenty years were identified. Sixteen studies that met the inclusion criteria were selected for further analysis. Two investigators independently extracted data from the clinical reports using a predefined protocol. We conducted a meta-analysis using random and mixed effects models with different moderators. We found that, on aggregate, the orlistat group reduced their BMI by 0.72 kg/m2 (P < 0.05) compared to the placebo group. In addition, a longer duration of intervention led to a greater decrease in BMI. Moreover, patients with comorbidities experienced a smaller change in BMI. In conclusion, the evidence suggests that orlistat moderately reduces BMI in obese subjects. The effect of lifestyle modifications, side effects, and drug interactions should be assessed in future studies.

ObjectiveTo establish a biorepository of clinical, metabolomic, and microbiome samples from adolescents with obesity as they undergo lifestyle modification. MethodsWe enrolled 223 adolescents aged 10-18 years with Body Mass Index [&ge;] 95th percentile, along with 71 healthy weight participants. We collected clinical data, fasting serum, and fecal samples at repeated intervals over 6 months. Here we present our study design, data collection methods, and an interim analysis, including targeted serum metabolite measurements and fecal 16S rRNA gene amplicon sequencing among adolescents with obesity (n=27) and healthy weight controls (n=27). ResultsAdolescents with obesity have higher serum alanine aminotransferase, C-reactive protein, and glycated hemoglobin, and lower high-density lipoprotein cholesterol when compared with healthy weight controls. Metabolomics revealed differences in branched chain amino acid related metabolites. We also observed differential abundance of specific microbial taxa and lower species diversity among adolescents with obesity when compared with the healthy weight group. ConclusionsThe Duke Pediatric Metabolism and Microbiome Study biorepository is available as a shared resource. Early findings suggest evidence of a metabolic signature of obesity unique to adolescents, along with confirmation of previously reported findings describing metabolic and microbiome markers of obesity. Clinical Trial RegistrationBiorepository: NCT02959034 Observational Trial: NCT03139877 What is already known about this subject?O_LIThe intestinal microbiome plays an important role in adult obesity and regulation of metabolism. Although it is well-established that obesity has its roots in childhood, very little is known about the role of the microbiome in pediatric obesity and how it changes during adolescence. C_LI What are the new findings in your manuscript?O_LIThis manuscript provides details of a new shared biorepository including clinical data, stool samples and plasma samples from a diverse cohort of 223 adolescents with obesity followed longitudinally over 6 months during a weight management intervention, as well as 71 adolescents with healthy weight as a comparison group. C_LIO_LIInterim analyses suggest that adolescents with obesity have microbiome signatures and metabolite profiles similar to adults, however key differences in microbial communities and metabolic by-products are identified. C_LI How might your results change the direction of research or focus of clinical practice?O_LIThe POMMS biorepository will be available for investigators to use in future research, to elucidate the underlying mechanisms of obesity and related chronic health conditions. C_LIO_LIPreliminary data reveal metabolite profiles that suggest adolescence may be a window of metabolic plasticity and disease reversibility C_LIO_LIMicrobiome and metabolomic signatures suggest potential biomarkers that may serve as prognostic or predictive factors in disease remission, or targets for future therapeutics. C_LI

Background & AimsWeight loss is associated with an improvement of insulin sensitivity. Both, a negative energy balance and changes of body composition are integrative components of weight loss interventions. However, the individual impact of these two components on insulin sensitivity and energy metabolism is unclear. MethodsWe performed a randomized controlled trial including 80 overweight or obese post-menopausal women. Participants randomly assigned to the intervention group underwent an 800 kcal/d liquid diet for 2 months followed by four weeks in which the formula diet was substituted by a calorie reduced healthy diet to facilitate further weight loss. This weight loss phase was followed by a 4-week weight maintenance phase, where weight stability was achieved by individualized daily caloric intake without negative energy balance. Volunteers of the control group were instructed to keep their weight stable during the entire period of 4 months. Metabolic phenotyping was performed in both groups at baseline (M0), after weight loss (M3) and after the maintenance period (M4). Additional phenotyping was performed during follow-up at 12 (M12) and 24 months (M24). Primary outcomes were changes of lean body mass (LBM) and changes of insulin sensitivity (ISIClamp) between baseline and M3 and M4. Estimates of energy metabolism were secondary endpoints. ResultsNo significant changes of body weight or LBM were found in the control group between any time points. A significant reduction of body weight, fat mass (FM) and LBM was found in the intervention group between M0 and M3, while no further change was seen between M3 and M4. Only subjects of the intervention group were characterized by an improvement of the second primary outcome ISIClamp at M3, which was preserved until M4. Notably, a lower resting energy expenditure per LBM (REELBM) at M3 as well as the individual difference of REELBM between M3 and M4 significantly predicted a stronger regain of fat mass during follow-up. ConclusionsIn summary, our data demonstrate that modulation of LBM and insulin sensitivity during weight loss is predominantly driven by changes in body weight and body composition, rather than an individual effect of negative energy balance. However, the variance in energy expenditure during negative and steady energy balance indicates a thrifty phenotype, which is highly susceptible to future regain of fat mass.

BackgroundIndividuals affected by obesity present different health trajectories and do not suffer from cardiometabolic complications all in the same way. There is a need to better understand obesity subtypes and to develop approaches for stratification. In this study we investigated both metabolomic and proteomic signatures in serum and blood plasma samples discriminating metabolically healthy from unhealthy obesity. MethodsWe investigated cross-sectional metabolomic and proteomic data from participants of the Cooperative Health Research in South Tyrol (CHRIS) study. Participants were grouped into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) based on available health data in the study. A total of 461 individuals were included in the analysis, with n=130 MHO and n=331 MUO. Random forest (RF) classifiers were used to discriminate metabolically healthy from unhealthy obesity and to identify molecular features characteristic of MHO/MUO. Linear regression models were used to assess associations between each relevant metabolite/protein and MHO/MUO phenotypes independently of age, sex and body composition. ResultsThe MHO/MUO RF classifier achieved a performance of AUC = 0.709, 95% CI = (0.698,0.721). Three plasma proteins and 12 circulating metabolites were identified as relevant predictors of MHO/MUO phenotypes. Linear regression models confirmed the Apolipoprotein C-III (APOC3) association to be independent of age, visceral fat composition, medication or serum triglyceride levels. ConclusionAPOC3 was identified as a novel predictor for obesity stratification, highlighting the importance of circulating triglyceride levels in relation to metabolic health.

ObjectiveTo estimate the association of obesity with severity (defined as use of invasive mechanical ventilation or intensive care unit admission) and all-cause mortality in coronavirus disease 2019 (COVID-19) patients. Patients and MethodsA systematic search was conducted from inception of COVID-19 pandemic through January 31st, 2021 for full-length articles focusing on the association of increased BMI/ Obesity and outcome in COVID-19 patients with help of various databases including Medline (PubMed), Embase, Science Web, and Cochrane Central Controlled Trials Registry. Preprint servers such as BioRxiv, MedRxiv, ChemRxiv, and SSRN were also scanned. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used for study selection and data extraction. The severity in hospitalized COVID-19 patients, such as requirement of invasive mechanical ventilation and intensive care unit admission with high BMI/ Obesity was the chief outcome. While all-cause mortality in COVID-19 hospitalized patients with high BMI/ Obesity was the secondary outcome. ResultsA total of 576,784 patients from 100 studies were included in this meta-analysis. Being obese was associated with increased risk of severe disease (RR=1.46, 95% CI 1.34-1.60, p<0.001, I2 = 92 %). Similarly, high mortality was observed in obese patients with COVID-19 disease (RR=1.12, 95% CI 1.06-1.19, p<0.001, I2 = 88%). In a multivariate meta-regression on severity outcome, the covariate of female gender, pulmonary disease, diabetes, older age, cardiovascular diseases, and hypertension was found to be significant and explained R2= 50% of the between-study heterogeneity for severity. Similarly, for mortality outcome, covariate of female gender, proportion of pulmonary disease, diabetes, hypertension, and cardiovascular diseases were significant, these covariates collectively explained R2=53% of the between-study variability for mortality. ConclusionsOur findings suggest that obesity is significantly associated with increased severity and higher mortality among COVID-19 patients. Therefore, the inclusion of obesity or its surrogate body mass index in prognostic scores and streamlining the management strategy and treatment guidelines to account for the impact of obesity in patient care management is recommended.

In the medical management of obesity, treating physicians observe significant heterogeneity in responses to pharmacotherapy. Indeed one of the most important clinical questions in obesity medicine is whether we can predict how an individual will respond to a particular pharmacotherapeutic agent. The present study examines patterns and predictors of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment. 182 women were assigned using single-blind randomization to either treatment with twice daily exenatide injections or to matched placebo injections with dietary counseling. Women who demonstrated > 5% weight loss after 12 weeks of treatment were deemed high responders and remained on study treatment for up to 52 weeks; women who lost < 5% body weight at 12 weeks were deemed low responders and stopped study treatment. We additionally characterized individuals who lost > 10% of body weight as super responders. Our primary outcome was change in body weight; secondary outcomes included changes in metabolic parameters including lipids, waist circumference, resting energy expenditure, and response to a meal tolerance test. We also performed an exploratory metabolomic analysis. Consistent with published literature, we observed individual heterogeneity in the weight loss response to exenatide and diet/placebo. Although there was no significant difference between treatment groups in the percentage of participants who achieved > 5% weight loss (56% of exenatide group and 76% of diet/placebo group), or those who achieved > 10% weight loss (43% of exenatide group and 55% of diet/placebo group), in both cases there was a trend toward a higher response rate in the group that received placebo with dietary counseling. In addition to achieving similar average weight loss, both treatment groups also demonstrated similar maximum weight loss. The range of maximum weight loss was greater in the diet/placebo group and there was more weight regain among individuals in the exenatide group compared to the diet/placebo group. In our exploratory metabolomic analysis, we observed lower baseline circulating cysteine concentrations in the exenatide responder group and we also found a trend toward higher baseline levels of serotonin, aminoisobutyric acid, anandamide, and sarcosine in the exenatide super responder group. We did not identify any metabolic predictors of weight loss in either the exenatide or the diet/placebo treatment group.

BackgroundCovid-19 disease causes significant morbidity and mortality through increase inflammation and thrombosis. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are states of chronic inflammation and indicate advanced metabolic disease. We sought to understand the risk of hospitalization for Covid-19 associated with NAFLD/NASH. MethodsRetrospective analysis of electronic medical record data of 6,700 adults with a positive SARS-CoV-2 PCR from March 1, 2020 to Aug 25, 2020. Logistic regression and competing risk were used to assess odds of being hospitalized. Additional adjustment was added to assess risk of hospitalization among patients with a prescription for metformin use within the 3 months prior to the SARS-CoV-2 PCR result, history of home glucagon-like-peptide 1 receptor agonist (GLP-1 RA) use, and history of metabolic and bariatric surgery (MBS). Interactions were assessed by gender and race. ResultsA history of NAFLD/NASH was associated with increased odds of admission for Covid-19: logistic regression OR 2.04 (1.55, 2.96, p<0.01), competing risks OR 1.43 (1.09-1.88, p<0.01); and each additional year of having NAFLD/NASH was associated with a significant increased risk of being hospitalized for Covid-19, OR 1.86 (1.43-2.42, p<0.01). After controlling for NAFLD/NASH, persons with obesity had decreased odds of hospitalization for Covid-19, OR 0.41 (0.34-0.49, p<0.01). NAFLD/NASH increased risk of hospitalization in men and women, and in all racial/ethnic subgroups. Mediation treatments for metabolic syndrome were associated with non-significant reduced risk of admission: OR 0.42 (0.18-1.01, p=0.05) for home metformin use and OR 0.40 (0.14-1.17, p=0.10) for home GLP-1RA use. MBS was associated with a significant decreased risk of admission: OR 0.22 (0.05-0.98, p<0.05). ConclusionsNAFLD/NASH is a significant risk factor for hospitalization for Covid-19, and appears to account for risk attributed to obesity. Treatments for metabolic disease mitigated risks from NAFLD/NASH. More research is needed to confirm risk associated with visceral adiposity, and patients should be screened for and informed of treatments for metabolic syndrome. Key QuestionsO_ST_ABSQuestionC_ST_ABSDoes NAFLD/NASH independently increase risk for poor outcomes from Covid-19? FindingsIn this observational study, a history of NAFLD/NASH was associated with a significantly increased odds of hospitalization. Metabolic surgery was protective against admission in persons with NAFLD/NASH and Covid-19. Metformin and glucagon like peptide 1 receptor agonists were associated with non-significant protecting against admission. MeaningTreatment for metabolic syndrome greatly reduce the elevated risk of hospitalization for Covid-19 among persons with NAFLD/NASH.

BackgroundIndividual weight loss response to the GLP-1 receptor agonist semaglutide varies considerably, with many possible contributing factors. Leveraging multiple clinico-genomic cohorts, we analyzed differences in weight loss trajectories according to patient characteristics, including a polygenic score (PGS) and metabolic risk factors, in semaglutide initiators with BMI [&ge;]27 kg/m2. MethodsThis longitudinal study utilized clinical-grade exome sequencing and electronic health record data from six U.S. cohorts within the Helix Research Network (n=134,806). A BMI PGS was calculated using 26,941 variants. Twelve-month weight loss trajectories were modeled using mixed effects models, and associations with demographics, PGS, comorbidities, medications, and laboratory results were evaluated. FindingsAmong 1,923 semaglutide users, the mean pretreatment BMI was 38.4 kg/m2. For those on doses [&ge;]1.7 mg, the mean body weight reduction was 7.3% at 6 months and 9.9% at 12 months. Over 12 months, low PGS was associated with an adjusted 1.5% and 1.8% additional weight loss compared to intermediate and high PGS, respectively (both p<0.01). Male sex, type 2 diabetes, hypertension, obstructive sleep apnea, and non-alcoholic fatty liver disease were each associated with 1.2%-1.9% less weight loss (all p<0.05). In type 2 diabetes, each 1%-increase in pretreatment hemoglobin A1c was associated with 0.6% less weight loss (p=0.0019). InterpretationAmong adults with overweight or obesity, a lower genetic predisposition to obesity is linked to greater weight loss on semaglutide. Additionally, metabolic health significantly impacts the drugs effectiveness. These findings underscore the importance of precision medicine in obesity management. FundingRenown Health Foundation. Nevada Governors Office of Economic Development. HealthPartners.

BackgroundChild eating behaviors are highly heterogeneous and their longitudinal impact on childhood weight is unclear. The objective of this study was to characterize eating behaviors during the first ten years of life and evaluate associations with BMI at age 11 years. MethodData were parental reports of eating behaviors from 15 months to age 10 years (n=12,048) and standardized body mass index (zBMI) at age 11 years (n=4884) from the Avon Longitudinal Study of Parents and Children. Latent class growth analysis was used to derive latent classes of over-, under-, and fussy eating. Linear regression models for zBMI at 11 years on each set of classes were fitted to assess associations with eating behavior trajectories. ResultsWe identified four classes of overeating; "low stable" (70%), "low transient" (15%), "late increasing" (11%), and "early increasing" (6%). The "early increasing" class was associated with higher zBMI (boys: {beta}=0.83, 95%CI:0.65, 1.02; girls: {beta}=1.1; 0.92, 1.28) compared to "low stable". Six classes were found for undereating; "low stable" (25%), "low transient" (37%), "low decreasing" (21%), "high transient" (11%), "high decreasing" (4%), and "high stable" (2%). The latter was associated with lower zBMI (boys: {beta}=-0.79; -1.15, - 0.42; girls: {beta}=-0.76; -1.06, -0.45). Six classes were found for fussy eating; "low stable" (23%), "low transient" (15%), "low increasing" (28%), "high decreasing" (14%), "low increasing" (13%), "high stable" (8%). The "high stable" class was associated with lower zBMI (boys: {beta} =-0.49; -0.68 -0.30; girls: {beta} =-0.35; -0.52, -0.18). ConclusionsEarly increasing overeating during childhood is associated with higher zBMI at age 11. High persistent levels of undereating and fussy eating are associated with lower zBMI. Longitudinal trajectories of eating behaviors may help identify children potentially at risk of adverse weight outcomes.

ContextRoux-en-Y gastric bypass (RYGB) has deleterious effects on bone mass, microarchitecture, and strength. Data are lacking on the skeletal effects of sleeve gastrectomy (SG), now the most commonly performed bariatric surgical procedure. ObjectiveWe examined changes in bone turnover, areal and volumetric bone mineral density (aBMD, vBMD), and appendicular bone microarchitecture and estimated strength after SG. We compared the results to those previously reported after RYGB, hypothesizing lesser effects after SG than RYGB. Design, Setting, ParticipantsProspective observational cohort study of 54 adults with obesity undergoing SG at an academic center. Main Outcome Measure(s)Skeletal characterization with biochemical markers of bone turnover, dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) was performed preoperatively and 6- and 12-months postoperatively. ResultsOver 12 months, mean percentage weight loss was 28.8%. Bone turnover marker levels increased, and total hip aBMD decreased -8.0% (95% CI -9.1%, -6.7%, p<0.01). Spinal aBMD and vBMD declines were larger in postmenopausal women than men. Tibial and radial trabecular and cortical microstructure worsened, as did tibial estimated strength, particularly in postmenopausal women. When compared to data from a RYGB cohort with identical design and measurements, some SG biochemical, vBMD, and radial microstructural parameters were smaller, while other changes were not. ConclusionsBone mass, microstructure, and strength decrease after SG. Some skeletal parameters change less after SG than after RYGB, while for others, we find no evidence for smaller effects after SG. Postmenopausal women may be at highest risk of skeletal consequences after SG.

BackgroundObesity is a chronic, heterogeneous condition, with risks, trajectories, and treatment responses that vary widely among individuals. However, research characterizing the heterogeneity of long-term obesity progression--and its impact on the development of obesity-associated outcomes and treatment responses--is scarce. ObjectivesWe aimed to identify progression subphenotypes in a real-world population with overweight or obesity over a period of up to 10 years using electronic health records (EHRs) and evaluate the heterogeneity of treatment effects (HTE) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) across these subphenotypes for major obesity-related disease outcomes. MethodsWe conducted a retrospective cohort study of adults from OneFlorida+ who were eligible for anti-obesity medication, defined by the presence of a documented diagnosis of obesity (BMI [&ge;] 30 kg/m{superscript 2}) or a BMI in the range of 27.0-29.9 kg/m{superscript 2} accompanied by at least one weight-related comorbidity. We developed an outcome-oriented graph neural network (GNN)-based model to identify progression subphenotypes of obesity. Within each subphenotype, we emulated a target trial of GLP-1RA users vs non-users, using propensity score matching and Cox proportional hazards models to evaluate obesity-related disease outcomes, including metabolic dysfunction-associated steatotic liver disease (MASLD), major atherosclerotic cardiovascular disease (ASCVD), stroke, heart failure (HF), and chronic kidney disease (CKD). ResultsAmong 237,103 adults with overweight or obesity, 58.1% were female, with a mean age of 51.8 years. The study population included 48.4% non-Hispanic White (NHW), 27.9% non-Hispanic Black (NHB), and 13.0% Hispanic individuals. Our GNN model identified three distinct progression subphenotypes: a progressive group (43.6%; "substantial-increase" BMI trajectory), an intermediate group (33.4%; "moderate-increase"), and a stable group (64.4%; "steady"). The mean follow-up durations were comparable across the subphenotypes (4.9-5.0 years). The progressive group exhibited greater baseline multimorbidity, higher opioid exposure, and an initially favorable neighborhood socioeconomic status that declined rapidly over time. The subphenotypes differed significantly in their risks of developing obesity-associated comorbidities and in all-cause mortality during follow-up (p < 0.001). GLP-1RA use was associated with a lower HF risk in two subphenotypes (HR (95% CI): 0.75 (0.61-0.91) and 0.74 (0.61-0.91), respectively) and with a possible increase in CKD risk in the progressive group (1.20 (1.02-1.41)). ConclusionsObesity progression subphenotypes derived from routine EHRs reveal markedly heterogeneity in trajectories, clinical risks, and treatment responses. Distinct BMI trajectory groups highlight the potential of data-driven, phenotype-guided care and expose meaningful variation in GLP-1RA treatment effects. These findings underscore the potential of longitudinal EHR analysis to advance precision obesity medicine and warrant prospective validation of HTE.

BackgroundEarly infancy and childhood are critical periods in the establishment of lifelong weight trajectories. Parents and early family environment have a strong effect on childrens health behaviors that track into adolescence, influencing lifelong risk of obesity. ObjectiveWe aimed to identify developmental trajectories of body mass index (BMI) from early childhood to adolescence and to assess their early individual and family predictors. MethodsThis was a secondary analysis of the Millennium Cohort Study and included 17,166 children. Weight trajectories were estimated using growth mixture modeling based on age- and gender-specific BMI Z-scores, followed by a bias-adjusted regression analysis. ResultsWe found four BMI trajectories: Weight Loss (69%), Early Weight Gain (24%), Early Obesity (3.7%), and Late Weight Gain (3.3%). Weight trajectories were mainly settled by early adolescence. Lack of sleep and eating routines, low emotional self-regulation, child-parent conflict, and low child-parent closeness in early childhood were significantly associated with unhealthy weight trajectories, alongside poverty, low maternal education, maternal obesity, and prematurity. ConclusionsUnhealthy BMI trajectories were defined in early and middle-childhood, and disproportionally affected children from disadvantaged families. This study further points out that household routines, self-regulation, and child-parent relationships are possible areas for family-based obesity prevention interventions.