BACKGROUND:Although semaglutide 2.4 mg has demonstrated significant weight loss efficacy in clinical trials, real-world data, particularly with regard to clinically complex and underrepresented populations, remain limited. OBJECTIVES:The study aims to assess the real-world effectiveness and patient-reported outcomes associated with the use of semaglutide 2.4 mg in individuals with severe and complex obesity. The study also intends to characterize weight loss response in pre-defined subgroups of patients and to identify predictors of weight loss using machine learning. METHODS:SEMASEARCH is a retrospective multicentric observational cohort embedded within the French early-access program for semaglutide 2.4 mg. A total of 1100 patients with severe obesity (BMI ≥ 40 kg/m2 with at least one treated obesity-related complication) were retrospectively included from 11 expert obesity centers, based on prospectively collected data at baseline, 6 months, and 12 months. Subgroups include patients with a history of bariatric surgery, binge eating disorder, hypothalamic obesity, age ≥ 60 years or altered body composition, BMI ≥ 60 kg/m2, and those receiving psychotropic medications. Assessments include clinical, biological, and body composition data, as well as standardized questionnaires evaluating eating behaviour, physical activity, sleep, quality of life, digestive symptoms, and mental health. PRIMARY OUTCOME:Body weight change since treatment initiation, with assessment at 6 and 12 months. SECONDARY OUTCOMES:Clinically meaningful weight loss (≥ 10%) at 12 months, metabolic improvements, patient-reported outcomes, body composition changes, and tolerance. EXPECTED IMPACT:SEMASEARCH will provide real-world evidence on Semaglutide 2.4 mg use in patients living with severe and complex obesity. It will also address major knowledge gaps in specific populations underrepresented in clinical trials and generate predictive models of weight loss response.

BACKGROUND:Individuals with severe obesity are at increased risk of severe influenza and may have impaired immune responses to vaccination. Recombinant influenza vaccine (RIV) may provide enhanced protection compared with egg-based standard-dose influenza vaccine (SD), but data in this high-risk population are limited. METHODS:The AP-HP FLUO trial (NCT05409612) was an open-label, randomized clinical trial conducted in 15 centers in France (November 2022-March 2023) with 6 months of follow-up. Adults with BMI ≥35 kg/m2 were randomized 1:1 to receive RIV or SD, using minimization by center, age (<50 vs ≥50 years), and BMI (<40 vs ≥40 kg/m2). The primary outcome was the ratio (RIV/SD) of geometric mean hemagglutinin-inhibition (HAI) titers (GMTs) for 4 influenza strains 28 days after vaccination. Safety and reactogenicity were also assessed. RESULTS:A total of 206 participants were included (104 RIV, 102 SD). Median age was 50 years, 60.2% were women, and median BMI was 41.0 kg/m2. At Day 28, GMT ratios favored RIV for A/H1N1 (1.6; 95% CI, 1.1-2.3), A/H3N2 (2.0; 95% CI, 1.3-3.2), and B/Yamagata (1.3; 95% CI, 1.0-1.8), but not for B/Victoria (0.9; 95% CI, 0.6-1.3). The effect did not vary significantly across the different age and BMI groups. By Day 180, titers did not differ significantly. Reactogenicity and safety profiles were similar between groups. CONCLUSIONS:In adults with severe obesity, RIV elicited stronger short-term humoral immune responses than an egg-based standard-dose vaccine, suggesting potential additional benefit for influenza prevention in this vulnerable population.

BACKGROUND:Obesity is a multifactorial condition and represents a major public health issue. In 5% of cases, obesity is monogenic, secondary to an abnormality in a gene of the leptin-melanocortin signaling pathway. OBJECTIVES:The aim of our retro-prospective descriptive study is to reclassify heterozygous variants of unknown significance (VUS) and to describe the clinical and biological phenotypes of the patients carrying these variants. METHODS:Our study population included adult and pediatric patients followed in the Hospices Civils de Lyon for severe obesity, with a heterozygous probably pathogenic variant or a variant of unknown significance on a specific gene of interest identified by genetic analysis between January 2018 and December 2022. Reclassification of variants was based on family segregation and the recent literature data. The data concerning medical history, phenotypic characteristics, and biological results were extracted from medical files. RESULTS:Twenty-six patients underwent family segregation analysis: 10 patients were identified as carriers of a heterozygous probably pathogenic variant or VUS with a positive segregation. All patients had early-onset obesity at a mean age of 2.8 years. CONCLUSIONS:Our study highlights the clinical relevance of family segregation in reclassifying VUS within the leptin-melanocortin pathway and underscores the diagnostic value of early obesity onset in identifying potential monogenic forms.

Aim Patients with type 2 diabetes (T2D) and obesity are at increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) with advanced fibrosis (AF), requiring systematic non-invasive assessment using liver stiffness measurement (LSM) or the ELF test. However, access to these biomarkers remains limited in diabetology. We therefore evaluated the diagnostic performance of a new point-of-care ultrasound device, Hepatoscope, for the risk stratification of AF. Methods Participants with T2D and/or obesity and MASLD age 40-80 years, BMI <40 kg/m2 prospectively included in a multi-centre study (NCT04435054) underwent LSM using vibration controlled transient elastography (LSM-VCTE, FibroScan) and 2D-transient elastography (LSM-2DTE) using Hepatoscope version 1 and ELF. Post-acquisition reprocessing of the LSM-2DTE data using the CE approved version 2 (LSM-2DTE-2) was performed in a subgroup of n=120 participants. The area under the ROC curve (AUROC) and 95% confidence interval (CI) were assessed for the detection of intermediate to high-risk of AF, defined by LSM-VCTE ≥ 8 kPa. Results Among 294 participants (83.3% T2D, 42.5% female, 71.4% obesity), 24.8% had LSM-VCTE ≥ 8kPa. Significant correlation was observed between LSM-VCTE and LSM-2DTE-1 r: 0.37 [0.26-0.47], P < 0.001 and was higher between LSM-VCTE and LSM-2DTE-2: r: 0.61 [0.47-0.71], P < 0.001. In the subgroup of 120 participants, the AUROC (95%CI) of LSM-2DTE-2 for the detection of LSM-VCTE ≥ 8kPa was 0.81 (0.72-0.89) compared to 0.64 (0.52-0.75) for ELF. Conclusion This proof-of-concept study provides evidence supporting the role of LSM-2DTE using the Hepatoscope in the risk stratification of AF in diabetology settings. Larger studies are needed to validate its performance.

As in the general population, people living with type 1 diabetes (PWT1D) are faced with overweight and obesity, which contribute to cardiovascular (CV) risk. However, the role of visceral adiposity, due to its adverse metabolic profile, should also be addressed in PWT1D. We aimed to assess the 10-year CV risk of PWT1D according to body mass index (BMI) and waist-to-height ratio (WHtR), a parameter for estimating visceral adiposity. In this cross-sectional study, PWT1D in primary CV prevention from the SFDT1 cohort were categorized by BMI status, either normal (18.5–24.9 kg/m2) or overweight/obesity (≥ 25 kg/m2), and by WHtR according to the validated threshold of 0.5. The 10-year CV risk was estimated using the Steno Type 1 Risk Engine and classified into three categories: low (< 10

BACKGROUND:Since 2007, single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) has been proposed as an alternative to Roux-en-Y gastric bypass (RYGB) in the treatment of obesity. We conducted a multicentre randomised trial, with the hypothesis that SADI-S could be more effective than RYGB at 2-year follow-up. METHODS:This multicentre, open-label, individually randomised superiority trial was conducted in France; patients were recruited from 22 bariatric institutions, mostly public academic hospitals. Key inclusion criteria were patients with a BMI ≥40 kg/m2 or ≥35 kg/m2 with obesity-related comorbidities (type 2 diabetes, hypertension, dyslipidaemia, sleep apnoea, or osteoarthrosis), and a candidate for SADI-S or RYGB gastric bypass as a primary surgery or after a sleeve gastrectomy. Main key exclusions included previous bariatric surgery (other than sleeve gastrectomy), inflammatory bowel disease, type 1 diabetes, and untreated Helicobacter pylori infection. Participants were randomly assigned (1:1) to SADI-S or RYGB, stratified by centre, failure of sleeve gastrectomy, and presence of type 2 diabetes. The primary endpoint was percentage excess weight loss (%EWL) at 2 years (%EWL=[(weight at 2 years - initial weight)/(initial weight - ideal weight)] × 100). The study is registered with ClinicalTrials.gov, NCT03610256 and is completed. FINDINGS:Between Nov 8, 2018, and Sept 29, 2021, a total of 381 patients were randomly assigned (intention-to-treat population) and included in the primary analysis (SADI-S: 190, RYGB: 191). Mean age was 44·4 years (SD 10·64), mean BMI was 46·2 kg/m2 (6·40), 265 (70%) were female, and 79 (21%) had a primary sleeve gastrectomy. 43 (12%) of 370 participants were lost to follow-up. At 2 years, the mean %EWL was statistically significantly higher in the SADI-S group compared with the RYGB group (-76·0% [SD 26·7] vs -68·1% [28·7], confirming the superiority of SADI-S (mean difference -6·72% [95% CI -12·64 to -0·80], p=0·026). The primary outcome was missing for 78 (20%) of 381 participants, with 46 (59%) of 78 participants in the SADI-S group and 32 (41%) of 78 in the RYGB group, p=0·09. The number of serious adverse events related to the surgical technique in the safety population, including all operated patients, was 40 in the SADI-S group including three anastomotic leaks and eight severe diarrhoea compared with 35 in the RYGB group including five internal hernia and five severe abdominal pain cases of which two required diagnostic laparoscopy. INTERPRETATION:SADI-S showed superior weight loss compared with RYGB at 2 years, with a similar safety profile. FUNDING:French Ministry of Health (Direction Générale de l'offre de Soin - DGOS).

Introduction The effects of bariatric surgery have largely been studied from a medical viewpoint, seeking to measure changes in anthropometric, physiological or quality-of-life factors after the operation. Few studies, however, have focused on the dynamics of lifestyle changes. Yet we know that changing lifestyle habits—which are often part of the established social configurations at the origin of morbid obesity—is essential for a sustainable recovery from obesity. We also know that the major bodily transformations that occur in the six to twelve months following surgery produce a high degree of biographical uncertainty and affect social interactions. From a sociological perspective, the authors propose to study the processes of disruption and re-establishment of lifestyle habits in the first 24 months following bariatric surgery.Methods and analysis The ChiBarAPS study relies on a mixed-method longitudinal survey, comprising three components: qualitative, quantitative, literature and data review. It aims to document three main dimensions, which must be articulated to understand the dynamics of change: (1) the work undertaken by patients on themselves in order to identify and measure the evolutionary effects of surgery, as well as to adapt to them; (2) the experience of using pre- and post-surgery information and support systems, and evaluating their effects on the agency of the people who have undergone surgery; (3) the evolution of social participation and lifestyle habits. The qualitative component concerns a cohort of 30 patients, interviewed in depth (2 hours) on these three dimensions, 6 months, 12 months and 24 months after the operation. The quantitative part uses questionnaires applied to a second group of 200 patients, following the same timeline.Ethics and dissemination This study complies with reference methodology MR004 of the French National Data Protection Authority and was registered by the Data Protection Officer of the University of Montpellier on the activity registry of the institution (24 April 2024). Ethics approval has been obtained from the University of Montpellier ethics research board (n°UM2024-037). Informed consent will be obtained from all participants before data collection. The project has received funding from the French National Research Agency (n°ANR-23-CE41-0020-01) from February 2024 to the end of January 2028. The first results of the research will be disseminated from 2026 onwards to researchers, health professionals and patient support organisations. The results of the study will then be published in peer-reviewed scientific journals, both national and international.

AIM:- To describe baseline characteristics and safety data of real-world use of semaglutide 2.4 mg. METHODS:- Patients with a body mass index (BMI) ≥40 kg/m2 and at least one of the following treated weight-related comorbidities (WRC: hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease) were eligible to receive treatment through Temporary Utilization Authorization (TUA: March to June 2022) or Early Access Program (EAP: July 2022 to October 2023). Data were collected according to Health Authorities' requirements. Only descriptive statistics were used. RESULTS:- Overall, 5,797 (62.8%) treatment requests were sent by sites specialized in obesity management. In total, 478 and 8,568 patients were treated within TUA and EAP cohorts respectively, with mean follow-up durations of 1.2 and 4.5 months, respectively. Mean (SD) BMI was 48.9 (9.7) and 47.0 (7.4) kg/m2, respectively. Age ranged from 18 to 81 years. In the EAP, 57.4%, 26.5%, 12.3% and 3.7% of patients had 1, 2, 3 and 4 WRC. In addition, 15.5% had type 2 diabetes, 18.1% reported depression and 15.4% had osteoarthritis. In the EAP, 247 (2.9%) patients discontinued treatment after a median time of 2.8 months (IQR: 1.2-5.1), mainly due to adverse events (AEs) (47.0%). During TUA, 3 patients discontinued due to AEs. Pancreatitis was reported in 7 cases overall. CONCLUSION:- The high number of treatment prescriptions in a short period highlights the high unmet medical need. No new safety concerns were identified in this population with severe obesity treated in a real-world setting.

Objective: Screening for advanced fibrosis (AF) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is recommended in diabetology. This study aimed to compare the performance of non-invasive tests (NITs) and 2-step algorithms for detecting patients with high-risk AF requiring referral to hepatologists. Research Design and Methods: A planned interim analysis of a prospective multi-center study including participants with type 2 diabetes and/or obesity and MASLD with comprehensive liver assessment including blood-based NITs, vibration-controlled transient elastography (VCTE) and two-dimensional shear-wave elastography (2D-SWE). AF risk stratification was determined by a composite criterion, including liver biopsy, magnetic resonance elastography, or VCTE ≥12 kPa depending on availability. Results: Among 654 patients (87% with type 2 diabetes, 56% male, 74% with obesity), 17.6% had intermediate/high risk of AF, and 9.3% had high-risk of AF. The AUROCs [95% confidence interval] of NITs for high-risk AF detection were: FIB-4: 0.78 [0.72-0.84], FibroMeter®: 0.74: [0.66-0.83], Fibrotest®: 0.78 [0.72-0.85], ELF™: 0.82 [0.76-0.87], SWE: 0.84 [0.78-0.89]. Algorithms with FIB-4/VCTE showed a good diagnostic performance for referral of intermediate/high-risk AF in specialized care in hepatology. An alternative FIB-4/ELF strategy showed a high NPV (88-89%) and a lower PPV (39-46%) at a threshold of 9.8. The FIB-4/2D-SWE strategy had a NPV of 91% and a PPV of 58-62%. Age-adapted FIB-4 threshold resulted in lower NPV and PPV in all algorithms Conclusion: The FIB-4/VCTE algorithm showed an excellent diagnostic performance demonstrating its applicability for routine screening in diabetology. ELF using an adapted low threshold at 9.8 may be used as alternative to VCTE.

INTRODUCTION:Although the physiologic alterations seen in obesity often affect the pharmacokinetics and pharmacodynamics of drugs, most clinical trials do not consider these aspects specifically for this population. To date, there is no list of potentially inappropriate medications for patients living with obesity. The aim of this study was to use the Delphi method to identify useful recommendations for the prescription of some specific drug classes in patients living with severe obesity. METHODS:We identified five therapeutic groups of drugs using data from the HEGP Clinical Data Warehouse. We conducted a literature review and sought the opinions of local experts to produce potential recommendations. We selected volunteer medical experts from the French network FORCE and set up a two-round Delphi method, concluded by a synthesis meeting, to establish a list of recommendations. In each round, the experts were asked to rate the potential recommendations. RESULTS:Forty-three proposed recommendations were evaluated in the first round. The experts approved four recommendations with a strong consensus and 16 with a relative consensus. In the second round, they approved six recommendations with a strong consensus and 13 with a relative consensus. CONCLUSION:This is the first study to use the Delphi method to produce a summary of consensus recommendations for several drug classes in patients living with severe obesity. It provides an expert-based consensus on the use of the five most commonly prescribed therapeutic drug classes and develops a list of recommendations for drug prescription in patients living with severe obesity.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity. We aimed to assess the impact of obesity on the performance of different noninvasive tests, including liver stiffness measurement (LSM) and Agile3+ (A3+), to detect advanced fibrosis (AF) in a population of patients with MASLD encompassing a wide range of BMI values. Methods: A total of 479 patients with MASLD were consecutively included (Lyon Hepatology Institute). Clinical data and noninvasive tests, including FibroTest, LSM, A3+, Fibrosis-4 (FIB-4), magnetic resonance elastography, and liver biopsies, were collected. AF was determined by a composite endpoint, i.e., histological stage >= F3, overt diagnosis of cirrhosis by magnetic resonance elastography, or concordant LSM >= 9.6 kPa and FibroTest >= F3. Results: The median BMI was 35.0 kg/m(2), and the prevalence of AF was 28.6%. Patients with BMI >= 35 versus <35 had a lower proportion of AF, i.e., 19.3% versus 38.1% (p < 0.001), but higher indeterminate status for AF (34.2% vs. 15.4%; p < 0.001). In the case of BMI >= 35, LSM had lower specificity to rule in AF (77.9%) versus A3+ (90.4%), but A3+ had decreased sensitivity to rule out AF. A sequential LSM/A3+ strategy achieved high specificity to rule in AF and lowered the proportion of indeterminate cases in patients with BMI >= 35. Conclusions: The grade of obesity affects the detection of MASLD-related AF. A sequential use of LSM/A3(+) could improve AF detection in patients with BMI >= 35.