BACKGROUND AND AIMS:Metabolic bariatric surgery (MBS) is highly effective for weight loss, yet up to 50 % of individuals regain weight within five years. Reductions in resting metabolic rate (RMR), linked to fat-free mass (FFM) loss, have been suggested as one contributing factor. Yet, the liver and kidneys are highly metabolic organs (∼30 % of RMR); therefore, changes in their volume may contribute to a greater-than-expected decline in RMR, known as metabolic adaptation (MA), which may promote weight regain. We aim to evaluate the impact of exercise on changes in organ volume and MA following MBS. METHODS:Fifty-eight adults with severe obesity (39.6 ± 10.6y, 114.3 ± 17.5 kg, 41.4 ± 4.1 kg/m2) were enrolled in an open-label randomized controlled trial and assigned to one of three exercise intervention groups pre MBS: aerobic (n = 15), resistance (n = 13), combined training (n = 14), or to a no-exercise control group (n = 16) for 26 weeks. Training sessions were online, supervised, and progressed to 60 min, three times/week. Pre- and post-intervention RMR was measured by metabolic cart, body composition by dual-energy X-ray, and liver and kidney volume using 3-T magnetic resonance imaging (MRI). RESULTS:Fifty-three participants (91 %) completed the intervention, and 47 were included in the final analysis. Significant reductions were observed in body weight (-31.1 ± 8.7 kg, -27 %), RMR (-356 ± 237 kcal/day, -17 %), kidney volume (-35.1 ± 25.2 cm3, -11 %), and liver volume (-384 ± 250 cm3, -21 %) (p < 0.01 for all), similarly across all groups. Crucially, reductions in liver and kidney volume were significantly associated with lower RMR (p < 0.001). The significant (P < 0.001) MA of -289 ± 190 kcal/day was independent of exercise volume or type. Liver volume accounted for 32.1 % of MA, FFM for 29.7 %, and kidney volume for 6.2 %. CONCLUSIONS:Our findings suggest that MA following MBS may be associated with a reduction in liver and kidney volume, potentially contributing to RMR decline. These findings highlight a potential organ-specific mechanism underlying MA and may prevent weight regain. CLINICALTRIALS:gov identifier: NCT04777305.

ABSTRACT Background Metabolic bariatric surgery (MBS) effectively reduces fat mass (FM), but how to best preserve muscle and bone mass after MBS is unknown. Objective This study aimed to evaluate the effect of aerobic, resistance and combined exercise regimens on body composition, bone mineral density (BMD) and physical function in adults following MBS. Methods Patients were randomized into aerobic, resistance, combined and control groups after undergoing MBS. Exercise groups completed a 26‐week supervised program (three sessions per week) with progressively increasing intensity. The primary outcome was the change in fat‐free mass (FFM) measured by dual‐energy X‐ray absorptiometry (DXA). Secondary outcomes included FM, hip, femoral neck and lumbar spine BMD, serum collagen type I C‐telopeptide (CTX) and physical function (e.g., 6‐min walk test and handgrip strength). Between‐group differences were assessed using Bayesian analysis of covariance (ANCOVA) adjusted for age, sex, surgery type and baseline body mass index, with credible differences inferred when the 95% credible interval of the standardized effect size excluded zero. Associations between outcomes were assessed using Pearson correlation. Results Of 443 eligible candidates, 58 participants (aged 18–65 years, 70% women, BMI 41.7 ± 4.4 kg/m2) were randomized to aerobic (n = 15), resistance (n = 13), combined (n = 14) or control (n = 16) groups, and 91.3% were included in the analysis. The combined exercise group preserved more FFM (−5.1 ± 2.8 kg vs. −7.7 ± 2.8 kg; ES 0.60 [0.41, 0.77]) and reduced more FM (−11.9% ± 5.7% vs. −10.1% ± 4.9%, ES −0.64 [−0.85, −0.40]) than control. Aerobic training most attenuated total hip BMD loss (−0.037 ± 0.033 g/cm2, −3.3%) compared with control (−0.058 ± 0.021 g/cm2, −5.4%; ES 0.69 [0.42, 0.92]) and modestly attenuated femoral neck BMD loss (ES 0.30 [0.11, 0.48]), with no differences at the lumbar spine. The relative increase in serum CTX was smaller in the aerobic (157.8%; ES −0.44 [−0.65, −0.18]) and combined groups (161.8%; ES −0.42 [−0.63, −0.17]) compared with control (196.4%). Physical function improved modestly, with aerobic training showing a greater improvement in walking distance than control (80.0 ± 56.4 m vs. 65.6 ± 39.2 m; ES 0.33 [0.08, 0.54]). Walking distance improvement correlated with weight loss. Handgrip strength was best preserved in the resistance group (ES 0.77 [0.47, 1.04]) and was positively correlated with protein intake. Conclusions Following MBS, combined aerobic and resistance training improved body composition by preserving FFM and reducing FM, while aerobic training most attenuated bone loss. Exercise was associated with modest improvements in physical function, supporting individualized exercise strategies to promote metabolic, musculoskeletal and functional health after MBS. Trial Registration ClinicalTrials.gov Identifier: NCT04777305.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to obesity and insulin resistance, and sustained weight loss is associated with histological improvement. Whether different obesity-management modalities exert weight-independent hepatic effects remains uncertain. METHODS:We conducted a systematic review and network meta-analysis (NMA) of randomised controlled trials evaluating lifestyle intervention, obesity management medications, endoscopic sleeve gastroplasty and metabolic and bariatric surgery in adults with BMI ≥ 27 kg/m2 and biopsy-confirmed MASH. The primary endpoint was MASH resolution without worsening of fibrosis. Study-level meta-regressions explored associations between total body weight loss (TBWL%) and histologic outcomes. RESULTS:Six RCTs (n = 1379) met inclusion criteria. Tirzepatide, semaglutide, sleeve gastrectomy and Roux-en-Y gastric bypass were superior to placebo or standard care for achieving MASH resolution. Because the network was weakly connected and largely placebo-anchored, indirect estimates were imprecise. Across study arms, greater TBWL% was associated with higher rates of MASH resolution and fibrosis improvement; however, these associations were strongly influenced by a small number of high-weight-loss surgical arms. CONCLUSIONS:Weight loss was consistently associated with histologic improvement across available RCTs. However, the limited evidence base, sparse network structure and ecological nature of the meta-regression preclude causal inference. These findings should be considered exploratory and hypothesis-generating, underscoring the need for adequately powered head-to-head trials.

This 2026 update integrates emerging trial evidence — particularly for weight loss and liver disease — to refine EASO’s treatment algorithm for obesity management.

Importance:Obesity and type 2 diabetes are major global health concerns associated with substantial clinical and economic burdens. Bariatric metabolic surgery (BMS) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective interventions, but their long-term impact on health care utilization costs remains incompletely understood. Objective:To compare short- and long-term health care utilization costs among patients with obesity and diabetes treated with GLP-1RAs vs those who underwent BMS. Design, Setting, and Participants:This observational, retrospective cohort study used electronic medical records from Clalit Health Services, the largest health care organization in Israel. Adults (aged ≥24 years) with obesity (body mass index [BMI] ≥30) and diabetes who underwent their first BMS or initiated GLP-1RA therapy between January 1, 2010, and December 31, 2022, were identified. Propensity score matching yielded 2721 matched pairs, who were followed up for up to 12.5 years (mean [SD], 6.5 [3.5] years), through December 31, 2023. Data cleaning and analyses were conducted from June to October 2025. Exposures:Treatment with GLP-1RAs or BMS. Main Outcomes and Measures:Health care utilization costs incurred by the health system, excluding costs of the index interventions. Attributable costs were estimated using a difference-in-differences approach and modeled with multivariable linear regression. Results:The matched cohort included 5442 adults (mean [SD] age, 51 [10] years; 3243 women [59.6%]; mean [SD] BMI, 40.5 [6.0]). Mean (SD) monthly follow-up costs were higher among patients treated with GLP-1RAs than those who underwent BMS ($415.3 [$746.7] vs $304.9 [$628.5]). The adjusted difference-in-differences method showed $109.0 higher monthly costs per patient for GLP-1RA treatment (SE = $17.0; P < .001), associated primarily with hospitalization costs ($43.9; SE = $13.3; P = .001) and non-GLP-1 medication costs ($52.5; SE = $4.4; P < .001). Most cost differences accrued within the first 4 years. BMS was associated with greater early reductions in BMI and hemoglobin A1c, whereas GLP-1RA treatment showed more modest but sustained effects. Conclusions and Relevance:This cohort study found that, among adults with obesity and diabetes, health care utilization costs were higher with GLP-1RA treatment than with BMS, excluding intervention costs, largely reflecting differences in early clinical trajectories. These findings suggest that, among patients eligible for both interventions, BMS may confer combined clinical and economic advantages over long-term follow-up.

INTRODUCTION:Bariatric metabolic surgery (BMS) alone or glucagon-like peptide-1 receptor agonists (GLP-1RA) alone are known to reduce major adverse cardiovascular events (MACEs). However, the benefit for primary prevention of MACE with use of GLP-1RA treatment after BMS is unclear. This retrospective cohort study assessed the associations of post-BMS GLP-1RA treatment with first incidence of MACE/all-cause mortality, as well as with predicted cardiovascular (CVD) risk and body mass index (BMI) and hemoglobin-A1c (HbA1c) levels, among patients with obesity and diabetes. METHODS:Adults who initiated GLP-1RA post-BMS were compared with individuals who did not. Groups were matched based on age, sex, BMI, HbA1c, years since BMS, and the nearest-neighbor propensity score for the probability of receiving GLP-1RA. Follow-up began at GLP-1RA initiation and ended on December 31, 2023. RESULTS:The study population included 476 GLP-1RA initiators and 952 matched BMS-only patients (mean [SD] age: 48.7 [9.5] years; 1,046 [73.2%] women). GLP-1RA initiation after BMS was associated with reduction in BMI (-7.0%) and HbA1c (-13.0%) and higher diabetes remission (78.0% vs. 61.6%). Ten-year predicted CVD risk was similar between users and nonusers before treatment initiation (0.053%) but was significantly lower among users during follow-up (0.039% vs. 0.046%). During a mean (SD) follow-up of 1.4 (0.8) years (maximum ∼10.6 years), there were 12.7 per 1,000 person months (n = 17) and 10.6 per 1,000 person months (n = 7) new cases of MACE and all-cause mortality in the BMS-only and GLP-1RA post-BMS group, respectively. No overall statistically significant association was observed between initiation of GLP-1RA after BMS and MACE/all-cause mortality. However, significant interaction was observed with time since BMS (p = 0.04), with a lower risk of MACE/all-cause mortality as the time from BMS increased. CONCLUSION:Initiation of GLP-1RAs after BMS was associated with lower BMI and HbA1c levels, higher diabetes remission, and reduced predicted CVD risk among patients with diabetes and obesity. Overall, GLP-1RA treatment after BMS did not further reduce the risk of MACE/all-cause mortality compared to BMS alone after a mean follow-up of 1.4 years. Given the observed time-dependent benefit of treatment after BMS, longer follow-up studies are needed to determine the optimal timing for initiation.

The primary analysis of the SELECT randomized clinical trial suggests that semaglutide reduced the rates of cardiovascular (CV) death, myocardial infarction, and stroke in patients with established CV disease (CVD) and overweight or obesity without diabetes. However, the effect of semaglutide on hospitalizations in this population remains unknown. To determine the impact of semaglutide on total hospital admissions and duration of hospital stay. The SELECT trial included patients aged 45 years or older with established CVD and a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 27 or higher without diabetes at 804 clinical settings across North America, South America, Europe, Asia, Africa, and Australia. Patients were randomized from October 2018 to March 2021. This prespecified exploratory analysis was conducted from February 2024 to September 2025. Once-weekly subcutaneous semaglutide, 2.4 mg, or placebo. The total number of hospital admissions and days in hospital between the semaglutide and placebo groups. A total of 17 604 patients (median [IQR] age, 61.0 [55.0-68.0] years; 4872 female patients [27.7%]; median [IQR] BMI, 32.1 [29.7-35.7]) were followed up for a median (IQR) period of 41.8 (33.0-47.0) months. There were 11 287 hospital admissions. The number of total hospitalizations was lower in the semaglutide group vs placebo for any indication (18.3 vs 20.4 admissions per 100 patient-years; mean ratio [MR], 0.90; 95% CI, 0.85-0.95; P < .001) and for serious adverse events (15.2 vs 17.1 admissions per 100 patient-years; MR, 0.89; 95% CI, 0.84-0.94; P < .001). The number of days hospitalized for any indication per 100 patient-years was lower in the semaglutide group vs placebo (157.2 vs 176.2 days; rate ratio [RR], 0.89; 95% CI, 0.82-0.98; P = .01), as well as hospitalizations for serious adverse events (137.6 vs 153.9 days; RR, 0.89; 95% CI, 0.81-0.98; P = .02). No heterogeneity was observed for the reduction of hospital admissions with semaglutide in selected subgroups, including BMI, age, and sex. In this prespecified exploratory analysis of the SELECT randomized clinical trial, the trial cohort had a high rate of hospital admissions. Treatment with once-weekly semaglutide was associated with significant reductions in hospital admissions and overall time spent in hospital, extending its benefits beyond CV risk reduction. ClinicalTrials.gov Identifier: NCT03574597

Background:High body mass index (BMI) is a modifiable cancer risk factor, projected to surpass smoking as the leading preventable risk factor. The impact of weight change from late adolescence to adulthood on cancer risk remains unclear. We aimed to assess the association between adolescence-to-adulthood BMI trajectories and obesity-related cancer risk. Methods:A population-based cohort study of 800,024 people (45.1% women) insured by a large state-mandated health provider. BMI was measured during military pre-recruitment evaluations during 1967-2018 in adolescence and in subsequent clinic visits in adulthood during 1998-2020. Follow-up began one year after an adult BMI measurement until cancer diagnosis, death, transfer to another health provider, or December 16, 2021. BMI trajectories from adolescence to adulthood were classified as lean-to-lean, lean-to-high, high-to-lean, and high-to-high (cutoff: sex-specific and age-specific 85th percentile in adolescence, defined according to the United States Centers for Disease Control and Prevention growth charts, and 25 kg/m2 in adulthood). Weight change was also assessed per 5% increments. The primary outcome was obesity-related cancers including esophagus, postmenopausal breast, liver and gallbladder, stomach, pancreas, colon and rectum, kidney, multiple myeloma, thyroid, uterus and ovary. The secondary outcome was obesity-related cancers diagnosed before age 50 years (early-onset cancers). Cox proportional hazards models were applied. Findings:During 7,610,263 person-years, 6,376 people were diagnosed with obesity-related cancers, at a mean age of 53.3 ± 9.8 years. Adjusted hazard ratios (HRs) were 1.31 (95% confidence interval [CI], 1.24-1.39) for lean-to-high, 1.01 (95% CI, 0.78-1.31) for high-to-lean, and 1.47 (95% CI, 1.34-1.61) for high-to-high groups, compared to the lean-to-lean group. Respective HRs for early-onset obesity-related cancers were 1.33 (95% CI, 1.20-1.47), 0.88 (95% CI, 0.60-1.31), and 1.39 (95% CI, 1.20-1.61). Each 5% weight gain conferred a 3% increased hazard (95% CI, 1.02-1.03), with a similar 3% increase for early-onset cancers (95% CI, 1.02-1.04). Cancer-specific risks included 3% (95% CI, 1.02-1.04) for postmenopausal breast cancer, 3% (95% CI, 1.01-1.04) for colorectal cancer, 4% (95% CI, 1.02-1.05) for thyroid cancer, 5% (95% CI, 1.04-1.07) for kidney cancer, and 8% (95% CI, 1.06-1.09) for uterine cancer. Some cancers, including leukemia and non-Hodgkin's lymphoma, were not associated with weight gain but were positively associated with high adolescent BMI. Interpretation:Maintaining a healthy BMI from adolescence to adulthood may reduce obesity-related cancer risk, including early-onset, highlighting the importance of early weight management strategies. Funding:Novo Nordisk, Israel.

Weight regain is a major long-term challenge in post-bariatric surgery. This study aimed to assess long-term weight regain (> 2 years) using a 25

OBJECTIVE:This study evaluates dementia and Parkinson's disease (PD) risk among patients with type 2 diabetes (T2D) and obesity initiating GLP-1 receptor agonists (GLP-1 RAs) compared with other oral glucose-lowering medications, addressing the unclear comparative neurocognitive effects despite GLP-1 RAs' neuroprotective potential in preclinical studies. RESEARCH DESIGN AND METHODS:This historical prospective cohort study used electronic health records from Clalit Health Services. Adults with T2D and obesity (body mass index [BMI] ≥30 kg/m²) initiating non-insulin glucose-lowering medications between 2008-2021 were included. After exclusions and 1:1 nearest-neighbor matching, the final cohort comprised 46,962 patients. Associations were assessed using Cox proportional hazards models. RESULTS:Among 46,962 matched participants (mean age, 62.8 years; 52.6% women), median follow-up period was 7 years. Dementia occurred in 1125 GLP-1 RA users (4.8%) and 1822 non-GLP-1 users (7.8%) (adjusted hazard ratio [HR], 0.86 (0.75-0.99)). PD occurred in 231 GLP-1 RA users (1.0%) and 338 non-GLP-1 users (1.4%) (0.90 (0.67-1.22)). In the secondary analysis, GLP-1 RA use was associated with lower risks of dementia compared with sulfonylureas (0.75 (0.61-0.93)) and PD (0.56 (0.36-0.86)). No significant differences were observed compared with DPP-4 inhibitors or SGLT2 inhibitors. Subgroup analyses showed stronger protective associations for dementia among women (0.78 (0.65-0.94)) and participants aged ≥65 years (0.82 (0.69-0.97)). CONCLUSIONS:The use of GLP-1 RAs was associated with a lower risk of dementia compared with other glucose-lowering therapies. These findings support the neuroprotective potential of GLP-1 RAs and highlight the importance of incorporating brain health into diabetes management strategies.

BACKGROUND:People with diabetes and obesity have an increased risk of hospitalisation and in-hospital complications. Rising prevalence of diabetes and obesity, including their co-occurrence, "diabesity", make guideline-compliant treatment increasingly important. However, evidence on specific in-hospital diabesity treatment is limited. We aimed to characterise inpatients with diabetes/diabesity and evaluate their in-hospital care to identify challenges in inpatient diabetes/diabesity management. METHODS:Cross-sectional data was collected from patient records and ward charts. We analysed differences between inpatients with and without diabesity and explored in-hospital diabetes treatment. We further compared inpatients with type 2 diabetes who started insulin treatment or received cardioprotective glucose-lowering agents to those who did not and used logistic regression to identify predictors of insulin initiation and use of cardioprotective agents. RESULTS:We included 207 people with diabetes from eight European hospitals, 50 % with diabesity. Most inpatients had a HbA1c >6.5 % (48 mmol/mol). Among inpatients with type 2 diabetes, one third did not have a recent HbA1c reading, blood glucose levels were monitored <3 times daily, and only 40 % of those with cardiovascular/renal disease received cardioprotective therapies. HbA1c, creatinine and at-home medications predicted insulin initiation, while admission cause and BMI predicted use of cardioprotective agents. CONCLUSIONS:We observed an underuse of cardioprotective glucose-lowering therapies, low rates of glycaemic monitoring, and low availability of HbA1c readings, concluding that clinical guidelines are not sufficiently implemented in everyday practice in Europe. Based on this, we advocate for better staff training, involvement of diabetologists, and raising awareness of the benefits of cardioprotective agents in the hospital.

Background:Both obesity and diabetes are associated with increased risk for specific types of cancer, generally termed obesity-related cancer (ORC). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and bariatric metabolic surgery (BMS) are well established treatments for diabetes and obesity, but their comparative effectiveness for the prevention of ORC is unknown. Here, we compare the incidence of ORC in adults living with obesity and diabetes who were treated with first-generation GLP-1RA or with BMS. Methods:An observational, retrospective cohort study based on electronic medical records data of Clalit health services, Israel. The study included patients aged ≥24 years, with obesity and diabetes, with no prior history of ORC, who received either of the interventions during 2010 through 2018. Overall, 3178 pairs were matched 1:1 based on sex, age, baseline BMI, time of treatment initiation, and smoking status. The study period extended from January 2010 until December 2023. The measured outcome was the incidence of ORC, defined as any of the following diagnoses: multiple myeloma, meningioma, adenocarcinoma of esophagus; stomach, colorectal, liver or bile duct, gallbladder, pancreas, corpus uteri, ovary, renal-cell kidney, thyroid, and postmenopausal breast cancer. Findings:Of the 6356 study participants, 3884 (61.1%) were females. At baseline, the mean age was 52.3 years (SD: 9.28), and the mean BMI was 41.5 kg/m2 (SD: 5.10). Participants were followed for a median of 7.5 years and up to 12.9 years. ORC occurred in 5.62 cases per 1000 person-years in BMS patients, and in 5.89 cases per 1000 person-years in GLP-1Ra patients; adjusted HR for GLP1-RA versus BMS 1.11 (95% CI: 0.86-1.44). Moreover, assessment of mediation through weight-loss resulted in an estimated direct effect of 41% (95% CI: 15%-59%) relative risk reduction of the pharmacotherapy. Interpretation:Our finding suggest that first-generation GLP1-RA treatment does not increase ORC risk in patients receiving GLP1-RA treatment for diabetes and weight loss. Moreover, this may point at additional pathways beyond weight loss in which GLP-1RAs might contribute to the decreased risk for ORC, such as reducing inflammation. However, future studies, including randomized controlled trials and larger prospective cohort studies are needed to validate the observed effects and explore the underlying mechanisms. Funding:No financial or in-kind support was provided for the conduct of this study.

BACKGROUND:The European Association for the Study of Obesity (EASO) recently introduced a new framework to define obesity that incorporates anthropometric measures beyond body mass index (BMI) and clinical comorbidities. However, this framework has not been validated. OBJECTIVE:To describe the distribution of overweight and obesity and determine the prevalence of complications and association of obesity with all-cause mortality using BMI categories and the new EASO framework. DESIGN:Cross-sectional and longitudinal analysis. SETTING:NHANES (National Health and Nutrition Examination Survey) from 1999 to 2018 linked to mortality data. PARTICIPANTS:A representative sample of the adult population in the United States aged 18 to 79 years. MEASUREMENTS:Obesity defined using BMI categories was compared with the new EASO definition. RESULTS:The study population included 44 030 adults. On the basis of the new EASO definition, 18.8% of adults who were previously defined as overweight based on BMI alone were now considered persons with obesity (PWO). Similar mortality risk was found among the newly identified PWO and persons with normal weight (hazard ratio [HR], 0.98 [95% CI, 0.87 to 1.10]), whereas higher risk was seen among persons with BMI of 30 kg/m2 or greater (HR, 1.19 [CI, 1.08 to 1.32]). However, when compared with persons with normal weight who did not have major morbidities, a higher risk was seen among the newly identified PWO (HR, 1.50 [CI, 1.20 to 1.88]), although this higher risk was no greater than the higher risk seen among persons with normal weight and comorbidities (HR, 1.74 [CI, 1.34 to 2.22]). Excess risk was seen among PWO compared with persons with overweight according to both the new EASO framework and the traditional BMI definition. The most prevalent complications among the newly identified PWO were hypertension (79.9%), arthritis (33.2%), diabetes (15.6%), and cardiovascular disease (10.5%). LIMITATION:Residual confounding; body weight assessed at a single time point. CONCLUSION:The new EASO framework may provide a more sensitive tool to diagnose obesity than the traditional BMI definition, but whether these newly identified adults with obesity would benefit comparably to obesity treatment as those traditionally included in treatment trials is uncertain. PRIMARY FUNDING SOURCE:Ariel University and the Holon Institute of Technology, Israel.

BACKGROUND:Fixed-dose combination of semaglutide/cagrilintide (CagriSema 2.4 mg/2.4 mg) has demonstrated significant and clinically relevant body weight reductions in adults with overweight or obesity compared with placebo. METHODS:The phase 3a, 68-week REDEFINE 1 trial randomized adults without diabetes with body mass index ≥30 kg/m2, or ≥27 kg/m2 with ≥1 obesity-related complication, to once-weekly CagriSema 2.4 mg/2.4 mg, semaglutide 2.4 mg, cagrilintide 2.4 mg, or placebo, plus lifestyle intervention. Secondary and post hoc analyses evaluated the antihypertensive effect from REDEFINE 1, focusing on CagriSema and placebo groups, by subgroup/category, including baseline body mass index, the presence of hypertension or resistant hypertension at baseline, and concomitant changes in the use of antihypertensive medications. RESULTS:Overall, 3417 participants underwent randomization; CagriSema: n=2108, semaglutide: n=302, cagrilintide: n=302, and placebo: n=705. Changes from baseline to week 68 in blood pressure (BP) were greater with CagriSema versus placebo (systolic BP: -10.9 versus -2.8 mm Hg; diastolic BP: -5.4 versus -1.7 mm Hg, respectively). The proportion of participants reaching BP targets at week 68 was 63.0% and 32.0% for CagriSema and placebo, respectively. The proportion of participants with resistant hypertension at baseline (n=167) that reached BP targets at week 68 was 42.0% and 29.3% for CagriSema and placebo, respectively (odds ratio, 1.7 [95% CI, 0.7-4.4]). Among participants who used antihypertensive medication during the study, 39.6% in the CagriSema group decreased or stopped treatment from week 0 to week 68 versus 18.8% with placebo. CONCLUSIONS:CagriSema presents clinically relevant reductions in BP across a wide range of participant subgroups, including those with resistant hypertension. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05567796.

BACKGROUND:Monlunabant, a novel cannabinoid receptor 1 (CB1R) inverse agonist, has shown encouraging weight loss efficacy and tolerability. We aimed to evaluate the efficacy and safety of monlunabant in individuals with obesity and metabolic syndrome. METHODS:This 16-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2a trial, conducted at 25 outpatient research centres in Canada, enrolled adults with obesity and metabolic syndrome. Participants were randomly assigned (1:1:1:1) by means of an interactive response system to once-daily oral tablets of monlunabant 10 mg, 20 mg, 50 mg, or placebo. The participants, site staff, sponsor, and contract research organisation were masked to treatment allocation. The primary endpoint was mean bodyweight (kg) change from baseline at week 16 versus placebo, assessed in all eligible randomised participants, whereas the safety analysis was done in all randomised participants who received at least one dose of trial product. The estimator for the primary estimand was analysed using a mixed model for repeated measures, assuming missing data are missing at random. This trial is registered with ClinicalTrials.gov (NCT05891834) and is complete. FINDINGS:From Sept 8, 2023, to Jan 26, 2024, 409 individuals were screened for eligibility. In total, 243 individuals were randomly assigned to monlunabant 10 mg (n=61), monlunabant 20 mg (n=61), monlunabant 50 mg (n=60), and placebo (n=61); 242 participants received treatment, including 167 (69%) females and 75 (31%) males. 183 (76%) of 242 participants completed the trial: 50 (82%) of 61 received monlunabant 10 mg, 42 (70%) of 60 received monlunabant 20 mg, 34 (57%) of 60 received monlunabant 50 mg, and 57 (93%) of 61 received placebo. At week 16, participants receiving monlunabant showed statistically significant weight loss compared with those receiving placebo (least squares mean difference vs placebo of -6·4 kg [95% CI -8·0 to -4·9] for monlunabant 10 mg, -6·9 kg [-8·5 to -5·3] for monlunabant 20 mg, and -8·0 kg [-9·7 to -6·4] for monlunabant 50 mg). Adverse events were mostly mild to moderate gastrointestinal and psychiatric disorders and were seen in 42 (69%) of 61 participants in the monlunabant 10 mg group, 47 (78%) of 60 participants in the monlunabant 20 mg group, 55 (92%) of 60 participants in the monlunabant 50 mg group, and 42 (69%) of 61 participants in the placebo group. Withdrawals due to adverse events appeared dose-dependent, occurring in eight (13%) participants who received monlunabant 10 mg, 16 (27%) who received monlunabant 20 mg, 25 (42%) who received monlunabant 50 mg, and none who received placebo, driven by nausea, anxiety, diarrhoea, irritability, and sleep disorder. No deaths were reported. INTERPRETATION:Participants receiving monlunabant showed statistically significant and clinically meaningful weight loss compared with those receiving placebo for all tested doses. Only slightly greater weight loss was observed at higher doses, whereas adverse events appeared dose dependent. Further investigation is needed to assess the safety and efficacy of lower doses of monlunabant, to evaluate its potential as a medication for obesity. FUNDING:Inversago Pharma (a Novo Nordisk company).

To estimate the recording rates and impact of overweight/obesity across selected countries in Europe and Asia–Pacific. IMPACT-O was a retrospective cohort study of electronic medical records and claims databases from France, Germany, Italy, Spain, the UK, Australia, and Japan. Recording levels and the number of adults with overweight/obesity [based on diagnostic codes and/or body mass index (BMI)] during 2018–2022 were estimated. BMI thresholds/categories and obesity-related complications (ORCs) were described for adults with ≥ 1 BMI record of ≥ 25.0 kg/m2 and ≥ 12 months observation before the index date. The number of active subjects across databases ranged from 1,203,674 to 22,413,902. BMI was recorded for 4.8–38.9

Obesity and associated complications can be managed by obesity medications, prompting the revision of criteria for the diagnosis and staging of this disease.