bluuebunny/crossref_metadata_2025_split huggingface dataset:
1626-P: Liver-Specific Silencing of INHBE with ARO-INHBE, an siRNA Therapeutic, for Metabolic Diseases
Authors: NGAI MICHELLE , LIU FENG , LI XIAOKAI , CHRISTY COLE , HAMILTON HOLLY , PEI TAO , HAMILTON JAMES , DING ZHI-MING 
Published: June 2024

Introduction and Objective: Incretin-based therapies are evidently powerful and effective for obesity and cardiometabolic outcomes. However, the accompanying loss of significant lean body mass (LBM) and gastrointestinal adverse effects are of concern, and have inspired identification of novel modes of action for fat loss while preserving LBM. Loss-of-function INHBE variants are associated with a lower abdominal to gluteofemoral fat ratio, and protection against type 2 diabetes. Silencing INHBE expression represents a novel therapeutic approach for obesity and metabolic diseases. Here we describe a liver targeted siRNA therapeutic designed to silence INHBE expression.
Methods: siRNA conjugates targeting hepatic INHBE were designed. The pharmacodynamic properties of ARO-INHBE were evaluated in cynomolgus monkeys, and the pharmacological impact was assessed in DIO and db/db mice using a mouse surrogate of ARO-INHBE. Body weight, body composition, glucose homeostasis, and lipid metabolism were assessed during the studies.
Results: In cynomolgus monkeys, ARO-INHBE achieved deep knockdown of INHBE transcripts for a duration of at least 85 days with subcutaneous injections at 3 mpk on D1 and D29. In DIO and db/db mice, weekly dosing of the ARO-INHBE surrogate significantly suppressed body weight gain and decreased fat mass, but maintained lean mass and glucose homeostasis. Treatment with the surrogate of ARO-INHBE also improved the sensitivity of the DIO mice to catecholamine, indicated by the increased circulating ketone levels.
Conclusion: ARO-INHBE effectively silences hepatic INHBE mRNA. In the DIO mouse model, liver-specific silencing of INHBE mRNA caused the suppression of fat mass gain, but preservation of LBM. A clinical lead siRNA targeting INHBE has been selected.

Disclosure
M. Ngai: None. F. Liu: None. X. Li: Employee; Arrowhead Pharmaceuticals, Inc. C. Christy: None. H. Hamilton: None. T. Pei: Employee; Arrowhead Pharmaceuticals, Inc. Stock/Shareholder; Ionis Pharmaceuticals. J. Hamilton: None. Z. Ding: None.
1632-P: Wild-Derived Chromosome 1 Substitution Strains—Unveiling Novel Insights into NASH Research
Authors: YANG XUSHAN , ZHENG JIE , HOU YUMENG , WU XINYI , LI ZHIYING , QI HAO 
Published: June 2024

Metabolic diseases, encompassing obesity, NASH, and diabetes, result from a complex interplay of factors, including genetics, lifestyle, and environment. However, conventional mouse models induced by diet or with single genetic alterations often fall short in accurately representing human metabolic diseases. In contrast to laboratory mice, wild mice exhibit a greater diversity of genetic polymorphisms, adapting to their natural environments. To enhance model fidelity, we created 11 wild-derived Chr1 substitution strains by replacing C57BL/6 mice's Chr1 with that from wild mice across 11 Chinese regions. Through phenotype screening, we identified 4 strains displaying spontaneously obesity and hepatic steatosis under chow diet. Notably, one strain named B6-Chr1KM mice displayed obvious obesity-related NASH phenotype (the total score of NAS was over 5).Transcriptomics analysis of the B6-Chr1KM liver tissue revealed unique gene expression patterns. KEGG analysis highlighted NASH-related pathways, including "Arachidonic acid metabolism." 398 genes specific to B6-Chr1KM were identified, with PPI analysis pinpointing top 10 hub genes as potential NASH research targets. In summary, our wild-derived Chr1 substitution strains provide valuable tools for metabolic disease study. B6-Chr1KM mice, in particular, offer a novel perspective for NASH research.

Disclosure
X. Yang: None. J. Zheng: None. Y. Hou: None. X. Wu: None. Z. Li: None. H. Qi: None.
1636-P: Targeting a Long Noncoding RNA lncMGC Ameliorates Obesity-Associated Adipose Tissue Dysfunction in Mice
Authors: ABDOLLAHI MARYAM , KATO MITSUO , LANTING LINDA L. , MALEK VAJIR , ZHANG LINGXIAO , NATARAJAN RAMA 
Published: June 2024

The long noncoding RNA (lncRNA) lncMGC, plays a pathological role in the diabetic kidney. However, its role in obesity, insulin resistance (IR), and type 2 diabetes is not known. Here we examined whether targeting lncMGC with a locked nucleic acid-modified LNA-GapmeR antisense oligonucleotide ameliorates weight gain, adipose dysfunction, and IR in high-fat diet (HFD) fed mice. Mechanistically, we also examined whether lncMGC promotes adipose tissue dysfunction via up/down-regulation of targets/genes involved in perigonadal white adipose tissue (gWAT) and brown adipose tissue (BAT) function and mitochondrial health. We tested lncMGC-GapmeR in HFD-fed wild-type (WT) and partially humanized lncMGC (hlncMGC) mice to assess the translational potential of targeting human lncMGC for obesity/IR. Male and female C57BL/6 WT and female hlncMGC mice were fed chow diet (Con) or HFD and injected with GapmeR-negative control (HFD-NC), or GapmeR targeting lncMGC (HFD-Gap) at 5 mg/kg/week/8 weeks. Body composition was assessed with Echo-MRI, and plasma insulin levels by ELISA. Using qPCR, we measured angiogenesis and adipogenesis markers in gWAT and mitochondrial function-related genes in BAT. Sections from gWAT and BAT were stained for histopathology. We found WT HFD-Gap and hlncMGC HFD-Gap mice exhibited significantly lower body weight, total body fat, and insulin levels compared to HFD-NC. HFD-induced adipocyte hypertrophy, gWAT inflammation markers (Tnfα, F4/80), impaired angiogenesis (Cd31, Vegfb), and adipogenesis (Pparg, cebpb) related-genes were attenuated in HFD-Gap mice versus HFD-NC. Furthermore, lncMGC GapmeR significantly reversed HFD-induced BAT whitening and impaired mitochondrial markers (Fis1, Ppargc1α, Tfam, Dio2) versus HFD-NC. These results show GapmeR targeting lncMGC alleviates HFD-induced obesity and adipose dysfunction via changes in key gWAT and BAT markers, highlighting its therapeutic potential for obesity and its complications.

Disclosure
M. Abdollahi: None. M. Kato: None. L.L. Lanting: None. V. Malek: None. L. Zhang: None. R. Natarajan: None.
1657-P: Neonatal Adiposity Distribution in Birth Weight Categories at Term
Authors: AZIMIRAD AFSHIN , LEKSHMI DEVIKA , SPADOLA ALEXANDRA C. , CATALANO PATRICK 
Published: June 2024

Introduction & Objective: Neonatal body composition may predict metabolic health over the lifespan better than birth weight (BW) alone. While lean body mass (LBM) correlates highly with BW, variation in neonatal adiposity is greater. To determine whether the conventional assignment of small, appropriate, and large for gestational age (SGA/AGA/LGA) at birth adequately characterizes neonatal adiposity.
Methods: Data were from a secondary analysis of a study of maternal metabolic differences in a cohort of term deliveries at a single academic center. Neonatal measurements and body composition analyses were performed within 72 hours using air-displacement plethysmograph (PEA POD). Anomalous newborns were excluded. Primary outcomes included body fat percentage (BF), fat mass (FM) and LBM. BW percentiles were determined using Fenton growth calculator and newborns were categorized into SGA (&lt;10%), AGA (10-90%) and LGA (&gt;90%).
Results: A total of 332 neonates were analyzed. The maternal cohort was 48% NHW, 39% NHB, 12% H, and 1% AAPI. Maternal characteristics were similar across BW categories except for smoking status. There were significant overlaps in measurements of adiposity between SGA and AGA, and between LGA and AGA.
Conclusion: In this diverse cohort BW category did not reliably distinguish underlying differences in neonatal adiposity. Body composition offers a novel tool to identify newborns at risk for adverse health outcomes.

Disclosure
A. Azimirad: None. D. Lekshmi: None. A.C. Spadola: None. P. Catalano: None.
1675-P: Patient Experiences with Tirzepatide in SURMOUNT-4
Authors: JOURAVSKAYA IRINA , KANU CHISOM , LING POON JIAT , MOJDAMI DONNA , COLLINS ELIZABETH , BURNS DANIELLE S. , KITCHEN HELEN , CARMICHAEL CHLOE 
Published: June 2024

Introduction & Objective: Exit interviews were conducted with participants of the SURMOUNT-4 clinical trial to understand their experiences of weight loss and maintenance of weight loss with tirzepatide.
Methods: SURMOUNT-4 was a phase 3 clinical trial of tirzepatide in adults living with obesity or overweight with at least one weight-related comorbidity. Participants received 36 weeks of maximum tolerated dose of tirzepatide in an open-label, lead-in treatment period, following which they were randomized to continue on tirzepatide or switch to placebo for a double-blind maintenance treatment period of 52 weeks. After completion of a 4-week safety follow-up period, cross-sectional qualitative exit interviews were conducted with 86 US-based participants.
Results: On average, exit interview participants lost 25kg during the open-label period. Most (n=84) described at least one physiological improvement during this period, such as increased energy (n=53). Participants (n=73) also reported positive impacts on their physical functioning including improved walking ability (n=36) and increased activity levels (n=30). Other improvements during this period pertained to emotional well-being (n=78), social life and relationships (n=64), activities of daily living (n=40), ability to work (n=15), and participation in hobbies (n=7). Participants were generally positive about the efficacy of tirzepatide (n=59) and how it reduced their appetite (n=35) and/or cravings (n=19). The most common aspect of treatment disliked by participants was gastrointestinal side effects (n=34). During the maintenance period, all participants on tirzepatide reported one or more additional improvements, or sustenance of the improvements achieved pre-randomization. In contrast, nearly all participants on placebo reported some loss of improvements experienced pre-randomization.
Conclusion: Participants were largely positive about tirzepatide’s effect on weight loss and the subsequent positive impacts on their broader well-being.

Disclosure
I. Jouravskaya: Employee; Eli Lilly and Company. C. Kanu: None. J. Poon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. D. Mojdami: Employee; Eli Lilly and Company. E. Collins: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate. D.S. Burns: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate. H. Kitchen: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate. C. Carmichael: Employee; Clarivate. Stock/Shareholder; Clarivate. Other Relationship; Clarivate.
1676-P: Tirzepatide Improved Mental and Psychosocial Function in Adults with Obesity or Overweight in the SURMOUNT-3 Trial
Authors: HUNTER GIBBLE THERESA , CAO DACHUANG , FORRESTER TAMMY D. , FRASEUR BRUMM JULIA , CHAO ARIANA 
Published: June 2024

Introduction & Objective: Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US for treatment of type 2 diabetes and obesity. Tirzepatide showed substantial additional weight reduction vs placebo (PBO) after intensive lifestyle intervention in the phase 3 SURMOUNT-3 (NCT04657016) trial. Here we report the effect of tirzepatide vs PBO on general (Short Form-36 Health Survey Version 2 acute form; SF-36v2) and weight-related (Impact of Weight on Quality of Life-Lite Clinical Trials Version; IWQOL-Lite-CT) mental health outcomes.
Methods: This double-blind, PBO-controlled trial randomized (1:1) adults (N=579) with body mass index ≥30 or ≥27 kg/m2 and ≥1 obesity-related complication (excluding diabetes), who had ≥5% weight reduction after a 12-week (W) intensive lifestyle intervention to receive tirzepatide maximum tolerated dose (MTD; 10 or 15 mg) or PBO once weekly up to W72. Exploratory endpoints assessed were changes from randomization to W72 in SF-36v2 (norm-based) Mental Component Summary (MCS) and its domain scores and IWQOL-Lite-CT Psychosocial composite score using analysis of covariance with the last observation before discontinuation carried forward. Higher scores indicate better health.
Results: At W72, improvement in SF-36v2 MCS score was comparable between tirzepatide MTD and PBO (Least squares mean [LSM] difference [diff] vs PBO: 0.9; p=0.182). Tirzepatide MTD significantly improved SF-36v2 Vitality (LSM diff vs PBO: 2.4), Social Functioning (1.6), Role-Emotional (1.9), and Mental Health (1.5) domain scores (all p&lt;0.05); and IWQOL-Lite-CT Psychosocial composite score (16.0; p&lt;0.001).
Conclusion: In the SURMOUNT-3 trial, adults with obesity or overweight treated with tirzepatide experienced significant improvement in multiple domains of general mental health and weight-related psychosocial function vs PBO after intensive lifestyle intervention.

Disclosure
T. Gibble: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. T.D. Forrester: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Brumm: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. A. Chao: Consultant; Eli Lilly and Company. Other Relationship; Eli Lilly and Company. Consultant; Boehringer-Ingelheim. Other Relationship; Weight Watchers International.

Funding
This study was funded by Eli Lilly and Company.
1677-P: AdOral—A Versatile Platform for Improved Oral Peptide Absorption
Authors: NAESSENS ULYSSE , GUTJAHR ALICE , BLACHE GRÉGORY , HAKIM SANA , MARECHAL AUDREY , NOEL ROMAIN , GAUDIER MARTIN , SOULA OLIVIER 
Published: June 2024

Oral delivery of therapeutic peptides reduces patient burden and increases adherence. Nevertheless, existing technologies have limited performance and versatility. AdOral® is an oral delivery platform based on non-specific MoA (Mechanism of Action) via intestine paracellular passage leading to improved absorption.The MoA of AdOral® and its permeation effect on several peptides were evaluated in vitro, using gold-standard Caco-2 monolayers. Then, AdOral® platform was evaluated in vivo, in rat and dog. In vitro, apparent permeability coefficient of insulin lispro and semaglutide were improved by 16 and 25 vs. control, mostly due to the concentration-dependent and reversible tight junctions opening, leading to paracellular passage of peptides. AdOral® has a distinct MoA and higher permeation enhancing properties compared to SNAC (effective concentration of 10 mM vs. 100 mM for SNAC). In rats, AdOral® had a good safety profile after daily oral administration for 2 weeks.In dogs, AdOral® capsules allowed oral absorption of semaglutide and insulin lispro, demonstrating the versatility of the platform. AdOral® semaglutide showed 2.5-fold improvement in median semaglutide AUC0-5h and bioavailability vs. Rybelsus®. Thus, AdOral® is a versatile and performant platform that could lead to cost-effective oral formulations for a wide range of therapeutic peptides.

Disclosure
U. Naessens: Employee; ADOCIA. Stock/Shareholder; ADOCIA. A. Gutjahr: Employee; ADOCIA. Stock/Shareholder; ADOCIA. G. Blache: Other Relationship; ADOCIA. S. Hakim: Employee; ADOCIA. Stock/Shareholder; ADOCIA. A. Marechal: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Noel: Employee; ADOCIA. Stock/Shareholder; ADOCIA. M. Gaudier: Employee; ADOCIA. Stock/Shareholder; ADOCIA. O. Soula: Board Member; ADOCIA. Stock/Shareholder; ADOCIA.
1682-P: Weight Endpoints in Randomized Controlled Trials (Rcts) of Adults Eligible for Antiobesity Medications (AOM)—A Systematic Literature Review (SLR)
Authors: BJORNSON ALISON , GARDNER MEGAN M. , DONATO BONNIE M.K. , SZABO SHELAGH M. , KORPACH SARAH G.C. , KUTI EFFIE 
Published: June 2024

Introduction & Objective: Obesity affects 40% of American adults; 75% of whom have multiple obesity related comorbidities (ORC). Here we synthesize data on body weight (BW) and waist circumference (WC) from trials of adults eligible for AOM (BMI ≥30kg/m2 or ≥27kg/m2 with ≥1 ORC).
Methods: An PRISMA-guided SLR was performed to identify published manuscripts (2018-23) and conference abstracts (2021-23) of RCTs in adults eligible for AOM. Mean (95% confidence interval [CI ]) treatment differences were reported for continuous variables and odds ratios (OR; 95%CI) for categorical variables. Change in % BW and WC (cm) was summarized at ≤12 weeks, ≤26 weeks, and ≥27 weeks. ORs for achieving ≥15% BW loss were also summarized.
Results: From 1935 records, 39 eligible studies reported on BW and 20 on WC. Relative to placebo, % BW loss ranged from -1.1 (-1.2, 1.0; dapagliflozin [DAPA] 10 mg) to -4.4 (-4.5, -4.3; exenatide 10 μg) ≤12 weeks; -1.5 (-1.6, -1.4) (DAPA 10 mg) to -8.9 (-10.0, -7.8; semaglutide [SGL] 2.4 mg) ≤weeks; and -0.5 (-0.6, -0.4; DAPA 10 mg) by 156 weeks to -17.8 (-19.3, -16.3; tirzepatide [TZ] 15 mg) by 72 weeks. Compared to placebo, OR (95% CI) for achieving ≥15% BW loss ranged from 2.2 (0.9, 5.5; liraglutide [LIR] 3.0 mg) to 24.7 (17.9, 34.1; TZ 15 mg). Relative to placebo, change in WC ranged from -0.2 (-1.1, 0.7; DAPA 10 mg) to -3.1 (-4.2, -2.0; SGL 2.4 mg) ≤12 weeks, -1.7 (-2.7, -0.7; DAPA 10 mg) to -4.4 (-5.4, -3.4; SGL 2.4 mg) ≤26 weeks, and -2.7 (-3.5, -1.9); LIR 3.0 mg) by 56 weeks to -14.5 (-15.9, -13.0; TZ 15 mg) by 72 weeks. Two studies compared interventions head-to-head.
Conclusions: Emerging pharmacotherapies are showing longer term and greater weight loss. While data on WC was less frequently reported, it can provide important insights on the risk of developing ORC. Between-study heterogeneity in design and populations was high; and future studies to explore the importance of these factors will help better inform quantitative evidence syntheses.

Disclosure
A. Bjornson: None. M.M. Gardner: None. B.M.K. Donato: Employee; Boehringer-Ingelheim. S.M. Szabo: None. S.G.C. Korpach: None. E. Kuti: Employee; Boehringer-Ingelheim.

Funding
Boehringer Ingelheim Pharmaceuticals, Inc.
1691-P: Clinical Outcomes in Patients with Obesity or Overweight Treated with Semaglutide 2.4 mg—A Real-World Retrospective Cohort Study in the United States (SCOPE 2)
Authors: MICHALAK WOJCIECH , FABRICATORE ANTHONY , O HARTAIGH BRIAIN , RUSEVA ALEKSANDRINA , ZHAO ZHENXIANG , UMASHANKER DEVIKA 
Published: June 2024

Introduction & Objective: This study assessed changes in clinical outcomes among patients with obesity or overweight treated with semaglutide 2.4mg versus no anti-obesity medications (AOM) in the US.
Methods: This retrospective database cohort study used the electronic health records linked to administrative claims from Komodo Health and included patients (≥18 years) with obesity, or overweight with ≥1 obesity-related comorbidity, who started therapy with semaglutide 2.4mg after June 15, 2021 and remained adherent for 12 months or those not treated with any AOM in the same period. Propensity score matching (1:4) was used to address treatment selection bias. Changes in weight from baseline to the end of 12 months follow-up, and proportions of patients achieving ≥5%, ≥10%, and ≥15% weight reduction were compared between the matched cohorts using generalized linear models.
Results: Matched cohorts (143 semaglutide 2.4mg patients and 571 no AOM patients) were balanced in baseline characteristics with mean (SD) BMI 39.8 (7.35) kg/m2, mean (SD) age 46 (10.9) years, and 77% were female. At 1-year post-index, semaglutide 2.4mg patients had a significantly greater reduction in weight (−15.0% vs. −1.3%, P&lt;0.001) and a greater proportion of patients achieved a weight reduction ≥5% (83.9% vs 20.1%), ≥10% (74.8% vs. 7.4%), and ≥15% (49.7% vs. 3.7%) (P&lt;0.001 for all three comparisons).
Conclusion: In this real-world study, patients with obesity or overweight treated with semaglutide 2.4mg demonstrated a greater, sustained, and clinically relevant reduction in body weight versus those not treated with an AOM. These changes are consistent with those observed in clinical trials.

Disclosure
W. Michalak: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk, Eli Lilly and Company. A. Fabricatore: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. B. O Hartaigh: Employee; Novo Nordisk A/S. A. Ruseva: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Z. Zhao: None. D. Umashanker: Consultant; Novo Nordisk.

Funding
Novo Nordisk Inc.
1697-P: Further Real-World Outcomes Using Medication and Intensive Lifestyle Intervention to Treat Obesity and Improve Diabetes at Scale
Authors: BOYD KIM , MEDEIROS KAELEN L. , KENYON ISABELLE , RYAN DONNA H. 
Published: June 2024

Introduction: More than 2/3 adults in the US have overweight or obesity. Increasing obesity rates profoundly impact diabetes and cardiometabolic disease. We established a digital metabolic health company to provide medically-supervised obesity treatment at scale.
Methods: The program used the combination of GLP-1 medication, medical supervision, and a proprietary lifestyle intervention. Patients who reached at least 12 months (mo) in the core program and a smaller subset who reached 24 mo were analyzed for weight change, metabolic labs (baseline and 12mo) and patient-completed questionnaires (baseline, 6, and 12mo) using data where available in this real-world setting.
Results: The cohort who reached at least 12mo included 6,167 patients. For members with HbA1c at both baseline and 12mo (n=2,568), there were 3.4% and 23.7% who met baseline A1c criteria for diabetes and prediabetes. Average weight loss at 12 and 24 months was 16.39% (n=5,341) and 16.02% (n=169). Average weight loss for patients with diabetes or prediabetes at 12, 15 and 18 mo was 15.6% (n=1,375), 16.6% (n=782), and 16.7% (n=385). Patients with diabetes and prediabetes saw average improvements for HbA1c of -1.5 and -0.47 percentage points, respectively. 78.2% of patients with HbA1c levels &gt;5.7% at baseline were &lt;5.7% at 12 months. Across the cohort, fasting plasma insulin levels decreased in 71.3% (n=1,978). Positive changes were also seen for other metabolic markers and patient-reported outcomes.
Conclusion: Patients in a digital metabolic health program achieved robust and sustained weight loss through 24 months. For those with diabetes or prediabetes, 84.2% achieved categorical improvement to diabetes status. Significant weight loss, reduction in HbA1c and insulin, improvements to other metabolic markers, and positive changes to health behaviors were also seen. These results offer promise in addressing the obesity epidemic and reversing its adverse impact on diabetes.

Disclosure
K. Boyd: Consultant; Calibrate. Employee; Caire, WndrHLTH. K.L. Medeiros: None. I. Kenyon: Employee; Calibrate Health Inc. D.H. Ryan: Advisory Panel; Altimmune Inc., Amgen Inc., Biohaven, Calibrate, Carmot Therapeutics, Inc., CinRx. Other Relationship; Epitomee. Advisory Panel; Gila Therapeutics. Other Relationship; Eli Lilly and Company, Novo Nordisk, Scientific Intake. Advisory Panel; Structure Therapeutics, Inc., Wondr Health. Other Relationship; Xeno. Advisory Panel; Zealand Pharma A/S.