bluuebunny/crossref_metadata_2025 huggingface dataset:
729-P: Metabolic Surgery for the Treatment of Type 2 Diabetes Mellitus in China—Five-Year Outcomes from a Prospective Multicenter Study
Authors: BAO YUQIAN , LIANG HUI , ZHANG PIN , WANG CUNCHUAN , JIANG TAO , ZHANG NENGWEI , ZHU JIANGFAN , YU HAOYONG , HAN JUNFENG , TU YINFANG , LIN SHIBO , ZHANG HONGWEI , YANG WAH , YANG JINGGE , CHEN SHU , FAN QING , MA YINGZHANG , MA CHIYE , WAGGONER JASON , TOKARSKI ALLISON , EDWARDS NATALIE , YANG TENGFEI , ZHANG RONGRONG , JIA WEIPING
Published: June 2023

The prevalence of type 2 diabetes (T2D) among adults in China is 10.9%-13.2%. Multicenter, long-term, prospective studies evaluating bariatric/metabolic surgery in obese patients with T2D in China are limited. This prospective study evaluated the 5-year impact of laparoscopic Roux-en-Y gastric bypass (RYGB; n=76 subjects, mean [SD] age 36.4 [9.5], 52.6% women, mean [SD] BMI 34.6 [4.9] kg/m2, mean [SD] glycosylated hemoglobin A1c [HbA1c] 8.3% [1.7%], mean [SD] duration diabetes 3.7 [2.7]) and sleeve gastrectomy (SG; n=25 subjects, mean [SD] age 41.1 [10.8], 44.0% women, mean [SD] BMI 36.4 [6.0] kg/m2, mean [SD] HbA1c 7.5% [1.5%], mean [SD] duration diabetes 2.4 [2.4]) on T2D at six centers in China from August 2014-April 2021. According to the composite measure of glycemic control for metabolic surgeries as suggested by the American Society for Metabolic and Bariatric Surgery, among 62 subjects evaluable at five years (50 RYGB, 12 SG), complete remission occurred in 28.6% (27.5% RYGB, 33.3% SG), partial remission in 27.0% (29.4% RYGB, 16.7% SG), improvement in 30.2% (29.4% RYBG, 33.3% SG), no change in 9.5% (7.8% RYBG, 16.7% SG), and recurrence in 4.8% (5.9% RYGB). Significant 5-year reductions in HbA1c (RYGB -1.7±2.1%, SG -1.8±1.1%), body weight (RYGB -19.8±8.4 kg, SG -21.2±6.0 kg), and BMI (RYGB -7.1±3.1 kg/m2, SG -7.7±2.1 kg/m2) were observed (all p<0.001). Five-year improvements in triglycerides and high-density lipoprotein cholesterol were also observed. Procedure-related serious adverse events occurred in 8 RYGB subjects (7.9%). To our knowledge, this is the first prospective, multicenter, 5-year study of bariatric/metabolic surgery in subjects with T2D in China. These data demonstrate that RYGB and SG achieved clinically meaningful, sustained impacts on T2D remission in many subjects for up to five years. Bariatric/metabolic surgery has enormous potential to provide a safe and effective option for appropriately selected subjects with T2D in China.

Disclosure

Y.Bao: None. Y.Tu: None. S.Lin: None. H.Zhang: None. W.Yang: None. J.Yang: None. S.Chen: None. Q.Fan: None. Y.Ma: None. C.Ma: None. J.Waggoner: Employee; Ethicon, Inc., Janssen Research & Development, LLC, Stock/Shareholder; Johnson & Johnson. H.Liang: None. A.Tokarski: Employee; Ethicon, Inc. N.Edwards: Consultant; Boston Scientific Corporation, EMD Serono, Inc., Ethicon, Inc., Johnson & Johnson, Becton, Dickinson and Company. T.Yang: None. R.Zhang: None. W.Jia: None. P.Zhang: None. C.Wang: None. T.Jiang: None. N.Zhang: None. J.Zhu: None. H.Yu: None. J.Han: None.

Funding

Ethicon, Inc.; Johnson & Johnson
730-P: Effects of Obstructive Sleep Apnea Treatment on Whole-Body and Adipose Tissue Insulin Sensitivity—Role of Senescence and Mitigation by Adjuvant Metformin Therapy
Authors: RODRIGUES SARA , DANTAS WAGNER S. , BEYL ROBBIE A. , HEBERT REBEKAH C. , GRIFFITH ISABELLA , TANKSLEY MAKAYLA , MADER EDWARD C. , KIRWAN JOHN P. , AXELROD CHRISTOPHER L. , RAVUSSIN ERIC , SINGH PRACHI
Published: June 2023

Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder linked to high type 2 diabetes risk. Positive airway pressure (PAP) therapy is the standard of care for OSA, but it inconsistently improves glucose homeostasis. Senescent cells are common in adipose tissue (AT) of patients with OSA and may impair insulin signaling. However, the effects of PAP therapy on AT senescence are not known. Addition of metformin, an insulin-sensitizer with anti-senescent effects, may be a good adjuvant therapeutic strategy to improve glycemic control in patients with OSA.

Methods: We randomly assigned 16 nondiabetic participants with OSA (Mean± SD; age: 50.9 ± 6.7 y, BMI: 36.5 ± 2.9 kg/m2) in a 1:1 ratio to receive either 2g metformin or placebo daily along with PAP therapy for 3 months in a double-blind pilot study. Whole body and AT insulin sensitivity was determined by 2h oral glucose tolerance test (OGTT). AT biopsy was obtained to estimate tissue insulin signaling and senescence.

Results: The metformin and placebo groups had comparable age, BMI and OSA severity at baseline. PAP compliance was 38% and 75% in the metformin and placebo groups, respectively. Matsuda Index, glucose area under the curve (2h AUC), and free-fatty acid suppression at baseline and follow-up were not different in metformin or placebo treated groups. Compared to baseline, insulin AUC and insulin to glucose AUC ratio during OGTT was unchanged in the metformin but increased in the placebo group. Metformin, but not placebo, was associated with increased insulin mediated AKT phosphorylation and decreased senescence biomarkers (p21 and MCP1) in AT during the follow-up visit.

Conclusion: Metformin, as adjunct to PAP therapy, attenuated insulin rises during OGTT, improved AT insulin signaling, and lowered senescence biomarkers in OSA patients. Larger trials of longer treatment duration are needed to determine if metformin can prevent diabetes in OSA patients.

Disclosure

S. Rodrigues: None. W.S. Dantas: None. R.A. Beyl: None. R.C. Hebert: None. I. Griffith: None. M. Tanksley: None. E.C. Mader: None. J.P. Kirwan: None. C.L. Axelrod: None. E. Ravussin: Research Support; Eli Lilly and Company, Novartis AG. Advisory Panel; Novartis. P. Singh: None.

Funding

National Institutes of Health (P30DK072476, U54GM104940); CAPES (88887.470405/2019-00 to S.R.)
734-P: High Pancreatic-Derived Factor Level Is Relative to a Lower Remission of Early Postpartum Impaired Glucose Tolerance in Women with History of Gestational Diabetes Mellitus
Authors: PEI LING , LAI FENGHUA , CHEN WENZHAN , CHEN NAN , ZENG RUI , YUE SHUFAN , LI ZETING , WANG CHENXUE , CAO XIAOPEI
Published: June 2023

Purpose: To clarify whether pancreatic derived factor (PANDER) predicted the remission of early postpartum impaired glucose tolerance (IGT) by lifestyle intervention among women with history of gestational diabetes mellitus (GDM).

Methods: IGT women with GDM history in a prospective cohort study were enrolled at postpartum 4-12 weeks. Subjects were grouped based on quarters of PANDER level at recruitment. After lifestyle intervention, the oral glucose tolerance test (OGTT) was performed and insulin levels were measured at one year postpartum. The relation between PANDER and glycemic outcome was analyzed with logistic regression and receiver operating characteristic curve (ROC).

Results: A total of 113 women were included. 55 (48.7%) of these IGT women were reversed to normal glucose tolerance at one year postpartum by lifestyle intervention. The odds of remission were lower in participants with high PANDER level than in those with low PANDER level. Compared those with PANDER<3.19ng/mL, women with PANDER>5.34 ng/mL, and PANDER>8.77ng/mL, were associated with a lower effect on remission of IGT (OR=0.31, 95%CI 0.11-0.90, P=0.031 and OR=0.12, 95%CI 0.04-0.41, P=0.001, respectively). After adjusting for other confounders, these associations remained in multivariable logistic regression. The area under the receiver operating characteristic curve (AUC) of PANDER for the remission of IGT was 0.702 (95% CI 0.595-0.809). When PANDER was combined with clinical information, the AUC reached 0.812 (95% CI 0.725-0.899) (P<0.001).

Conclusions: High PANDER level in early postpartum was closely associated with the remission of IGT by lifestyle intervention in women with GDM history at one year postpartum.

Disclosure

L.Pei: None. F.Lai: None. W.Chen: None. N.Chen: None. R.Zeng: None. S.Yue: None. Z.Li: None. C.Wang: None. X.Cao: None.

Funding

Sun Yat-sen University (2017001); Science and Technology Foundation of Guangzhou City (201803010101)
735-P: Baseline Characteristics in the REVERSE-IT Study, a 24-Week, 600-Person Randomized Placebo-Controlled Study of the Metabolic Effects of the Combination of Five Plant Extracts TOTUM-63 (T63)
Authors: OTERO YOLANDA F. , SIRVENT PASCAL , ERIK JOHANSEN ODD , CHAVANELLE VIVIEN , BARGETTO MAXIME , SAPONE VERONIQUE , BOUCHARD-MERCIER ANNIE , LE JOUBIOUX FLORIAN , BOISSEAU NATHALIE , MAUGARD THIERRY , CAZAUBIEL MURIELLE , PEREIRA BRUNO , GUIGAS BRUNO , HADJADJ SAMY , PELTIER SEBASTIEN , MARETTE ANDRE , BARD JEAN-MARIE
Published: June 2023

The role of natural based products to support glucose control in people with prediabetes or early type 2 diabetes (T2D) (i.e. dysglycemia) is debated. T63 is a polyphenol-rich substance composed by artichoke, chrysanthellum, olive leaf, bilberry, and black pepper extracts, and studied in REVERSE-IT (NCT04423302), an ongoing 24 weeks, multi-center, multi-country clinical trial involving people with dysglycemia. It tests the hypothesis that 5 g T63 vs placebo (PBO) leads to significant reduction in fasting plasma glucose, while secondary outcomes include effects on lipids, blood pressure (BP), weight and waist circumference. The confirmatory primary analysis will compare T63 vs PBO when provided TID (double-blinded) and is powered based on minimum 174 completers in each arm. Effects of T63 BID vs PBO will be analyzed open label. A total of n=627 were recruited over 2 years from 61 sites across 7 European countries. Mean age is 57 years, BMI 32.2 kg/m2, and HbA1c 6.1% (table 1). The majority have prediabetes (78.3%), with a better glycemic profile and BP compared to those with T2D (21.7%). REVERSE-IT has enrolled an appropriate population to help inform clinical decision making on the use of plant-extract based T63 to support glucose homeostasis in people with dysglycemia. Readout is expected in the second half of 2023.

Disclosure

Y.F.Otero: Employee; Valbiotis. T.Maugard: None. M.Cazaubiel: Board Member; Valbiotis. B.Pereira: None. B.Guigas: Advisory Panel; Valbiotis, Research Support; Valbiotis. S.Hadjadj: Consultant; Bayer Inc., Novo Nordisk, Valbiotis, Research Support; AstraZeneca, Novartis, Speaker's Bureau; Abbott Diagnostics, Boehringer-Ingelheim. S.Peltier: Board Member; Valbiotis. A.Marette: Advisory Panel; Valbiotis, Amancia, Plexus, Acasti. J.Bard: Consultant; Valbiotis, Biofortis France, Stock/Shareholder; Valbiotis. P.Sirvent: Board Member; Valbiotis. O.Johansen: Employee; Nestlé Health Science. V.Chavanelle: Employee; Valbiotis. M.Bargetto: Employee; Valbiotis. V.Sapone: None. A.Bouchard-mercier: Employee; Valbiotis. F.Le joubioux: Employee; Valbiotis. N.Boisseau: None.
736-P: Projecting the Number of Type 2 Diabetes Cases and Their Complications Prevented under Different Primary Prevention Strategies
Authors: SHAO YIXUE , SHAO HUI , IMPERATORE GIUSEPPINA , HOLLIDAY CHRISTOPHER S. , ZHANG PING
Published: June 2023

Preventing type 2 diabetes (T2D) involves reducing T2D risk factors at the population level (PL) and lowering the risk of developing T2D in groups at higher risk (GHR). We used the 2013-2018 National Health and Nutrition Examination Survey data to generate a nationally representative population of adults without diabetes. Using the CDC-RTI T2D Cost-Effectiveness simulation model, we estimated the number of T2D cases and their complications prevented by two hypothetical combined PL and high-risk strategies compared with no intervention over 10 years: a moderate strategy (MS) consisting of an annual T2D risk reduction (RR) of 4% at the PL and a RR of 35%, 17.5%, and 10.5% in years 1, 2, and 3 in GHR using a moderate lifestyle intervention program (LIP); an intensive strategy (IS) consisting of an annual RR of 6% at the PL and a RR of 40%, 20%, and 12% over 3 years in GHR using an intensive LIP. We assumed a 50% LIP participation rate. We also assessed % of T2D prevented by the PL strategy alone under MS or IS. The MS and IS would prevent 667,317 and 926,265 T2D cases over 10 years. Of the total cases prevented, 68.3% and 73.9% were due to PL strategy with MS and IS. The prevented complication cases increased with the number of prevented T2D cases. Curbing the national T2D epidemic, implementing both the cost-effective LIP in GHR and PL strategies is needed.

Disclosure

Y.Shao: Employee; Biogen. H.Shao: Consultant; Lilly Diabetes. G.Imperatore: None. C.S.Holliday: None. P.Zhang: None.
737-P: A Wearable Device (CGM and Activity Tracker) RCT for Postpartum Women with a History of Gestational Diabetes—Preliminary Findings on Anthropometry Measures and Self-Reported Lifestyle Behaviours
Authors: LING ELAINE QUAH PHAIK , SYAZA RAZALI NURUL , CHAI SALLY M.H. , FADZULLY FADZLYNN , RYAN LEE W.K. , WAI KU CHEE , LING LOY SEE , HIAN TAN KOK
Published: June 2023

Background: Women with a history of gestational diabetes mellitus (GDM) have a 7-fold increased risk for subsequent development of type 2 diabetes mellitus (T2DM). Continuous glucose monitoring systems (CGMS) and exercise trackers have not been thoroughly explored in any Asian postpartum diabetes prevention studies. Objective: The Integrated Hyperglycaemia Incentivised Postnatal Surveillance (I-HIPS) study aims to investigate the efficacy of a personalized lifestyle intervention programme using wearables along with physical activity (PA) and diet modification to achieve healthy weight loss in postpartum women with history of GDM.

Methods: Women were randomized to receive the intervention or standard medical care. The intervention group received a CGM sensor and exercise tracker, along with nutrition, exercise and personalized goal-setting workshops. Anthropometric measures (weight, BMI and waist circumference (WC)) and PA assessed using the International Physical Activity Questionnaire were examined between the two arms at the 6-month follow-up. Changes in dietary behaviors in the intervention group were assessed using a validated 6P tool.

Results: Twenty-six recruited women had completed the 6-month follow-up. At 6-month, compared with the controls, women receiving intervention achieved a mean difference in the reduction of weight by 0.5 kg, BMI by 0.2 kg/m2 and WC by 0.8cm (p>0.05). The intervention group had increased PA (mean difference: +990 MET mins/week), compared to the controls (mean difference: +298 MET mins/week) (p>0.05) at 6-month. Between baseline and 6-month, women in the intervention group showed a reduction in the frequency of snack and beverage intakes (p=0.01).

Conclusion: Preliminary findings suggest a trend toward better health outcomes in the intervention group with improved dietary behaviour.

Disclosure

P.Quah: None. N.Razali: None. S.M.H.Chai: None. F.Fadzully: None. L.W.K.Ryan: None. C.Ku: None. S.Loy: None. K.Tan: None.

Funding

National Medical Research Council of Singapore (MOH-000504-03)
740-P: Six Subclasses with Glucose and Insulin Curves during OGTTs Capture Distinct Metabolic Characteristics and the Most Common Pathway to T2D in a Cohort of Koreans
Authors: KIM JINMI , YI WOOK , KIM DOOHWA , IM MYUNGSOO , RYANG SOREE , KIM MINSOO , JIN KIM YEONG , JOO KIM IN , JIN KIM YOUNG , KANG HYUK , CHUNG STEPHANIE T. , SHERMAN ARTHUR , SOO KIM SANG , HA JOON
Published: June 2023

Heterogeneity of glucose abnormalities makes prevention and treatment of diabetes challenging. Subclasses of people at high risk have been identified based on glucose profiles during OGTTs. However, previous work on subclasses lacks longitudinal confirmation. Here, we used glucose and insulin during OGTTs and k-means clustering to classify subclasses of people without diabetes and then determined the model-derived beta-cell function (BCF) and insulin sensitivity (IS) within each subclass. We identified metabolic risk and the most common pathway to T2D by tracking transitions of subclasses over the 16-year Korean Genome Epi. Study. Participants underwent OGTTs every 2 years for up to 16 years or until diabetes (N=2682, BMI=24.4±2.9 kg/m2, age 49.8±7.6 y). 1) 6 subclasses: Cluster A: Normal BCF, Normal IS, B: Mildly impaired BCF and IS, C: Impaired BCF, mildly impaired IS, D: Strong BCF, impaired IS, E: Mildly impaired BCF, impaired IS, F: Strong BCF, severely impaired IS; 2) Cluster C had the highest risk for T2D, HR: 10.7 (8.0, 14.1), compared to cluster A, followed by Clusters E, B, F, and D; Transition from A to B and C was the most common pathway; A, B, and C together comprised 86% of the cohort. Clustering using glucose and insulin classified 6 subgroups showing distinct metabolic parameters and identified the most common pathway to T2D in Koreans.

Disclosure

J.Kim: None. H.Kang: None. S.T.Chung: None. A.Sherman: None. S.Kim: None. J.Ha: None. W.Yi: None. D.Kim: None. M.Im: None. S.Ryang: None. M.Kim: None. Y.Kim: None. I.Kim: None. Y.Kim: None.

Funding

Busan Economic Promotion Agency; National Research Foundation of Korea (2022H1D3A2A01063552); Korea Health Industry Development Institute (HI18C2383); dkNET New Investigator Pilot Program in Bioinformatics; National Institute of Diabetes and Digestive and Kidney Diseases
744-P: Reach and Effectiveness of the University of California Diabetes Prevention Program Initiative
Authors: GHOLAMI MARYAM , JACKSON NICHOLAS , LOEB TAMRA B. , YOUNG CHUNG UN , RAMM KATE , SHEDD KELLY , SOETENGA SAMANTHA , HAMILTON ALISON B. , ELASHOFF DAVID , MANGIONE CAROL , KENRIK DURU O. , MOIN TANNAZ
Published: June 2023

The University of California (UC) system implemented the Diabetes Prevention Program (DPP) across UC campuses to address diabetes and obesity risk. We examined the reach and effectiveness of this novel, university-based DPP delivery approach. We compared weight change at 12-mo follow-up among 3 groups of overweight/obese UC beneficiaries: 1) those who reported receiving DPP invitation letters and enrolled in DPP (DPP enrollees), 2) those who were sent DPP invitation letters but did not enroll (DPP aware non-enrollees), and those who were not sent letters and did not enroll (controls). Using EHR, administrative and UC DPP cohort data, we conducted an interrupted time series to compare differences in the rate of weight change 12-mo after DPP enrollment for enrollees, receipt of DPP letters for non-enrollees or proxy enrollment date for controls. Our analysis included 7,465 UC beneficiaries (142 DPP enrollees, 2,494 DPP aware non-enrollees, 4,829 controls). UC beneficiaries had a mean age of 42 (SD 13), 51% were female, 26% Asian, 6% Black, 16% Hispanic, 6% Multi/Other, 1% Native American, 34% White, and 12% Unknown. DPP enrollees were older (mean age 49 [SD 11]), mostly women (75%), and more diverse (32% Asian, 7% Black, 21% Hispanic, 4% Multi/Other and 1% Native American). During the 12-mo follow-up, the rate of weight change was -0.60 lbs/mo among DPP enrollees. The within-person change in rate of weight loss was significantly greater among DPP enrollees compared to DPP aware non-enrollees (Δ-0.93 vs Δ-0.03 lbs/mo, difference = -0.90, p <.001). We found no difference in weight loss among DPP enrollees and DPP aware non-enrollees compared to controls. We found that the UC DPP Initiative reached a diverse group of UC beneficiaries and was effective for weight loss among enrollees. However, UC DPP invitation letters to raise DPP awareness were not associated with weight change in the absence of DPP enrollment. University based approaches to DPP delivery may help enhance reach of DPP among at risk adults.

Disclosure

M.Gholami: None. C.Mangione: None. O.Duru: None. T.Moin: None. N.Jackson: None. T.B.Loeb: None. U.Chung: None. K.Ramm: None. K.Shedd: None. S.Soetenga: None. A.B.Hamilton: None. D.Elashoff: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK124503–02)
75-OR: Cold-Responsive Proteolytic Rewiring of Mitochondria Safeguards White Fat Thermogenic Remodeling
Authors: FU TINGTING , SUN WANPING , ZHOU ZHENG , XU ZHISHENG , YAN MAO , YANG LIKUN , YIN YUJING , GAN ZHENJI
Published: June 2023

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity acting both as protein quality surveillance and regulatory enzymes. It remains unclear, however, whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switch such as white-to-beige conversion of adipocytes. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for conversion from white-to-beige adipocytes during white adipose tissue (WAT) browning. MitoTimer reporter and chemical thiol probe analysis reveal that thermogenic stimulation selectively promotes mitochondrial proteostasis in WAT via mitochondrial protease LONP1 both in vivo and in vitro. Disruption of LONP1-dependent proteolysis substantially impairs cold or b3-AR agonist induced adipocyte identity programming, evidenced by the remarkably attenuated formation of UCP1+ multilocular adipocytes in IWAT from Lonp1 f/f/Adipoq-Cre (LONP1 AKO) mice. LONP1 AKO mice exposed to cold had lower body temperature, elevated serum TG and FFA levels. Chow-fed LONP1 AKO mice also developed glucose intolerance. “AdipoChaser” system “pulse-chase” lineage tracing experiments confirm that LONP1 ablation markedly blocks the direct cell fate programming of pre-existing mature adipocytes. Importantly, augmented LONP1 expression corrects aging-related impairments in white-to-beige adipocytes conversion. 10-month-old adipocyte-specific Lonp1 overexpression mice had significantly lower body weight and fat mass as a result of elevated energy expenditure. Thus, the identification of LONP1 as a critical safeguard of WAT beiging holds promise for translational applications in enhancing white-to-beige adipocytes conversion capacity relevant to a variety of metabolic disease states and during aging.

Disclosure

T.Fu: None. W.Sun: None. Z.Zhou: None. Z.Xu: None. M.Yan: None. L.Yang: None. Y.Yin: None. Z.Gan: None.
758-P: Changes in Liver and Abdominal Fat in Tirzepatide-Treated Patients Achieving Normoglycemia in the SURPASS-3 MRI Substudy
Authors: RODRÍGUEZ ÁNGEL , CUSI KENNETH , GASTALDELLI AMALIA , NICOLAY CLAUDIA , TORCELLO-GOMEZ AMELIA , FERNANDEZ LANDO LAURA
Published: June 2023

Tirzepatide (TZP), a novel, once-weekly GIP/GLP-1 receptor agonist, significantly reduced liver fat content (LFC) and volumes of visceral and abdominal subcutaneous adipose tissue (VAT and ASAT) vs insulin degludec in a subpopulation of patients in the SURPASS-3 phase 3 trial. This post-hoc analysis evaluated changes from baseline to Week 52 in these outcomes and other clinical and laboratory parameters in TZP-treated patients achieving or not achieving normoglycemia (HbA1c <5.7%) at Week 52.

LFC, VAT and ASAT volumes were assessed with MRI prior to randomization and at Week 52 in insulin-naïve patients with type 2 diabetes inadequately controlled on metformin with/without SGLT-2i and fatty liver index ≥60 at baseline. Analyses used pooled data from all TZP arms (5, 10, and 15 mg).

Patients achieving HbA1c <5.7% were slightly younger and had lower baseline HbA1c and VAT vs those not achieving HbA1c <5.7%. Substantial reductions in LFC, VAT and ASAT volumes, weight, HbA1c, and overall improvement in lipids profile were observed in both subsets of patients (Table). Among patients achieving HbA1c <5.7% and ≥5.7%, respectively, 56% and 27% achieved LFC <6%, and 91% and 64% achieved ≥30% reduction in LFC.

In summary, in TZP-treated patients, changes in LFC, VAT and ASAT, and lipids were more pronounced in those achieving normoglycemia.

Disclosure

Á.Rodríguez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. A.Gastaldelli: Advisory Panel; Pfizer Inc., Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Fractyl Health, Inc., Merck Sharp & Dohme Corp., Other Relationship; Pfizer Inc., Speaker's Bureau; Eli Lilly and Company. C.Nicolay: Employee; Eli Lilly and Company. A.Torcello-gomez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. L.Fernandez lando: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
76-OR: Axon Guidance Molecule Slit3 Is Essential for Cold-Induced Remodeling of BAT Neurovasculature and Thermogenesis
Authors: DUARTE AFONSO SERDAN TAMIRES , CERVANTES HEIDI E. , NETO FELIPPE M. , TSENG YU-HUA , SHAMSI FARNAZ
Published: June 2023

Brown adipose tissue (BAT) is primarily responsible for regulating body temperature through adaptive thermogenesis. Enhancing energy expenditure through the activation of BAT thermogenesis is a promising strategy to prevent and reverse obesity and its cardiometabolic sequelae. Brown adipocytes are embedded in a dense network of blood vessels and sympathetic nerves that supports their thermogenic activity. Increasing the density of blood vessels and sympathetic innervation is essential for enhanced thermogenesis in cold. However, how these distinct processes are spatiotemporally regulated is not clear. To define the mediators of intercellular crosstalk in the BAT, we used single-cell transcriptomic analysis of BAT to build a network of ligand-receptor interactions. We identified Slit guidance ligand 3 (Slit3) as a new adipokine that mediates the crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. Using a combination of in vivo gain and loss of function studies, we showed that Slit3 is essential for cold-induced angiogenesis and sympathetic innervation in BAT. Loss of Slit3 reduced the density of blood vessels and sympathetic neurites in BAT. Consequently, mice lacking Slit3 expression in BAT exhibited severe cold intolerance, increased lipid accumulation and whitening of BAT, and reduced expression of thermogenic and mitochondrial genes in BAT. Conversely, the overexpression of Slit3 enhanced cold-induced BAT thermogenesis. Our mechanistic studies identified the key regulatory events that control Slit3 signaling in BAT. Collectively, these findings established the essential role of Slit3 signaling in regulation of BAT thermogenesis and introduced Slit3 as a new niche factor that promotes adipose tissue health. These studies introduced a potential node of intervention for improving systemic metabolism through the expansion of thermogenic fat.

Disclosure

T.Duarte afonso serdan: None. H.E.Cervantes: None. F.M.Neto: None. Y.Tseng: Consultant; Cellarity, LyGenesis. F.Shamsi: None.

Funding

National Institutes of Health (K01DK125608)
764-P: Time in Range and Time in Tight Range in Tirzepatide-Treated Patients Achieving Normoglycemia in the SURPASS-3 CGM Substudy
Authors: BERGENSTAL RICHARD M. , RODRÍGUEZ ÁNGEL , BENNEYWORTH BRIAN D. , NICOLAY CLAUDIA , BROWN KATELYN
Published: June 2023

Tirzepatide (TZP), a novel once-weekly GIP/GLP-1 receptor agonist, demonstrated superior glycemic control vs insulin degludec (IDeg) in SURPASS-3 CGM. This post-hoc analysis evaluated changes from baseline to Week (Wk) 52 in Time in Range (TIR) (71-180 mg/dL), Time in Tight Range (TITR) (71-140 mg/dL), and glycemic variation (within-day coefficient of variation (CV) and Mean Amplitude of Glycemic Excursions (MAGE)) in TZP-treated patients achieving or not achieving HbA1c <5.7% at Wk 52. Interstitial glucose values were collected by CGM at 5-minute intervals for 7 days at baseline, Wk 24, and Wk 52 in a subset of patients in the SURPASS-3 trial. Analyses used pooled data from all TZP arms (5, 10, 15 mg) only due to limited sample size for IDeg patients achieving HbA1c <5.7% at Wk 52. Patients achieving HbA1c <5.7% were slightly younger, had lower HbA1c and FSG, and higher TITR and TIR vs those not achieving HbA1c <5.7% at baseline (Table). Increases in daily TITR and TIR from baseline (61.02% and 41.12% respectively) were seen in patients achieving HbA1c <5.7% while those not achieving HbA1c <5.7% had increased daily TITR and TIR of 36.62% and 32.40% (Table). Within-day CV and MAGE were reduced in both patient groups but more apparent in those achieving HbA1c <5.7%. In TZP-treated patients, improvements in TIR, TITR, and glycemic variability were more pronounced in those achieving HbA1c <5.7%.

Disclosure

R.M.Bergenstal: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Hygieia, Onduo LLC, Sanofi, Vertex Pharmaceuticals Incorporated, Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, UnitedHealth Group. Á.Rodríguez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. B.D.Benneyworth: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Nicolay: Employee; Eli Lilly and Company. K.Brown: Employee; Eli Lilly and Company.

Funding

Eli Lilly and Company
765-P: A Single Ascending Dose Study of the Novel GLP-1 Receptor Agonist GL0034 (Utreglutide) in Obese Individuals without Diabetes
Authors: THENNATI RAJAMANNAR , BURADE VINOD S. , NATARAJAN MUTHUKUMARAN , SHAHI PRADEEP , NAGARAJA RAVISHANKARA , PANCHAL SATISH T. , AGRAWAL SUDEEP K. , JANDRAIN BERNARD , DUVAUCHELLE THIERRY , GARCIA-OCANA ADOLFO , RUTTER GUY A. , PRATLEY RICHARD E. , THORENS BERNARD , VILSBØLL TINA
Published: June 2023

The novel incretin analogue, GL0034 (GL), has potent agonist activity at glucagon-like peptide 1 (GLP-1RA) receptor. The primary objective of this phase 1 study in people with obesity was to assess the safety and tolerability of single-ascending doses of GL. Healthy individuals (N=24) with BMI ≥30 kg/m2 were randomized (6:2) to increasing doses of subcutaneous GL (1,520, 2,000 and 2,520 μg) or placebo once-weekly during four weeks. GL pharmacokinetics and key exploratory pharmacodynamic parameters (triglyceride, leptin levels and body weight) were assessed (Table). Most common GL-related adverse events were gastrointestinal with dose-dependent nausea, decreased appetite and vomiting. No injection site reactions or any other adverse events were noted. GL maximum concentrations ranged from 227 to 367 ng/mL, and mean half-life ranged from 99 to 118 h. Triglyceride levels were reduced from baseline following treatment with GL 2,000 and 2,520 μg dose at day 8. Decreases in leptin levels were dose-dependent. Reduction in body weight versus baseline reached a maximum of 3.3 kg with the 2,520 μg dose at day 8 and this effect was sustained through day 22 at every GL dose (Table). In conclusion, once-weekly GL demonstrated clinically relevant reductions in body weight in obese individuals and was well tolerated.

Disclosure

R.Thennati: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. G.A.Rutter: Consultant; Sun Pharmaceutical Industries Ltd. R.E.Pratley: Other Relationship; Bayer Inc., Corcept Therapeutics, Dexcom, Inc., Gasherbrum Bio, Inc., Hanmi Pharm. Co., Ltd., Hengrui (USA) Ltd., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. B.Thorens: Advisory Panel; Sun Pharmaceutical Industries Ltd. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. V.S.Burade: None. M.Natarajan: None. P.Shahi: None. R.Nagaraja: None. S.T.Panchal: None. S.K.Agrawal: None. B.Jandrain: None. T.Duvauchelle: None.
767-P: TERN-601, a Novel Oral GLP-1R Agonist, Suppresses Food Intake and Improves Glucose Tolerance in Transgenic Mice Expressing Human GLP-1 Receptor
Authors: JONES CHRISTOPHER , QUINN KEVIN P. , NELSON CARA H. , OSBORN OLIVIA , LUEHR GARY , JASPER JEFFREY R.
Published: June 2023

Synthetic peptide agonists of the GLP-1 receptor (GLP-1R) are approved for the treatment of diabetes and obesity based on their ability to lower blood glucose and induce weight loss. TERN-601 is a novel, oral small molecule GLP-1R agonist in preclinical development. In vitro, TERN-601 potently stimulated (EC50 = 2.9 ± 0.8 nM) intracellular cAMP generation, a downstream consequence of GLP-1R activation, in CHO-K1 cells stably expressing human GLP-1R. In vivo, single oral doses of TERN-601 (10, 30, or 60 mg/kg) led to significant dose-dependent suppression of food intake (2- to 24-hours post dose) in transgenic C57BL/6J mice (n = 10 per group) expressing human GLP-1R (hGLP-1R). In an intraperitoneal glucose tolerance test (IPGTT) on overnight fasted hGLP-1R mice (n = 7 per group), single oral doses of TERN-601 (0.3, 1, and 3 mg/kg) administered 30 minutes prior to IP glucose injection significantly lowered blood glucose area under the curve (AUC0-120min) with comparable efficacy to liraglutide (0.3 mg/kg). TERN-601 is a potent, orally bioavailable small molecule agonist of human GLP-1R in preclinical development for the treatment of chronic obesity. In transgenic mice expressing human GLP-1R, single oral doses of TERN-601 significantly suppressed food intake and improved glucose tolerance. Together these data support the continued development of TERN-601.

Disclosure

C.Jones: Employee; Terns Pharmaceuticals. K.P.Quinn: None. C.H.Nelson: Employee; Terns Pharmaceuticals, Gilead Sciences, Inc., Stock/Shareholder; Terns Pharmaceuticals, Gilead Sciences, Inc. O.Osborn: Employee; Terns, Stock/Shareholder; ClicBio. G.Luehr: None. J.R.Jasper: Advisory Panel; Rubedo Life Sciences, Employee; Terns Pharmaceuticals, Rubedo Life Sciences.
769-P: Effect of Food on the Pharmacokinetics, Safety, and Tolerability of Orforglipron (LY3502970), an Oral, Nonpeptide GLP-1 Receptor Agonist
Authors: MA XIAOSU , LIU RONG , PRATT EDWARD J. , BENSON CHARLES , BHATTACHAR SHOBHA N.
Published: June 2023

Orforglipron [OFG (LY3502970)] is an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1 RA). This reports the results of 2 studies that assessed PK, safety, and tolerability of OFG in healthy subjects, fasted and fed state, after single and repeated doses.

Studies A and B were phase 1, randomized, open-label, crossover studies evaluating the effect of food on OFG concentration in healthy adults after a single 3 mg dose (study A) and after a 16 mg daily dose (study B), which was reached by weekly dose escalation starting with 2 mg.

Based on statistical analysis, Cmax was 23% (study A) and 21% (study B) lower in the fed state. AUC(0-∞), and AUC(0-24) were 24% (study A) and 18% (study B) lower when administered with food. Tmax and T1/2 were similar with or without food. In study A and B, treatment emergent adverse events (TEAEs) were mild. In study B, TEAEs occurred most often with the starting dose and decreased with dose escalation. The most common TEAEs in study B were decreased appetite (69.7%), nausea (48.5%), and vomiting (45.5%).

Overall mean exposure to OFG based on Cmax and AUC was numerically lower when administered with food and had little effect on Tmax and T1/2. Based on exposure response relationship, PK differences are unlikely to result in clinically meaningful differences in OFG safety and efficacy. Phase 3 studies are planned without food or water restrictions.

Disclosure

X.Ma: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Liu: None. E.J.Pratt: Employee; Eli Lilly and Company. C.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. S.N.Bhattachar: None.
772-P: Tirzepatide vs. Basal Insulins in People with T2D and Different Baseline Glycemic Patterns—Post Hoc Analyses of the SURPASS-3 and -4 Trials
Authors: GIORGINO FRANCESCO , FRANCO DENISE R. , NICOLAY CLAUDIA , HEMMINGWAY ANDREA , RODRÍGUEZ ÁNGEL , WIESE RUSSELL
Published: June 2023

While basal insulins act primarily by reducing fasting serum glucose (FSG), the once-weekly GIP/GLP-1 receptor agonist tirzepatide targets both FSG and postprandial glucose (PPG). This post-hoc analysis assessed the efficacy of tirzepatide vs insulin degludec (SURPASS-3) and glargine (SURPASS-4) in people with T2D and different baseline glycemic patterns. We assessed change from baseline to Week 52 in HbA1c, FSG, and PPG across subgroup categories in participants on assigned treatment without rescue medication (efficacy estimand) using mixed-model repeated measures. Four subgroups were defined by different combinations of FSG and PPG (low FSG/low PPG, low FSG/high PPG, high FSG/low PPG, high FSG/high PPG). Low and high FSG and PPG were split based on median values of these parameters in SURPASS-3 (162 and 187 mg/dL) and -4 (164 and 197 mg/dL). While reductions in FSG were generally similar between tirzepatide and the basal insulins in both studies, decreases in PPG were greater with tirzepatide in all subgroups. This resulted in greater HbA1c reductions with tirzepatide vs basal insulin in all subgroups. The extent of reduction in FSG, PPG, and HbA1c in each subgroup was related to baseline values of these parameters. These data support previous observations of superior glycemic control with TZP compared with basal insulin, irrespective of baseline FSG and PPG levels.

Disclosure

F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. D.R.Franco: Advisory Panel; Abbott, Eli Lilly and Company, Medtronic, Speaker's Bureau; Eli Lilly and Company, Boehringer Ingelheim and Eli Lilly Alliance, Medtronic, Sanofi, AstraZeneca, Roche Diabetes Care, Abbott Diabetes. C.Nicolay: Employee; Eli Lilly and Company. A.Hemmingway: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Á.Rodríguez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Wiese: Employee; Eli Lilly and Company.

Funding

Eli Lilly and Company
775-P: Predictors of Glycemic Control in Older People with Type 2 Diabetes Treated with iGlarLixi—A Pooled Analysis
Authors: MUNSHI MEDHA , RITZEL ROBERT , MCCRIMMON RORY J. , HRAMIAK IRENE , LAUAND FELIPE , MELAS-MELT LYDIE , SOUHAMI ELISABETH , ROSENSTOCK JULIO
Published: June 2023

For older adults (>65 years) with type 2 diabetes (T2D), iGlarLixi can be a simple and effective therapeutic option. We aimed to identify factors associated with achieving target HbA1c <7% and derived Time in Range (dTIR) ≥70% in this population in response to once daily iGlarLixi.

This post-hoc, pooled analysis of 4 randomized trials included 465 people advancing from oral (LixiLan-O), GLP-1 RA (LixiLan-G), or insulin (LixiLan-L; SoliMix) therapies to iGlarLixi for 26 or 30 weeks. HbA1c and dTIR responses were assessed at baseline (BL) and end of treatment (EOT) for each participant and classified as attained (<7.0% or dTIR ≥70%) or unattained (≥7.0% or <70%). dTIR was calculated from 7-point self-monitored plasma glucose profiles from the three LixiLan studies (LixiLan-O. G, and L). Potential predictive factors were analyzed by univariable and multivariable stepwise logistic regression.

Overall, 60% of participants achieved HbA1c <7.0% and 87.5% achieved dTIR ≥70%. Predictors of attained HbA1c response (p<0.05) included lower BL HbA1c and lower BL insulin dose. Predictor of attained dTIR response (p<0.05) was higher BL fasting plasma glucose (FPG; Table), while sex, T2D duration, and obesity had no predictive value.

To conclude, in older people with T2D treated with iGlarLixi, consideration of BL HbA1c and FPG, as well as BL insulin dose may improve achieving individualized glycemic targets.

Disclosure

M.Munshi: Consultant; Sanofi. R.Ritzel: Consultant; Novo Nordisk, Sanofi, Speaker's Bureau; Novo Nordisk, Sanofi, Pfizer Inc., Merck Sharp & Dohme Corp., Lilly. R.J.Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. I.Hramiak: Research Support; Eli Lilly and Company, Novo Nordisk, Sanofi, Speaker's Bureau; Canadian Medical & Surgical Knowledge Translation Research Group (CMS), Insulet Corporation, Medtronic, Merck & Co., Inc., Bayer Inc. F.Lauand: Employee; Sanofi. L.Melas-melt: None. E.Souhami: Employee; Sanofi, Stock/Shareholder; Sanofi. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc.

Funding

Sanofi
776-P: Comparative Effectiveness of SC Semaglutide in Adults with T2D in U.S. Routine Clinical Practice—Year 1 Results of SEPRA, a Randomized Pragmatic Clinical Trial
Authors: BUSE JOHN B. , SOULE BENJAMIN P. , HARTY BRIAN J. , CHRISTENSEN HELENE N. , CZIRAKY MARK J. , WILLEY VINCENT , SKIBSTED SIMON
Published: June 2023

SEPRA, a 2-year, ongoing, open-label, randomized, pragmatic study (NCT03596450) compares the effects of once-weekly SC semaglutide (sema) with physician's choice SOC when added to ≤2 oral antidiabetic medications for treatment intensification in US health-insured adults with T2D. The objective is to generate real-world evidence to support routine clinical decision making and complement clinical trial data. The primary endpoint is the proportion of patients who achieve HbA1c <7% at 1 year. Patients (N=1278) were randomized to receive sema according to label (n=644) or SOC excluding sema (n=634). All other treatment was per routine clinical care. Baseline characteristics were comparable (Table 1). Most common SOC medications were other GLP-1RAs (71.3%) and SGLT2is (15.5%). Sema dosing at 1 year was 26.6% at 0.25 mg, 30.4% at 0.5 mg and 24.4% at 1 mg (10.6% ended study and 7.6% not on sema at year 1). Use of sema resulted in a significantly greater proportion of patients achieving HbA1c <7% and body weight reduction vs SOC at 1 year (Table 1). A lower proportion of sema patients required additional treatment intensification in year 1 of the study vs SOC. No new safety concerns were identified. SEPRA demonstrates the superior effect of sema vs physician's choice SOC and that sema is an efficacious, durable treatment option in routine clinical practice.

Disclosure

J.B.Buse: Consultant; Alkahest, Anji Pharmaceuticals, AstraZeneca, Bayer Inc., Biomea Fusion, Inc., Boehringer Ingelheim International GmbH, CeQur SA, Cirius Therapeutics, Inc., Corcept Therapeutics, Eli Lilly and Company, GentiBio, Glycadia, Glyscend Inc., Janssen Pharmaceuticals, Inc., Mellitus Health, Pendulum Therapeutics, Praetego, LLC, Stability Health, Terns, Inc, Valo, Other Relationship; Novo Nordisk, Research Support; Dexcom, Inc., Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend Inc., Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. B.P.Soule: Employee; Novo Nordisk. B.J.Harty: Research Support; Novo Nordisk. H.N.Christensen: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk A/S. M.J.Cziraky: Other Relationship; Novo Nordisk. V.Willey: Other Relationship; Novo Nordisk A/S. S.Skibsted: Employee; Novo Nordisk A/S.

Funding

Novo Nordisk
779-P: Intensification of Glucagon-Like Peptide-1 Receptor Agonists Therapy with First and Second Generation Basal Insulins—The RESTORE-G Real-World Study
Authors: NAPOLI RAFFAELE , LAROSA MONICA , NICOLUCCI ANTONIO , CHIARA ROSSI MARIA , CANDIDO RICCARDO , STUDY GROUP RESTORE-G
Published: June 2023

ADA guidelines suggest that in patients needing insulin treatment, combination therapy with a glucagon-like peptide 1 receptor agonist (GLP1-RA) is recommended for greater efficacy, durability of treatment effect, and weight and hypoglycemia benefit. However, when treatment with GLP1-RA needs to be intensified, switch to insulin approach is still very common. It is also known that second generation basal insulins (2BI) provide similar or improved efficacy with a better safety profile compared to first generation basal insulins (1BI). Aim of this RESTORE-G sub-study was to perform a propensity-score adjusted comparative effectiveness analysis of adding-on/switching to 2BI vs. 1BI in patients on GLP1-RA therapy (±oral hypoglycemic agents) needing intensification. Table shows sample sizes, patients characteristics and effectiveness results.

Data shows that 2BI vs. 1BI was associated with significantly larger improvements in HbA1c and FBG both in add-on and switch approaches. In the switch approach, 2BI produced lower weight gain versus 1BI. Switching vs. adding on was associated with a more frequent use of short acting insulin. Both 1BI and 2BI were poorly titrated.

Disclosure

R.Napoli: Advisory Panel; Sanofi, Eli Lilly and Company, Novo Nordisk, Research Support; Novo Nordisk, AstraZeneca, Speaker's Bureau; Sanofi, Eli Lilly and Company, Novo Nordisk, AstraZeneca, MSD Life Science Foundation. M.Larosa: None. A.Nicolucci: Board Member; AstraZeneca, Research Support; Novo Nordisk, Sanofi, Sobi, Shionogi & Co., Ltd., AlfaSigma, Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. M.Rossi: Research Support; Sanofi, Novo Nordisk, Shionogi & Co., Ltd., AlfaSigma. R.Candido: None. Restore-g study group: n/a.

Funding

Sanofi
781-P: Sustained-Release Formulation Development and Preclinical Evaluations of Monthly or Bimonthly Injectable Semaglutide and Tirzepatide
Authors: G JUNG JIN , CHANG SEUNG-GU
Published: June 2023

Objective: Accumulated real-world data indicates strong tendencies to develop long-acting formulating drug. This study aimed for optimization and preclinical development of the sustained-release formulation of Semaglutide (PT403) and Tirzepatide (PT404) to explore whether they are applicable for bi-monthly (once every two months) injectable drugs.

Methods: Semaglutide or Tirzepatide dissolved in acetic acid with diverse combination of biodegradable PLGA polymers was applied to the ultrasonic spray dryer that produces API-encapsulated microspheres. The pharmacokinetic profiles of PT403 and PT404 were tested in rats and minipigs after a single subcutaneous injection.

Results: Both optimized formulation of PT403 and PT404 have demonstrated favorable physicochemical properties, showing uniformly sized microspheres (20±3 μm). Furthermore, the aggregation issue of Semaglutide, which was not observed in PT404, was solved by applying PROW technology. Also, increased encapsulation rates and higher drug loading (~8%) showed higher bioavailability, no initial burst and a short lag phase (<3 days). Additionally, the release of PT403 initiated from 3 days to 70 days in minipigs, which potentially indicates every two months injectable (Q8W) in humans, compared to the once-a-weekly (QW) Semaglutide and Tirzepatide. Lastly, double injection of PT403 can easily reached the therapeutic window with 1.4 of the Peak-to-Through ratio, based on simulated PK profiles in repeated injection in human.

Conclusion: Evidence from recent formulation studies of PT403 and PT404 indicates that Peptron's SmartDepot technology is strongly applicable for long-acting drugs. The comprehensive results of formulation development, preclinical data, and mass production will provide the basis for successful clinical development of PT403 and PT404 as monthly or bi-monthly injectable diabetes and obesity drugs.

Disclosure

J.Jung: None. S.Chang: None.