bluuebunny/crossref_metadata_2025 huggingface dataset:
690-P: Relationship of Diabetes Distress and Symptoms of Autonomic Nervous System Dysregulation in Type 1 Diabetes Adults
Authors: DE GROOT MARY , MYERS BARBARA A. , STUMP TIMOTHY , DANA DEBORAH , KOLACZ JACEK , PORGES STEPHEN W.
Published: June 2024

Purpose: To test the association of autonomic nervous system (ANS) dysregulation symptoms and diabetes distress (DD) in type 1 diabetes (T1D) adults. 556 US adults with self-identified T1D completed a web-based survey in May 2023, including demographics, ANS reactivity symptoms (Body Perception Questionnaire; BPQ, validated against physiologic measures), diabetes-related distress (Diabetes Distress Scale-28 T1D; DDS), depressive symptoms (PHQ-8) and anxiety (GAD-7). Mean age was 45.1 years (S.D. = 15.7), 73.2% female, 95.3% White, with a median annual household income of $60,000-100,000. Mean self-reported A1c was 6.7% (S.D. 1.0%). 72.5% reported using an insulin pump. Mean hypoglycemic episodes per week was 5.7 (9.9). Mean age at diabetes diagnosis was 20.6 years (S.D. 14.7) and mean duration of diabetes was 25.4 (S.D. 17.6) years. The sample reported high levels of comorbid hypertension (33.0%), dyslipidemia (28.6%), thyroid disorder (34.5%) and depression (28.8%). Mean total item DDS score was 2.3 (S.D. 0.8; moderate severity). The highest scores were observed in the powerlessness (mean = 3.2; S.D. 1.3), hypoglycemia distress (mean = 2.7, S.D. 1.3) and physician distress (mean = 2.4; S.D. 1.2) subscales. Mean PHQ-8 score was 6.8 (S.D. = 5.5; mild) and the mean GAD-7 score was 5.9 (S.D. 5.3, mild). BPQ mean T scores were 48.9 (S.D. 8.4) for Supradiaphragmatic and 50.6 (S.D. 8.9) for Subdiaphragmatic Reactivity subscales. Controlling for covariates, clinical categories of the DDS predicted significant differences in BPQ subscale T scores. Greatest differences in BPQ scores were observed between ‘no/little/low’ and ‘high’ distress DDS categories on all subscales (p’s <= 0.001), with ‘high’ DDS having the highest BPQ scores. Findings confirm a relationship between ANS reactivity symptoms and diabetes-related distress in adults with T1D, consistent with the Polyvagal Theory. Development of interventions that target ANS regulation to treat DD for T1D adults are needed.

Disclosure

M. de Groot: None. B.A. Myers: None. T. Stump: None. D. Dana: None. J. Kolacz: None. S.W. Porges: None.

Funding

Indiana University School of Medicine
705-P: Health Literacy on Self-Management in Older Adults with Type 2 DM—Mediating Role of Self-Efficacy
Authors: KIM MINJIN , CHOEL LEE SANG , SUCK GOO YOUNG , PARK SUNHEE
Published: June 2024

Background & Aims: In this digital era, eHealth literacy serves as a key factor influencing diabetic self-management; hence, further investigation into the psychological mechanisms underlying this relationship is necessary. This study aimed to determine if self-efficacy mediates the relationship between eHealth literacy and diabetes self-management in older adults with Type 2 diabetes (T2DM).

Methods: A cross-sectional study was undertaken, encompassing 105 Korean older adults with T2DM drawn from two outpatient clinics. Data on eHealth literacy, diabetes self-management, and self-efficacy were collected with structured self-report questionnaire. The data were analyzed using SPSS PROCESS Macro 4.0.

Results: We found that self-efficacy mediated the relationship between eHealth literacy and self-management. eHealth literacy and self-efficacy promote diabetes self-management, and higher eHealth literacy among older adults with T2DM can positively influence their diabetes self-management.

Conclusion: This study evaluated eHealth literacy and self-efficacy in diabetes self-management tasks among older adults with T2DM, which may help health care providers in tailoring individualized diabetes self-management care. Furthermore, strategies to enhance their access to internet-based information on diabetes health may contribute to improved diabetes self-management.

Disclosure

M. Kim: None. S. Lee: None. Y. Goo: None. S. Park: None.
709-P: Status and Influencing Factors of Resilience in Middle-Old Age Adults with Type 2 Diabetes on Insulin Therapy at Home
Authors: YANG QIAOLING , HE QIANYU , CHENG LI
Published: June 2024

Introduction &Objective: Middle-old age adults with type 2 diabetes on insulin therapy at home often have a range of psychological issues because of the illness, which significantly affects both their physical and mental well-being and the therapeutic outcome. The aim of this study was to examine the status of resilience in this population and explore its influencing factors.

Methods: From September 2019 to January 2021, a total of 168 middle-old age adults with type 2 diabetes on insulin therapy were investigated by self-designed general and disease data questionnaire, Connor Davidson Resilience Scale (CD-RISC), Diabetes Management Self-efficacy Scale (DMSES), Social Support Rating Scale (SSRS) and Medical Coping Modes Questionnaire (MCMQ). Statistic methods including t-test, analysis of variance and multiple linear regression analysis were adopted to the data analysis.

Results: The CD-RISC score was (58.20±14.26), and the average score of optimism dimension is the highest(2.61±0.93). Multiple linear regression analysis showed that self-efficacy, social support and the coping style of facing and avoiding were the protective factors for resilience, and the coping style of yielding is the risk factor for resilience(all P<0.05).

Conclusion: The resilience of the middle-old age adults with type 2 diabetes treated with insulin at home is sub optimal. Medical staff and family members should assist them in developing a proper medical coping style and provide them social support to boost their resilience.

Disclosure

Q. Yang: None. Q. He: None. L. Cheng: None.
753-P: Eating Behavior in Adults with Type 2 Diabetes from a Phase 2 Study of Retatrutide
Authors: KANU CHISOM , BOYE KRISTINA , LING POON JIAT , GOETZ IRIS A. , WILLIAMSON SUZANNE E. , LOU JITONG , COSKUN TAMER
Published: June 2024

Retatrutide (RETA), a triple-hormone receptor agonist of GIP, GLP-1, and glucagon receptors, showed clinically meaningful improvements in HbA1c and robust body weight reductions in adults with T2D in a Phase 2 study. We compared eating behavior during treatment with RETA vs. placebo or dulaglutide (DU) in this study.

Adults with T2D were randomized to subcutaneous placebo QW, DU 1.5 mg QW, or RETA 0.5, 4, 8, or 12 mg QW for 36 weeks in this double-blind, double-dummy Phase 2 study. Eating behavior was assessed at baseline and Week 36 using the 51-item Eating Inventory comprised of three domains: Cognitive Restraint of Eating, Disinhibition, and Perceived Hunger.

Overall, 281 adults with mean baseline age 56 y, T2D duration 8.1 y, HbA1c 8.3%, and BMI 35.0 kg/m2 were randomized. At Week 36, adults treated with RETA 8 mg and 12 mg had significantly reduced Eating Inventory Disinhibition and Perceived Hunger scores vs. placebo. Adults treated with RETA 12 mg also had significantly reduced Disinhibition and Perceived Hunger scores vs. DU and a significantly reduced Cognitive Restraint of Eating score vs. placebo at Week 36.

RETA treatment significantly improved some eating behaviors such as overeating and hunger management more than placebo or DU in a dose-dependent manner, and improved other eating behaviors such as portion control and avoiding high calorie foods more than placebo in adults with T2D.

Disclosure

C. Kanu: None. K. Boye: Employee; Eli Lilly and Company. J. Poon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. I.A. Goetz: Employee; Eli Lilly and Company. S.E. Williamson: Consultant; Eli Lilly and Company, Takeda Pharmaceutical Company Limited, GlaxoSmithKline plc, Novo Nordisk, Lundbeck. J. Lou: None. T. Coskun: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
763-P: CagriSema Improves Insulin Sensitivity in Diet-Induced Obese Rats
Authors: SECHER ANNA , BRAND CHRISTIAN L. , RAUN KIRSTEN
Published: June 2024

Introduction & Objective: CagriSema (CS), a combination of the long-acting analogues of amylin (cagrilintide) and glucagon-like peptide-1 (semaglutide), is in clinical development for treatment of obesity and type 2 diabetes. Rodent studies have shown that CS treatment results in weight loss. It is unknown whether CS also leads to improvement of insulin sensitivity in diet-induced obese (DIO) rats which was the objective of this study.

Methods: DIO male rats were allocated into three groups (n=6) matched on body weight (BW), fat mass and fat-free mass: vehicle control (VC), CS, and a vehicle group that was weight matched (VWM) to CS by calorie restriction. BW and food intake (FI) were measured at baseline and during treatment. Food availability in VWM was adjusted daily. CS rats received 2 nmol/kg, sc, qd of each drug. After 21 days of treatment rats were instrumented (isoflurane) with carotid (sampling) and jugular (infusions) catheters. After 9-11 days recovery rats were subjected to a 180 min hyper-insulinemic (15 pmol/kg/min) euglycemic (~5.7 mM) clamp. 3H-glucose and 14C-2-deoxy-glucose (2DG) were employed to measure hepatic glucose production (HGP), glucose uptake (GU), and tissue 2DG uptake.

Results: FI initially decreased to 10% of baseline and BW reduced by 10% in CS and VWM rats. FI progressively returned to VC at the end of treatment without increase in BW. No change in fasting plasma glucose was observed, but insulin decreased by 40% (p<0.03) in CS compared to VC. Clamp glucose infusion rates increased by 4.2- and 2.6-fold over VC in CS (p<0.001) and VWM (ns), respectively. No significant differences in HGP but GU increased by 3.3- (p=0.002) and 1.6-fold (ns) over VC in CS and VWM, respectively. 2DG uptake increased in muscle but not in fat tissues in CS compared to VC.

Conclusion: CS increased insulin sensitivity in DIO rats by improving glucose uptake in muscle but not in fat tissues. An ongoing, higher-powered study will investigate the effects of CS and the two mono-components on insulin sensitivity in DIO rats.

Disclosure

A. Secher: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. C.L. Brand: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. K. Raun: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S.
767-P: A Phase 1b/2a Study of the Safety and Tolerability of GSBR-1290, a Novel Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA), in Healthy Overweight/Obese Volunteers (HOV) and Participants with Type 2 Diabetes Mellitus (T2DM)
Authors: COLL BLAI , ZHANG JINQIANG , CHEN LIBO , IBARRA LANI , YUE HUIBIN , BARTH ALINE , BACH MARK A.
Published: June 2024

Introduction: GSBR-1290 is a novel, oral, non-peptide GLP-1RA and a potential alternative to injectable or oral peptides used for the treatment of T2DM and obesity. These studies were designed to evaluate the safety, tolerability, and efficacy of GSBR-1290.

Methods: Phase 1b: The safety and tolerability of multiple ascending doses of GSBR-1290 (5-90mg) and its effects on body weight (BW) were investigated in 24 HOV over 4 weeks. Phase 2a: The effects of GSBR-1290 on safety, tolerability, HbA1c, glucose, and BW were investigated in 54 participants with T2DM (45 and 90mg) over 12 weeks and in an interim 8-week analysis of 40 HOV (120mg).

Results: Phase 1b: There were no study discontinuations (d/c) due to adverse events (AEs). Most AEs were mild and GI-related, consistent with GLP-1RAs. BW was significantly reduced (up to 4.9% placebo-adjusted, p=0.013) over 4 weeks. Phase 2a T2DM: Two participants d/c from the study due to an AE (1 attributed to study drug: 2.8% d/c rate). Placebo-adjusted HbA1c (45 mg: -1.01%, p=0.008; 90 mg: -1.02%, p=0.001), BW (45 mg: -3.51%, p=0.0019; 90 mg: -3.26%, p=0.0013), and plasma glucose (45 mg: -2.70, p=0.01; 90 mg: -2.50, p=0.0008) were significantly reduced at day 84. Phase 2a Obesity: There were no study d/c due to AEs. Placebo-adjusted BW decreased though day 56 (120 mg: -4.74%; p<0.0001). Complete 12-week results from the cohort of 24 additional participants will be available at presentation. For all phase 2a, AEs were mild-moderate and GI-related, with no SAEs related to GSBR-1290.

Conclusions: GSBR-1290 demonstrated favorable safety and tolerability in this Phase 1b/2a study in participants with T2DM and in HOV. GSBR-1290 demonstrated clinical benefits in lowering BW, blood glucose, and HbA1c. These data provide clinical proof-of-concept of GSBR-1290 and support further clinical development in T2DM and obesity.

Disclosure

B. Coll: Employee; Structure Therapeutics, Inc. J. Zhang: Employee; Structure Therapeutics, Inc. L. Chen: Employee; Structure Therapeutics, Inc. L. Ibarra: Employee; Structure Therapeutics, Inc. H. Yue: Employee; Structure Therapeutics, Inc. A. Barth: Employee; Structure Therapeutics, Inc. M.A. Bach: Employee; Structure Therapeutics, Inc.

Funding

Structure Therapeutics, Inc
77-PUB: Deep Learning–Powered Islet Quantification for Type 1 Diabetes
Authors: KANG SANGHOON , PENALOZA APONTE JESUS D. , MORILLO MICHAEL , ELASHKAR OMAR , WADDINGTON NICHOLAS , LAMB DAMON , JU HUIWEN , CAMPBELL-THOMPSON MARTHA , KIM SARAH
Published: June 2024

Introduction & Objective: Islets in patients with type 1 diabetes (T1D) display a high degree of heterogeneity in sizes, numbers, architecture, endocrine and immune cell type compositions, and capillary density, compared to nondiabetic controls (ND). Extensive whole slide imaging (WSI) data collected through the JDRF Network for Pancreatic Organ donors with Diabetes (nPOD) is an opportunity to analyze T1D progression. We aimed to enhance the efficiency of quantitative WSI analysis using deep learning.

Methods: Multiple computational approaches were explored, including OpenCV, Hover-Net, Segment Anything Model (SAM), and a pixel classifier. We leveraged HiPerGator, UF supercomputer, and QuPath, open-source software widely used for WSI analysis. We tested the developed workflow using 30 WSI data (two slides from the pancreas tail region for five subjects in three disease states: ND, autoantibody+, and T1D).

Results: Among the tested approaches, we selected two deep learning models, SAM and the pixel classifiers implemented in QuPath. SAM was employed to yield precise boundaries of the islets within the Region of Interest (ROI) boxes implemented by the stain classifier. The pixel classifier was further applied to segment the areas corresponding to insulin and glucagon within each islet. We automated counting CD3+ cells detected inside and within 20um outside around the perimeter of the islets. For the testing data, we acquired accurate quantitative measurements for the areas of insulin and glucagon inside islets and the count of CD3+ cells.

Conclusion: With the developed workflow, we enhanced the efficiency of quantifying features of the WSI data. It also assists in defining insulitis more accurately by counting the number of CD3+ cells. We intend to utilize our workflow to extract features from a large set of WSI obtained through the JDRF nPOD program. Analyzing extracted features from WSI will aid in understanding T1D progression.

Disclosure

S. Kang: None. J.D. Penaloza Aponte: None. M. Morillo: None. O. Elashkar: None. N. Waddington: Employee; Pfizer Inc. D. Lamb: None. H. Ju: None. M. Campbell-Thompson: None. S. Kim: None.

Funding

JDRF (3-SRA-2022-1157-S-B)
775-P: Influence of Eating Behavior on Therapeutic Effects of GLP-1 Receptor Agonists over a One-Year Period
Authors: KOIDE YUYA , KATO TAKEHIRO , KUBOTA SODAI , SAKAI MAYU , TAKAHASHI YOSHIHIRO , TAKAO KEN , MIZUNO MASAMI , HIROTA TAKUO , HORIKAWA YUKIO , NISHIMURA KAYOKO , HAYASHI MAKOTO , DAIDO HISASHI , MARUYAMA TAKAKO , KURODA EIJI , YABE DAISUKE
Published: June 2024

To evaluate the relationship of GLP-1RA therapy on HbA1c and body weight with eating behavior, a multicenter, prospective, observational study was conducted in Japanese individuals with T2D who had begun taking GLP-1RAs. The participants received two questionnaires: the Dutch Eating Behavior Questionnaire (DEBQ) and the Food Frequency Questionnaire (FFQg) and received blood tests and anthropometric measurements before and one year after initiation of a GLP-1RA. The DEBQ includes 33 questions regarding External, Emotional, and Restrained eating behaviors, i.e., eating prompted by external stimuli such as the appearance and smell of food, eating prompted by emotions such as anger and anxiety, and eating restrained by considerations for health, for example, respectively. Fifty-seven individuals (age 60.7±13.1 years; duration of diabetes 14.8±14.9 years, and BMI 29.1±5.6) participated in the study. HbA1c, body weight and % body fat were significantly reduced by GLP-1RA treatment overall [HbA1c (%), 8.1±1.5 to 7.0±1.2, p<0.001; body weight (kg), 78.2±19.0 to 74.2±19.7, p<0.001; and % body fat (%), 35.3±7.6 to 32.9±8.7, p<0.001], while muscle mass was not affected [muscle mass (kg), 47.4±11.0 to 47.4±10.9, p=0.929]. Macronutrient intake was significantly decreased in all participants. The DEBQ external eating score (2.95±0.77 to 2.49±0.69, p <0.001) significantly decreased, while the restrained eating score (2.83±0.73 to 3.00±0.76, p =0.133) and the emotional eating score (1.99±0.86 to 1.85±0.66, p=0.516) did not show significant change. In correlation analyses, a higher external eating score was found to be significantly associated with a greater reduction in HbA1c (Pearson's correlation coefficient r= -0.28, p= 0.036) and body weight (r= -0.300, p=0.025). Thus, GLP-1RAs exert a greater therapeutic effect in individuals with diabetes who are prompted to eat by external stimuli such as the appearance and smell of food than by emotional triggers or health considerations.

Disclosure

Y. Koide: None. T. Kato: None. S. Kubota: None. M. Sakai: None. Y. Takahashi: None. K. Takao: None. M. Mizuno: None. T. Hirota: None. Y. Horikawa: None. K. Nishimura: None. M. Hayashi: None. H. Daido: None. T. Maruyama: None. E. Kuroda: None. D. Yabe: Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Kyowa Kirin Co., Ltd. Research Support; Terumo Corporation, Taiho Pharmaceutical Co. Ltd.
780-P: Soli-SWITCH—Efficacy and Safety of Switching to iGlarLixi from Premixed Insulins (PI) in People with Type 2 Diabetes (T2D)
Authors: HALUZIK MARTIN , CYPRYK KATARZYNA , ALVAREZ AGUSTINA , LAUAND FELIPE , CORP DIT GENTI VALERIE , BAKINER OKAN , LIM SOO
Published: June 2024

Introduction & Objective: iGlarLixi, a once-daily injectable fixed-ratio combination of insulin glargine 100 U/mL + lixisenatide, has demonstrated improved glycemic control in people with T2D vs its monocomponents and may be a simplified treatment option vs PI. The Soli-SWITCH study (EudraCT number 2021-003711-25) assessed the efficacy and safety of switching to iGlarLixi in people with T2D currently receiving PI.

Methods: In this phase 4, 24-week, single-arm study, participants switched from PI to iGlarLixi at baseline. Key inclusion criteria: age ≥18 years, diagnosed with T2D, received PI for ≥3 months and <10 years, ± oral antidiabetic drugs; HbA1c ≥7.5% to ≤10.0%. Those who experienced severe hypoglycemia <6 months before screening were excluded. The primary endpoint was change in HbA1c from baseline to Week 24. Key secondary endpoints included the proportion of participants achieving HbA1c <7% at Week 24 and safety.

Results: Overall, 162 participants received iGlarLixi (60% aged ≥65 years; 55% male; 88% PI twice-daily dosing; median duration of diabetes, 16.0 years). Mean PI dose at baseline was 39.5 units (U) (standard deviation [SD] 13.4), mean iGlarLixi dose at Week 24 was 40.6 U (SD 13.3). Mean baseline HbA1c (8.5%) was reduced by 1.2% (SD 0.9%; 95% confidence interval [CI], -1.4, -1.1) at Week 24. At Week 24, 37.6% participants had achieved a HbA1c target of <7% (95% CI: 30.0, 45.7). Median body weight change from baseline to Week 24 was -0.9 kg (95% CI: -1.5, -0.3). Fasting and post-prandial plasma glucose decreased from baseline to Week 24 by 45.6 mg/dL (SD 52.4) and 67.6 mg/dL (SD 65.1), respectively. Confirmed symptomatic hypoglycemia occurred in 38.3% of participants (ADA level 1: 35.8%; ADA level 2: 15.4%; ADA level 3: 0.0%). No new safety signals were observed.

Conclusion: Switching from PI to iGlarLixi offered a simplified treatment option, with improved glycemic outcomes in people with T2D, with added weight benefits and low hypoglycemia risk.

Disclosure

M. Haluzik: Advisory Panel; Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Johnson & Johnson Medical Devices Companies. Consultant; Merck & Co., Inc., Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Johnson & Johnson Medical Devices Companies, Novatin. Research Support; Sanofi. Speaker's Bureau; Sanofi, Novo Nordisk. K. Cypryk: Research Support; Novo Nordisk, Sanofi. Speaker's Bureau; Novo Nordisk, Eli Lilly and Company, Sanofi, Merck & Co., Inc. A. Alvarez: Employee; Sanofi. Stock/Shareholder; Sanofi. F. Lauand: Employee; Sanofi. Stock/Shareholder; Sanofi. V. Corp dit Genti: Employee; Sanofi. O. Bakiner: None. S. Lim: None.

Funding

Sanofi
786-P: Real-Life Effectiveness of iGlarLixi (Insulin Glargine 100 U/ml and Lixisenatide) in People with Type 2 Diabetes (T2D) according to Baseline BMI
Authors: KIS JANOS T. , SEUFERT JOCHEN , HALUZIK MARTIN , VERA CARINE , TOURNAY MATHILDE , BONNEMAIRE MIREILLE , FREEMANTLE NICK , GUJA CRISTIAN
Published: June 2024

The majority of people with T2D are overweight or have obesity. It is important to evaluate the influence of Baseline (BL) BMI on iGlarLixi effectiveness. In the European REALI pooled database, we analyzed patient-level data of 1406 people with uncontrolled T2D initiating iGlarLixi treatment over 24 weeks: 894 (64%) had BL BMI ≥30 kg/m2 and 510 (36%) had BL BMI <30 kg/m2. The overall mean±SD age was 61±9 years. Median T2D duration was 9 years (IQR, 5.0 to 13.0). At BL, mean HbA1c was 9.10% in the BMI ≥30 kg/m2 group and 9.03% in the BMI <30 kg/m2 group. The least-square mean HbA1c change from BL to Week 24 was similar at -1.38% and -1.47%, respectively (Fig 1A). Mean±SD body weight decreased by 2.6±4.9 kg in the BMI ≥30 kg/m2 group and by 0.7±4.4 kg in the BMI <30 kg/m2 group (Fig 1B). The mean iGlarLixi daily dose increased from 0.21 U/kg (20.5 U) at BL to 0.38 U/kg (35.6 U) at Week 24 in the BMI ≥30 kg/m2 group and from 0.23 U/kg (17.7 U) to 0.40 U/kg (30.4 U) in the BMI <30 kg/m2 group. Symptomatic hypoglycemia reports and gastrointestinal side effects were low in both groups. This analysis demonstrated that initiation of iGlarLixi in people with uncontrolled T2D is effective and safe in clinical practice, regardless of Baseline BMI. HbA1c markedly improved in both groups, with a more prominent weight loss in people with obesity.

Disclosure

J.T. Kis: None. J. Seufert: Consultant; Sanofi. Advisory Panel; Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim, Sanofi, Lilly Diabetes. Advisory Panel; Abbott. Speaker's Bureau; Abbott, Novo Nordisk. Advisory Panel; Novo Nordisk. M. Haluzik: Advisory Panel; Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Johnson & Johnson Medical Devices Companies. Consultant; Merck & Co., Inc., Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Johnson & Johnson Medical Devices Companies, Novatin. Research Support; Sanofi. Speaker's Bureau; Sanofi, Novo Nordisk. C. Vera: None. M. Tournay: None. M. Bonnemaire: None. N. Freemantle: Consultant; Sanofi, ALK-Abelló, AstraZeneca, Vertex Pharmaceuticals Incorporated. Other Relationship; ICON. Consultant; Thea. C. Guja: Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Berlin-Chemie AG, Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi, Servier Laboratories, KRKA, Viatris Inc.

Funding

Sanofi
788-P: Synergistic Body Weight Reduction of GLP-1 Analog Ecnoglutide and Amylin Analogs in Preclinical Animal Models
Authors: ZOU HAIXIA , WU XINLE , LI YAN , ZHU RUI , WANG RUIPENG , HAO SUJUAN , LI ZHAOYING , WANG YAXU , DENG JIANHUI , JONES CATHERINE L. , FENAUX MARTIJN
Published: June 2024

Introduction & Objective: Both GLP-1 and amylin are peptide hormones that reduce food intake, delay gastric emptying, and decrease glucagon levels. Combination of GLP-1 and amylin analogs promotes weight loss and glucose control in clinical trials. The objective of this study was to assess the efficacy of GLP-1 analog ecnoglutide (XW003) combined with novel amylin analogs in rodent models.

Methods: Amylin peptides were designed and tested in CHO-K1 CRE reporter cells expressing the amylin receptor complex (human calcitonin receptor and Ramp3) (AMY3) or calcitonin receptor alone (CTR). Combinations of amylin analogs and ecnoglutide were evaluated for body weight reduction in SD rats (single subcutaneous injection) and diet induced obese (DIO) rats (subcutaneously dosed once a day for 21 days). Cagrilintide (Novo Nordisk), an amylin analog in Phase 3 trials, was used as a comparator.

Results: Novel amylin analogs Cmpd A and Cmpd B activated both AMY3 and CTR receptors with similar potencies to cagrilintide. The EC50 values for Cmpd A, Cmpd B, and cagrilintide, respectively in the AMY3 assay were 0.017 nM, 0.028 nM, and 0.041 nM and in the CTR assay were 0.028 nM, 0.046 nM, and 0.042 nM. In SD rats, combination of 3 nmol/kg ecnoglutide and 3 nmol/kg Cmpd A induced synergistic body weight loss at 24 hours post-injection by -7.7%, compared to -1.1% for 3 nmol/kg ecnoglutide and -3.6% for 3 nmol/kg Cmpd A alone. In DIO rats, body weight loss on Day 22 was -19.7% for a combination of 3 nmol/kg ecnoglutide and 3 nmol/kg Cmpd B, compared to -15.4% for 3 nmol/kg ecnoglutide and -1.2% for 3 nmol/kg Cmpd B.

Conclusion: Novel amylin analogs (Cmpd A and Cmpd B) showed similar in vitro activities to cagrilintide. In preclinical animal models, combination of amylin analogs with GLP-1 analog ecnoglutide demonstrated a synergistic effect on body weight reduction.

Disclosure

H. Zou: Employee; Sciwind Biosciences. X. Wu: Employee; Sciwind Biosciences. Y. Li: Employee; Sciwind Biosciences. R. Zhu: Employee; Sciwind Biosciences. R. Wang: Employee; Sciwind Biosciences. S. Hao: Employee; Sciwind Biosciences. Z. Li: Employee; Sciwind Biosciences. Y. Wang: Employee; Sciwind Biosciences. J. Deng: Employee; Sciwind Biosciences. C.L. Jones: Employee; Sciwind Biosciences. M. Fenaux: None.

Funding

Sciwind Biosciences
797-P: Multiomic Comparison of GLP1R Analogues Interaction Networks
Authors: WICIK ZOFIA , NOWAK ANNA , EYILETEN CEREN , POSTULA MAREK
Published: June 2024

GLP1R agonists are drugs increasingly used in clinical practice in patients with type 2 diabetes, and obesity. Subsequent clinical trials indicate their beneficial effects, including cardioprotection, but the exact mechanisms of those actions are still not known. We performed integrative analysis of four GLP1R interaction networks and associated metabolomic and lipidomic datastes. Interactomics revealed 130 common genes among semaglutide, exenatide, tirzapeptide, and retatrutide, primarily associated with diabetes-related processes, including obesity and hyperglycemia. Noteworthy findings encompassed ontological terms related to cardiovascular diseases (CVDs), such as hypertension, calcium regulation in cardiac cells, and amino acid accumulation-induced mTOR activation. Additionally, enrichment in gene sets linked to longevity, less recognized terms like fatty liver disease, chemokine signaling, and sirtuin interactome, were observed.Specific processes for tirzapeptide included behavior-related terms and hydrochloric acid secretion, while retatrutide exhibited associations with fibrosarcoma, thinking and speaking disturbances, and adipogenesis signaling. Shared processes like primary ciliary dyskinesia differed in implicated genes. Metabolomics identified shared metabolites associated with diverse pathways, including galactose metabolism and nitric oxide-related pathways. Lipidomics highlighted enriched phenotypes and pathways, such as arachidonic acid metabolism and cholesterol biosynthesis. Integration of interaction networks with metabolomic and lipidomic data revealed top interactors and impacted metabolites, shedding light on the intricate molecular landscape of GLP1R. These findings contribute valuable insights into the potential therapeutic implications and broader health considerations of GLP1R agonists.

Disclosure

Z. Wicik: None. A. Nowak: None. C. Eyileten: None. M. Postula: None.

Funding

Polish Medical Research Agency (2019/ABM/01/00037)
799-P: Nephroprotective Effects of a Novel Long-Acting GLP-1/GIP/GCG Triple Agonist, HM15275, in Preclinical Models of Acute and Chronic Kidney Diseases
Authors: MYEONG LEE SEON , PARK EUNJIN , KUK KIM JUNG , REYEON KANG HYE , KIM JEONG A. , KIM YOHAN , HONG SUNGHEE , BAE SUNGMIN , HYUN LEE SANG , YOUNG CHOI IN
Published: June 2024

Introduction & Objective: Obesity is associated with the risk of chronic kidney disease (CKD). Recently, potential benefits of incretin drugs on cardio- and renal-related outcomes were demonstrated. The aim of this study is to evaluate whether HM15275, which shows a potent anti-obesity effect with optimized GLP-1/GIP/GCG activity balance, also has a renal protective effect.

Methods: To investigate therapeutic effect on acute kidney injury, unilateral ureteral obstruction (UUO) mice were administered with HM15275, followed by determining the kidney structure and renal fibrosis. In angiotensin II (Ang II) mice, spontaneously hypertensive rats (SHR), and AMLN mice, renal fibrosis and function were determined after 2 ~ 16 weeks treatment. Human primary podocytes and renal proximal tubular epithelial cells (RPTEC) were used for in vitro mechanistic study. Tirzepatide (TZP) was used as comparative control.

Results: UUO-induced increased pro-col1α1 in the kidney was robustly attenuated by HM15275 (-35.3% vs. TZP; p<0.05). In Ang II mice, HM15275 treatment showed significantly less renal dysfunction (BUN, serum creatinine, and uACR). Similarly, elevated levels of renal pro-col1α1 were significantly attenuated by HM15275 (-40.3% vs. TZP; p<0.01). In SHRs, urinary albumin excretion (-76.5% vs. TZP; p<0.01) and uACR (-72.0% vs. TZP; p<0.01) were significantly improved by HM15275 treatment for 16 weeks. Consistently, improvement of gluomerulosclerosis was observed in AMLN mice. In mechanistic study, suppression of stress-induced apoptosis in podocytes and reduced expression of EMT markers in RPTEC well explain how HM15275 could provide renal protection effects in AKI and CKD models.

Conclusion: HM15275 improved renal damage and fibrosis more effectively than TZP. Considering the observation in podocytes and RPTEC, HM15275 might have direct nephroprotective effects in addition to the improvement of metabolic abnormalities.

Disclosure

S. Lee: None. E. Park: None. J. Kim: None. H. Kang: None. J.A. Kim: None. Y. Kim: None. S. Hong: None. S. Bae: None. S. Lee: None. I. Choi: None.
823-P: Molecular and Pharmacological Properties of GZR4, a Once-Weekly Insulin Analog
Authors: XING WANCAI , CHEN WEI , ZHANG YINING , GAO JING , HE ANSHUN , ZHANG JUN , DENG YING , XUE FANGKAI , WANG YONGCHUN , FU HAO , ZHANG RUNYAO , HUANG JINHUI , GAN ZHONGRU
Published: June 2024

Introduction: It was reported that the complex, formed between acylated insulin and human serum albumin (HSA), enters an essentially inactive albumin-bound depot, leading to a dramatically decreased potency.

Objectives: This study was performed to develop a more potent once-weekly insulin analog GZR4 and investigate its molecular and pharmacological properties.

Methods: In vitro assays were employed to characterize the biological attributes of GZR4 through its interactions with HSA and insulin receptor (IR), intracellular signaling, and cellular metabolic responses. In vivo efficacy was evaluated in T1DM STZ treated rats and db/db mice, with Icodec (once-weekly insulin under development) as positive control.

Results: GZR4 was designed by introducing C22 fatty acid to B29 lysine of insulin backbone (A14E, B16H, B25H, desB30 human insulin) through 12×OEG linker. GZR4 displayed 2-fold increase in HSA binding, while 1.5-fold decrease in IR-A binding, 2.5-fold decrease in IR-B binding compared with insulin Icodec. In the presence of HSA, a sandwich binding model showed GZR4 retained IR binding response with 10.2 RU while Icodec essentially displayed no binding, IR phosphorylation activity relative to human insulin was 0.233%±0.012% and 0.034%±0.002% for GZR4 and Icodec respectively. In adipocytes, GZR4 stimulated lipogenesis in a similar dose-dependent manner as human insulin. HbA1c-lowering capability of GZR4 was 3 times higher than that of Icodec in TIDM STZ treated rats and db/db mice.

Conclusions: Current studies demonstrate that the length of the OEG linker between insulin and fatty acid plays an essential role on the potency of the acylated insulins. In the presence of HSA, GZR4 retains partially in vitro bioactivity while Icodec entered an essentially inactive state. Accordingly, GZR4 showed higher in vivo hypoglycemia efficacy than Icodec. Pharmacological evaluation revealed that GZR4 has the potential to be a novel once-weekly basal insulin with lower dosing compared to Icodec.

Disclosure

W. Xing: None. W. Chen: None. Y. Zhang: None. J. Gao: None. A. He: None. J. Zhang: None. Y. Deng: None. F. Xue: None. Y. Wang: None. H. Fu: None. R. Zhang: None. J. Huang: None. Z. Gan: None.
833-P: Understanding Attitudes about Basal Insulin—Insights from a Global Survey of People with Type 2 Diabetes
Authors: HELLER SIMON R. , GOPALAKRISHNAN UNNIKRISHNAN AMBIKA , AKKUS OKTAY , LINJAWI SULTAN , SHAH MANSI J.
Published: June 2024

Introduction & Objective: Basal insulin is recommended as the initial insulin therapy for people with type 2 diabetes (T2D) when glycaemic control cannot be achieved with other glucose-lowering therapies. We aimed to understand the experiences of people with T2D treated with basal insulin, barriers to basal insulin therapy use among those who are insulin naïve, and perceptions of once-weekly insulin.

Methods: A cross-sectional, online survey was conducted from March-April 2023 among adults with T2D in Australia, France, India, Mexico, Saudi Arabia, South Korea, and United Kingdom. Descriptive statistical analyses were performed.

Results: A total of 700 people self-reporting a T2D diagnosis completed the survey (347 basal insulin treated/353 insulin naïve). The burden of managing T2D was higher among insulin treated who were more likely than insulin naïve people with T2D to strongly agree that they were tired of worrying about their T2D (47% vs 34%), worry about having a severe low glucose event (39% vs 27%) and were overwhelmed by both their T2D (36% vs 26%) and the number of all medicines they need to take (41% vs 29%). Only 52% of all people with T2D were satisfied with their current T2D medication; 58% of insulin treated were satisfied with their basal insulin. Although 86% of all people with T2D felt it was important for their T2D to be controlled, only 52% thought it was currently in control. Some people with T2D (31%) forgot to take their basal insulin/T2D medication at least sometimes. When shown a profile of a once-weekly basal insulin, 86% and 65% of insulin treated and insulin naïve people with T2D, respectively, reported being highly likely to use it if recommended by their healthcare provider. People with T2D agreed a once-weekly basal insulin would be convenient to take (73% insulin treated vs 56% insulin naïve) and easy to administer (71% vs 45%).

Conclusion: This survey identified challenges in T2D management and insulin use, some of which may be addressed by once-weekly basal insulin.

Disclosure

S.R. Heller: Research Support; Dexcom, Inc. Speaker's Bureau; Novo Nordisk. Other Relationship; Eli Lilly and Company. Speaker's Bureau; Medtronic. Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Vertex Pharmaceuticals Incorporated. A. Unnikrishnan: Speaker's Bureau; Sanofi. Other Relationship; Novo Nordisk. Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Abbott, Intas Pharmaceuticals Ltd. Research Support; Torrent Pharmaceuticals Ltd. O. Akkus: Employee; Novo Nordisk. S. Linjawi: None. M.J. Shah: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk.

Funding

Novo Nordisk A/S
860-P: Effects of the Combination Treatment with SGLT2 Inhibitors and GLP1 Receptor Agonists among Japanese Patients with Type 2 Diabetes Mellitus and Obesity
Authors: MATSUSHITA TAKAYA , KOBAYASHI KAZUO , KAWANAMI DAIJI , TOYODA MASAO
Published: June 2024

Background: The combination treatment of sodium glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP1Ras) is increasing in clinical practice. We previously reported that the preceding drug did not influence the renal outcomes in patients with this combination treatment, however, the decrease in body weight (BW) was larger in the GLP1Ra-preceding patients compared to the SGLT2i-preceding patients. In this post-hoc study, we analyzed the difference in the effect by the combination treatment on clinical findings depending on the presence or absence of obesity.

Method: A retrospective study was conducted in 643 patients who were treated with both SGLT2i and GLP1Ra. Patients were divided into two groups; 373 patients with body mass index (BMI) of <30 and 270 patients with BMI≥30.The comparison between two groups was performed by propensity score inverse probability weighting method using a generalized linear model.

Results: After the combination treatment, significant larger decrease in BMI was observed in patient with BMI≥30 compared to those with BMI<30 (1.0[95% confidence interval (CI), 0.5,1.6, p<0.001]. There were no significant differences of the change in hemoglobin A1c, mean arterial pressure, and alanine aminotransferase, however, the achievement rate for the target of <130/80 mmHg tended to low in patients with BMI≥30 compared to those with BMI<30, with odds ratio of 0.74 [95%CI, 0.50, 1.11, p=0.15].

Conclusion: After the combination treatment of SGLT2i and GLP1Ra, greater BW loss was observed in obese patients, however non-obese patients might be more advantageous in blood pressure control.

Disclosure

T. Matsushita: None. K. Kobayashi: None. D. Kawanami: None. M. Toyoda: None.
870-P: Long-Term Efficacy and Safety of Crisugabalin Besilate in Chinese patients with Diabetic Peripheral Neuropathic Pain
Authors: ZHANG TINGTING , GUO XIAOHUI , LI HONGMEI , MA JIANHUA , YUKUN LI , JIANG CHENGXIA , LIU JIE
Published: June 2024

Introduction & Objective: Chronic diabetic peripheral neuropathic pain (DPNP) exerts serious adverse effects on patients' emotions and quality of life. Crisugabalin has shown favorable efficacy and safety in a phase II/III study in Chinese patients with DPNP. In this open-label extension study, we further evaluated the long-term safety and efficacy of Crisugabalin Besilate.

Methods: A total of 301 patients with DPNP from the previous phase II/III trial were enrolled in this 52-week open-label study. Patients received Crisugabalin Besilate capsule 40mg twice daily. Pain intensity was measured with Short-Form McGill Pain Questionnaire (SF-MPQ), including Pain Rating Index (PRI), Visual Analogue Scale (VAS), and Present Pain Intensity (PPI).

Results: All the efficacy indicators of SF-MPQ showed continuous decrease throughout the trial, and the scores at week 52 were significantly different compared with baseline. The mean changes in PRI and VAS from baseline at week 52 were -2.5±3.97 and -23.4±19.38, respectively, and that the proportion of subjects with PPI ≤ 1 increased by 19% from baseline. 86.4% subjects experienced a total of 1095 Treatment Emergent Adverse Events (TEAEs) during the study, including 203 drug-related TEAEs with the incidence of 38.9%. The most common drug-related TEAEs were dizziness (27.2%) and somnolence (8.3%), and the majority were mild to moderate. The incidence of TEAEs leading to dose reduction was 14.3%.

Conclusions: Long-term treatment with Crisugabalin Besilate is effective and safe for pain relief in Chinese patients with DPNP.

Disclosure

T. Zhang: None. X. Guo: None. H. Li: None. J. Ma: None. L. Yukun: None. C. Jiang: None. J. Liu: None.

Funding

Haisco Pharmaceutical Group, Sichuan, China
879-P: The Effects of the Combination of Dorzagliatin and Canagliflozin on Glucose Homeostasis in Mice
Authors: HAN DONGNA , ZHANG TINGTING , MENG SHI , CHEN LI , LI CHANGHONG
Published: June 2024

Dorzagliatin is a newly approved glucokinase activator for treatment of type 2 diabetes. The mechanisms include improved GLP-1 secretion, restoration of islet function and increased insulin sensitivity in the liver. Canagliflozin is an SGLT2 inhibitor. To establish basis for clinical combination therapy, this study aims to assess the effects of combining these two drugs on the regulation of glucose homeostasis in mice. In single dose studies, wild-type mice were given either dorzagliatin (30 mg/Kg), canagliflozin (30 mg/Kg) or a combination of both. Then each group followed by a glucose challenge. Mice were also daily given either dorzagliatin (15 mg/Kg), canagliflozin (30 mg/Kg) or a combination for 5 days. Glucose and hormone levels were measured at random time, after overnight fasting, and 3 hours refeeding. Canagliflozin reduced glucose levels and enhanced glucose tolerance without affecting hormone secretion. In contrast, dorzagliatin exhibited comparable glucose-lowering effects by elevating insulin and GLP-1 secretion, with unaltered glucagon secretion. The combined medications enhanced glucose tolerance by augmenting the secretion of insulin, glucagon, and GLP-1. Canagliflozin, when used in combination with dorzagliatin, resulted in an amplification of glucagon secretion following a glucose challenge. Following 5 days of treatments, dorzagliatin demonstrated superior results in reducing glucose levels at random and 3 hours refeeding time points by increasing insulin and GLP-1 release. On the other hand, canagliflozin was more effective in lowering fasting glucose levels. When the two medicines were combined, glucose levels reduced at all time points, while the stimulatory effects of dorzagliatin on insulin and GLP-1 were maintained. This study has verified that GKA and SGLT2i reduce glucose levels through distinct mechanisms. GKA achieves this by enhancing the secretion of insulin and GLP-1. Both mechanisms of action are preserved when two drugs are combined.

Disclosure

D. Han: Employee; Nanjing Ascendrare Pharmaceutical Technology. T. Zhang: None. S. Meng: Employee; Nanjing Ascendrare Pharmaceutical Technology. L. Chen: None. C. Li: Employee; Hua Medicine (Shanghai) LTD., Nanjing AscendRare Pharmaceutical Technology.

Funding

National Natural Science Foundation of China (82070802)
898-P: AAV-FGF21 Gene Therapy Extends Healthspan in Old Mice
Authors: JIMENEZ VERONICA , SACRISTAN VICTOR , GARCIA MIQUEL , JAMBRINA CLAUDIA , CASANA ESTEFANIA , MUÑOZ SERGIO A. , LEON XAVIER , RIBERA ALBERT , ELIAS IVET , FERRE TURA , BOSCH FATIMA
Published: June 2024

Introduction & Objective: Aging is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. This deteriorative process is also accompanied by major changes in body composition that lead to an increase in body weight and insulin resistance. As population ages, obesity, diabetes and dementia are three related conditions that are increasing in prevalence and share common pathways. We have previously shown that intramuscular (IM) administration of AAV1 vectors encoding FGF21 (AAV1-FGF21) in young healthy mice prevented the increase in body weight gain, adiposity and insulin resistance associated with aging.

Methods: AAV vectors with high tropism for skeletal muscle carrying a murine FGF21 coding sequence (AAV-FGF21) were administered into the quadriceps, gastrocnemius, and tibialis cranialis muscles of each hind limb of 1-year-old C57Bl6 mice.

Results: IM administration of AAV1-FGF21 in aged mice mediated long-lasting increase in FGF21 circulating levels, which extended health and life span and reverted age-related insulin resistance, body weight gain, and neuromuscular and cognitive decline. Moreover, this treatment also modulated gene expression in major relevant metabolic organs as well as in the brain.

Conclusion: These results underscore the potential of FGF21 gene therapy to promote healthy aging. Moreover, all these results further highlight the safety of the skeletal muscle-directed AAV1-FGF21 gene therapy.

Disclosure

V. Jimenez: None. V. Sacristan: None. M. Garcia: None. C. Jambrina: None. E. Casana: None. S.A. Muñoz: None. X. Leon: None. A. Ribera: None. I. Elias: None. T. Ferre: None. F. Bosch: None.
903-P: Glycemic Control Enhancement with Imeglimin in Type 2 Diabetes Mellitus
Authors: GUPTA ABHINAV , DUGGAL RANJANA
Published: June 2024

Imeglimin is a first-in-class oral hypoglycemic agent used for the treatment of T2DM and targets mitochondrial bioenergetics to ameliorate insulin resistance and enhance β-cell function. It has also been shown to improve glycemic control when added to metformin or sitagliptin monotherapy in T2DM inadequately controlled with these drugs alone. We conducted a real World observational study (n=115) for 1 year follow up for the patients in whom Imeglimin was used as a third line agent (GLYCEM-IN Trial). The mean FPG at baseline was 280.8 mg/dl (±61.5, 95% CI 268.6 to 293.1) which reduced to 176.2 mg/dl (±64.9, 95% CI 163.3 to 189), significant reduction by -104.7 mg/dl (p<0.0001). The mean PPG at baseline was 326.4 mg/dl (±64.7, 95% CI 313.6 to 339.2) which reduced to 209.3 mg/dl (±75.3, 95% CI 194.3 to 224.3), significant reduction by -117.7 mg/dl (p<0.0001). The mean HbA1c at baseline was 8.7% (±0.86, 95% CI 8.5 to 8.8) which reduced to 8.2% (±0.77, 95% CI 8.1 to 8.4), significant reduction by -0.45 (p<0.0001). The mean PPG at baseline was 1.1 mg/dl (±0.15, 95% CI 0.14 to 1.13) which reduced to 0.7 mg/dl (±0.1, 95% CI 0.68 to 0.72), significant reduction by -0.39 mg/dl (p<0.0001). Imeglimin demonstrated significant efficacy as a third line treatment for T2DM. It notably decreased mean fasting plasma glucose by 104.7 mg/dl and postprandial glucose by 117.7 mg/dl. HbA1c levels showed a meaningful reduction of 0.45%. These results suggest that Imeglimin effectively enhances glycemic control in T2DM patients inadequately managed with other monotherapies.

Disclosure

A. Gupta: None. R. Duggal: None.