bluuebunny/crossref_metadata_2025_split huggingface dataset:
793-P: Biased GLP-1 Analog Ecnoglutide (XW003) Has Improved Efficacy Relative to Unbiased Peptides
Authors: WANJUN GUO , ZOU HAIXIA , ZHU ZHIYI , LI YAO , NING JING , ZHENG QING , LI YAN , ZHU RUI , JONES CATHERINE L. , FENAUX MARTIJN , XU SUSAN , JUNAIDI MOHAMMED K. 
Published: June 2024

Introduction & Objective: Ecnoglutide (XW003) is a cAMP-biased GLP-1 analog being developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. The objective of this analysis was to compare the preclinical and clinical efficacy of ecnoglutide to unbiased GLP-1 peptides.
Methods: Ecnoglutide was assessed for cAMP production and β-arrestin recruitment in GLP-1R reporter cell lines. Glucose control was tested in db/db mice administered a single subcutaneous dose of GLP-1 analogs, with blood glucose recorded for 144 h. Body weight and insulin response were evaluated in db/db mice dosed with once daily injections of GLP-1 analogs for 42 days. A 20 week Phase 2 study was conducted in 145 patients with T2DM (ecnoglutide 0.4, 0.8, or 1.2 mg). Comparator clinical results were obtained from published reports.
Results: In vitro, cAMP induction was similar for ecnoglutide and semaglutide. EC50 values for β-arrestin recruitment were also similar, however, maximum recruitment and receptor internalization were lower for ecnoglutide. In mice, a single dose of ecnoglutide led to more sustainable decreases in blood glucose compared to semaglutide, extending glucose suppression by up to 48 h. In mice, ecnoglutide also significantly improved weight control and induced higher levels of insulin versus semaglutide. The increased preclinical potency of ecnoglutide translated into clinical efficacy. T2DM patients administered up to 1.2 mg ecnoglutide for 20 weeks had a -2.39% reduction in HbA1c. This compared to -1.14% reported for liraglutide (1.8 mg at 52 weeks), -1.55% to -1.86% for semaglutide (1.0 mg at 30-40 weeks), and -1.46% for dulaglutide (1.5 mg at 26 weeks). Furthermore, 1.2 mg ecnoglutide showed comparable HbA1c reductions to the biased dual GIP/GLP-1 receptor agonist, tirzepatide (15 mg), which reduced HbA1c by -2.30% at 40 weeks.
Conclusion: Bias for the cAMP pathway results in sustained signaling that correlates with increased clinical efficacy compared to unbiased GLP-1 analogs.

Disclosure
G. Wanjun: Employee; Sciwind Biosciences. H. Zou: Employee; Sciwind Biosciences. Z. Zhu: None. Y. Li: Employee; Sciwind Biosciences. J. Ning: None. Q. Zheng: Employee; Sciwind Biosciences. Y. Li: Employee; Sciwind Biosciences. R. Zhu: Employee; Sciwind Biosciences. C.L. Jones: Employee; Sciwind Biosciences. M. Fenaux: None. S. Xu: None. M.K. Junaidi: None.

Funding
Sciwind Biosciences
819-P: A Novel Premix Insulin GZR101 for Diabetes Management
Authors: CHEN WEI , XING WANCAI , ZHANG YINING , HE ANSHUN , GAO JING , SHI QIMIN , XUE FANGKAI , WANG YONGCHUN , ZHANG JUN , YU DONGLI , CUI CHENG , XIE TIAN , GAN ZHONGRU 
Published: June 2024

Introduction: Inadequate glycemic control in patients with premix insulin regimen is often due to the short half-life and pronounced peak-to-trough ratio of basal insulin. This necessitates the development of a premix insulin containing basal insulins with an extended half-life and steady pharmacokinetic (PK) profile.
Objective: This study evaluated and characterized GZR33, an ultra-long half-life basal insulin, and GZR101 which is composed by GZR33 and insulin aspart.
Methods: The binding affinity of GZR33 to the human insulin receptor (hIR) was analyzed in vitro using surface plasmon resonance. IR activation was examined in CHO cells in the presence and absence of human serum albumin (HSA). Adipogenesis was measured in 3T3L1 MBX cells. Potency was tested in vivo in streptozotocin-induced T1DM rats and db/db T2DM mice, using insulin degludec (iDeg) and iDegAsp as controls. PK studies were assessed in Sprague-Dawley rats.
Results: GZR33 was constructed by linking a C22 fatty diacid side chain to desB30 human insulin via a 6×OEG linker. GZR33 exhibited strong hIRA and hIRB binding (dissociation constants: 2.86E-6 M and 1.28E-6 M). It activated IRA and IRB with EC50 of 370.13 ± 94.86 nM and 477.48 ± 64.28 nM, respectively, in 0.5% HSA, and induced adipogenesis with an EC50 of 2.45 ± 0.81 nM. PK studies showed a dose-dependent increase in maximum concentration and exposure, with a T½ of 5.45 h for GZR33 (2.3 h for iDeg). In T1DM rats and T2DM mice, GZR33 outperformed iDeg in reducing HbA1c and FBG, demonstrating a potency at least three-fold higher than iDeg. Additionally, GZR101's glucose-lowering effect was proportional to the GZR33 dosage in diabetic models.
Conclusion: Traditional basal insulins display a 24-hour glucose-lowering effect with noticeable peaks, leading to fluctuating blood glucose in patients. However, a basal insulin with over 3-day longevity and once-daily dosing, like GZR33, can achieve a nearly peak-less PK profile at steady-state. Consequently, GZR101 emerges as a promising once-daily premix insulin candidate.

Disclosure
W. Chen: None. W. Xing: None. Y. Zhang: None. A. He: None. J. Gao: None. Q. Shi: None. F. Xue: None. Y. Wang: None. J. Zhang: None. D. Yu: None. C. Cui: None. T. Xie: None. Z. Gan: None.
822-P: Influence of the Functionally Selective Insulin Analog NNC-965 vs. Insulin Glargine (IGla) on Cardiac Structure and Function
Authors: JORDAN JENS , GERLACH DARIUS , HARALDSSON HENRIK , HEISE TIM , HERBRAND THERESA , LYBY KARSTEN , TANK JENS , NISHIMURA ERICA , PLUM-MOERSCHEL LEONA , THÓRISDÓTTIR ÓLÖF , JOHANSSON LARS 
Published: June 2024

NNC-965 selectively stimulates insulin receptors with greater Akt and less MAPK activation, which improved vascular function, insulin sensitivity (IS), and weight gain versus conventional basal insulin in diabetic rats. We hypothesized that improved vascular function on NNC-965 unloads the heart thereby improving left ventricular (LV) structure and function. We compared the effects of NNC-965 and IGla on flow-mediated dilation (FMD), IS, body weight, vascular function and cardiac function/structure (assessed by MRI) in 86 people with type 2 diabetes on basal insulin ± oral agents in a randomized, double-blind study over 26 weeks. NNC-965 improved FMD and IS versus IGla (table). Glycemic control and liver fat responded similarly to both insulins, but body weight and fat mass increased more with NNC-965. LV ejection fraction and LV stroke volume slightly decreased with NNC-965 and increased with IGla, but the differences were not significant. We observed no clinically relevant changes in LV mass, LV enddiastolic and endsystolic volume by either treatment.
In conclusion, NNC-965 showed some characteristics of a functionally selective insulin but increased body weight. The observed improvement in FMD might lead to long-term reductions in cardiovascular risk; however, studies with longer treatment duration may be needed to assess effects on cardiac function and structure.

Disclosure
J. Jordan: Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. Speaker's Bureau; Menarini. Advisory Panel; Theravance. Stock/Shareholder; Eternygen. D. Gerlach: None. H. Haraldsson: Employee; Antaros Medical. T. Heise: Research Support; ADOCIA, AstraZeneca, Biocon, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Genova, Novo Nordisk A/S. Consultant; Gan&Lee Pharmaceuticals. Speaker's Bureau; Eli Lilly and Company. Research Support; Altimmune Inc., Sanofi, Zealand Pharma A/S, BIOTON, Civica Foundation, Enyo Pharma, Gan&Lee Pharmaceuticals, Nanexa AB, SamChunDang Pharm. Co. T. Herbrand: None. K. Lyby: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. J. Tank: None. E. Nishimura: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. L. Plum-Moerschel: Other Relationship; Novo Nordisk A/S, Eli Lilly and Company, Zealand Pharma A/S, Betagenon, Nanexa, Neodyne, Biocon, Spiden, BIOTON, Gan & Lee Pharmaceuticals. Ó. Thórisdóttir: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. L. Johansson: Stock/Shareholder; Antaros Medical. Employee; Antaros Medical.
825-P: Evaluation of the Pharmacokinetic Profile of Insulin Efsitora Alfa (Efsitora) Administered Subcutaneously at Different Injection Sites
Authors: LEOHR JENNIFER , SURIYAPPERUMA SUBHA , GHOSH ARITRA , WATERS DAVID G. , FUKUDA TSUYOSHI 
Published: June 2024

Purpose: Efsitora is an insulin receptor agonist designed for once-weekly administration. Injection region preference varies among people with diabetes. This study compared the pharmacokinetic profile of efsitora when administered subcutaneously (SC) into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability.
Method: This was a single-center, 2-part, randomized study conducted in healthy participants. Part A was a parallel design to assess the relative bioavailability of efsitora following a single 100U dose administered SC into the upper arm or thigh, compared to the abdominal wall (N=153). Part B was a 2 period, crossover design to determine the absolute bioavailability of efsitora following a single 100U dose administered SC into the abdominal wall compared to a 44U IV administration (N=10). Blood was sampled for pharmacokinetics for 65 days (~9 weeks) post-dose.
Results: All 90% CIs for the ratios of total efsitora exposure or maximum efsitora concentration of the thigh or upper arm, vs abdomen were contained within 0.80 and 1.25. The absolute bioavailability was 86% into the abdominal wall. Efsitora was well tolerated after single SC injections and IV bolus administration.
Conclusion: Efsitora can be injected SC into the abdomen, upper arm, or thigh, without a change in exposure.

Disclosure
J. Leohr: None. S. Suriyapperuma: Employee; Eli Lilly and Company. A. Ghosh: None. D.G. Waters: Employee; Eli Lilly and Company. T. Fukuda: Employee; Eli Lilly and Company.
828-P: Glycemic Outcomes with Rapid Insulin vs. Ultrarapid Insulin in Omnipod 5 (OP5)
Authors: MAHER MONIQUE , SAKAMOTO CASEY , COBRY ERIN C. 
Published: June 2024

Ultrarapid insulins (Lyumjev, Fiasp) are designed to reduce post-prandial excursions and may be beneficial in automated pumps. There is no published data on ultrarapid insulins in the OP5 system. We evaluated glycemic and behavioral measures after switching to ultrarapid insulin.
Data was reviewed retrospectively from people with T1D on OP5 with minimum 3 months rapid insulin prior to switching to ultrarapid. Glycemic measures included A1c, TIR, TBR, TAR, SD, CoV. Surrogates for bolus behavior were override frequency and boluses/day. Linear mixed models were used. Qualitative reports from clinical documents were reviewed.
Of 40 youth and young adults (mean age 12.6 yrs, 46% female, mean T1D duration 5.4 yrs, mean A1c 7.0±0.2%), 13 were using Fiasp and 27 were using Lyumjev. No statistical significances were seen in TIR, TBR, TAR, SD, CoV, A1c, and boluses/day. GMI was higher with Lyumjev and overall. Override frequency was less in Lyumjev and overall. Review of 15 clinical reports showed positive experiences after switching, with less perceived postprandial excursions.
Clinically significant glycemic differences were not seen with ultrarapid insulin with OP5, suggesting that these insulins are interchangeable in an automated system. However, satisfaction and bolus overrides improved with ultrarapid insulin. A larger sample size and meal-specific measures are needed to connect patient experience with glycemic outcomes.

Disclosure
M. Maher: None. C. Sakamoto: None. E.C. Cobry: Advisory Panel; Dexcom, Inc. Other Relationship; Dexcom, Inc.
878-P: Effect of Finerenone on Resistant Hypertension in Type 2 Diabetes Mellitus—A Randomized Controlled Trial in Indian Population
Authors: GADVE SHARVIL S. , GADVE SNEHA S. , GADVE SHRIYA , CHAVANDA KETKI S. , HANAMSHETTI SATISH 
Published: June 2024

Background: Mineralocorticoid Receptor Antagonists are effective for resistant hypertension. However data of effect of finerenone, a novel non-steroidal mineralocorticoid receptor anatagonist in Indian patients with T2DM & resistant hypertension is limited. We assessed the efficacy of finerenone in these subjects.
Research Design & Methods: This was a 16-week randomized controlled trial in 84 subjects presenting with resistant hypertension in specialized diabetes care unit in India. They were randomly assigned to treatment with a daily 10 mg of finerenone (n = 42) or to an alternative antihypertensive regimen (n = 42), on top of any ongoing regimen and prevailing lifestyle prescriptions. Finerenone dose was increased to 20 mg daily after 4 weeks after assessment of potassium level. All subjects were seen at 0 weeks, 2 weeks, 4 weeks and then once every 4 weeks. The primary outcome was change in office blood pressure (BP) during follow-up, and secondary outcomes were changes in serum potassium, sodium, & creatinine levels.
Results: Finerenone was associated with significant decrease in office systolic BP (-22 vs. -12 mmHg; p = 0.016), and in diastolic BP (-12 vs. -4 mmHg; p = 0.006). After 2 month, 78% patients in finerenone arm & 46% in alternative arm were controlled (BP &lt; 130/80 mmHg), with significant office BP reduction from 154 ± 16/89 ± 11 to 129 ± 10/79 ± 8, vs. 156 ± 8/88 ± 8 to 142 ± 12/81 ± 10 mmHg in the alternative group. After 4 months an additional 6 % patients in finerenone arm & 5 % patients in alternative arm were controlled with further intensive lifestyle intervention.There was no significant variation in potassium, sodium & creatinine levels in both groups. Hyperkalemia was seen in 2 patients in each arm and could be managed without much concern.
Conclusion: Finerenone was effective in reducing BP to optimal levels in T2DM Indian patients with resistant hypertension & well tolerated and no significant concern of change in potassium level.

Disclosure
S.S. Gadve: None. S.S. Gadve: None. S. Gadve: None. K.S. Chavanda: None. S. Hanamshetti: None.
88-OR: Glucose Regulation of Adipose Tissue Browning by CBP/p300 and HDAC3-Mediated Reversible Acetylation of CREBZF
Authors: CUI AOYUAN , SU WEITONG , LIN JING , DING DONG , JIANG YANG , ZHENG ZENGPENG , HUANG MENGYAO , CAI GENXIANG , WEI SHUANG , LI WENJING , SHEN JIAXIN , FANG XIA , WEN JIAN , HUO YANLING , WEI XIAOYI , LI LIANJIA , LIU ZHAN , QIAN KEYU , ZHAO JIUXIANG , LI YU 
Published: June 2024

Glucose uptake is highly induced under cold exposure in adipose tissue, and glucose is required for generating heat during cold-induced nonshivering thermogenesis. However, the regulatory mechanism is largely unknown. Here, we uncovered a glucose sensor, a novel metabolic regulator CREBZF, that mediates the regulatory effects of glucose on browning of adipose tissue. In human white adipose tissue and inguinal white adipose tissue (iWAT) in mice, expression levels of CREBZF were remarkably induced by glucose. Glucose administration induces rectal temperature and thermogenesis in white adipose of control mice. Interestingly, these effects are further potentiated by CREBZF deficiency in adipose tissue. Consistently, during cold exposure, adipose tissue-specific CREBZF knockout mice display enhanced thermogenic gene expression, browning of iWAT and adaptive thermogenesis. Mechanistically, Lys208 acetylation modulated by transacetylase CREB-binding protein (CBP)/p300 mediates the glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Moreover, deacetylase HDAC3 interacts with and removes the acetylation modification of CREBZF. The induced CREBZF by glucose further associates with PGC-1α and represses its transcriptional activity on thermogenic gene expression. Importantly, expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic condition. Our results reveal an unknown mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.

Disclosure
A. Cui: None. W. Su: None. J. Lin: None. D. Ding: None. Y. Jiang: None. Z. Zheng: None. M. Huang: None. G. Cai: None. S. Wei: None. W. Li: None. J. Shen: None. X. Fang: None. J. Wen: None. Y. Huo: None. X. Wei: None. L. Li: None. Z. Liu: None. K. Qian: None. J. Zhao: None. Y. Li: None.

Funding
National Key R&D Program of China (2019YFA0802502), National Natural Science Foundation of China (81925008), Shanghai Science and Technology Commission (19140903300)
929-P: A Study to Evaluate Clinical and Metabolic Profile of Type 2 Diabetes Patients Receiving SGLT2 Inhibitors
Authors: KANDULA SRINIVAS , MESHRAM MINAL A. , SONWANE ANAND C. ,   ESQ.
Published: June 2024

Aim: The aim of the study was to determine the efficacy of SGLT2i and its impact on metabolic profile of type 2 diabetes (T2DM) patients with reference to serum glucagon and blood ketones.
Methodology: The study was conducted in T2DM patients with inadequate glycemic control on a background therapy of either metformin and sulphonylurea (Group A) or metformin and DPP4 inhibitor(Group B) Blood samples were taken for estimation of fasting plasma glucose (FPG), post prandial plasma glucose (PPPG), HbA1c, beta-hydroxybutyrate (β-HB) and glucagon levels. Empagliflozin 10mg, was added to the existing anti-diabetic medication. The metabolic parameters were reassessed after 12 weeks.
Results: At the end of 12 weeks glucagon levels increased significantly (28.8 ± 28.74 at baseline vs 108 ± 74 pg/ml; p&lt;0.001). A significant increase in β-HB levels was also observed (0.1 ± 0.07 mmol/L at baseline versus 0.12 ± 0.07 mmol/L (p=0.03). FPG, PPPG and HbA1c decreased significantly by 30.33mg%, 53.16mg% and 1.05% respectively(p&lt;0.01) In group A, FPG and PPPG decreased by 34.43 mg/dl and 51.71mg/dl respectively (p&lt;0.001) with a mean HbA1c reduction of 1.09% (p&lt;0.001) Serum glucagon and β-HB levels increased significantly [82.63 pg/ml (p&lt;0.001) and 0.04 mmol/L (p&lt;0.01) respectively]. In group B, there was decrease in FPG (mean difference 23.6mg %; p=0.003) and PPPG (mean difference 55.5mg%; p&lt;0.001) at 12 weeks. HbA1c reduction of 0.99% was observed. (p=0.003) There was a significant increase in glucagon levels (mean difference +73.52 pg/ml; p&lt;0.001).
Conclusion: Addition of Empagliflozin to T2DM patients with inadequate glycemic control on either metformin and sulphonylurea or metformin and DPP4 inhibitors significantly improved efficacy. Plasma glucagon and β-HB levels increased with chronic empagliflozin treatment suggesting a change in substrate utilization towards fat.

Disclosure
S. Kandula: None. M.A. Meshram: None. A.C. Sonwane: None.
936-P: Effects of SGLT2i and Pioglitazone on FIB-4 Index in Patients with Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD)—A Real World Retrospective Study from India
Authors: PADHYE DAKSHATA , SESHADRI KRISHNA 
Published: June 2024

In this retrospective study of 279 type 2 diabetes mellitus (T2DM) patients with metabolic dysfunction-associated steatotic liver disease (MASLD) in India, the clinical effectiveness of pioglitazone and sodium-glucose co-transporter 2 inhibitors (SGLT2i) was investigated. The primary endpoint, assessed at a one-year follow-up, focused on changes in fibrosis (FIB-4) index and the aspartate aminotransferase to platelet ratio index (APRI score). Of the 276 patients analyzed, 50% were on SGLT2i treatment, with 46% at low risk and 11% at high risk of advanced fibrosis. Of the total (276) patients, 46% of patients were at low risk of advanced fibrosis and 11% were at high risk for advanced fibrosis and majority (50%) were on SGLT2i treatment. At follow up there is a statistically significant reduction in the mean (SD) FIB-4 index (1.92 (1.22) vs. 1.68 (0.99)) and APRI score (0.42 (0.34) vs. 0.33 (0.21)); p &lt;0.001. Among treatment-groups, there is a significant difference in the mean FIB-4 index both at baseline (F: 4.23; p &lt;0.05) and follow up (F: 3.45; p &lt;0.05); mean APRI score, the significance was observed only at baseline (F: 2.84; p &lt;0.05). Importantly in all the treatment groups, there is a clinically significant improvement in FIB-4 index and APRI score. These findings suggest that the combination therapy may be beneficial in managing MASLD, particularly in reducing fibrosis indices in T2DM patients in the Indian population

Disclosure
D. Padhye: None. K. Seshadri: None.
940-P: Efficacy and Safety of Enavogliflozin vs. Dapagliflozin as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Based on Renal Function—A Pooled Analysis of Two Randomized Controlled Trials
Authors: SANG LYU YOUNG , MO HONG SANG , LEE SIEUN , CHO BOYOUNG , PARK CHEOL-YOUNG 
Published: June 2024

Introduction & Objective: We assessed the efficacy and safety of enavogliflozin 0.3 mg, a newly developed SGLT-2 inhibitor, in patients with type 2 diabetes mellitus based on kidney function via pooled analysis of two 24-week, randomized, double-blind phase III trials.
Methods: Data from 470 patients were included (enavogliflozin: 0.3 mg/day, n = 235; dapagliflozin: 10 mg/day, n = 235). The subjects were classified by mildly reduced (60 ≤ eGFR &lt; 90mL/min/1.73 m², n = 247) or normal eGFR (≥ 90 mL/min/1.73 m², n = 223).
Results: In the mildly reduced eGFR group, enavogliflozin significantly reduced adjusted mean change of HbA1c and fasting plasma glucose levels at week 24 compared to dapagliflozin (−0.94% vs. −0.77%, P = 0.0196). Enavogliflozin showed potent blood glucose-lowering effects regardless of renal function (HbA1c: -0.84% and -0.96% in the normal and mildly reduced eGFR groups, respectively, P = 0.0744). Conversely, dapagliflozin significantly decreased the glucose-lowering efficacy as the renal function decreased (HbA1c: -0.95% and -0.80% in the normal and mildly reduced eGFR group, respectively, P = 0.0488). Enavogliflozin 0.3 mg induced a higher urinary glucose excretion rate in both groups. The enavogliflozin group showed a significant decrease in the insulin resistance homeostatic model. No significant differences in blood pressure, weight loss, or HOMA-β values were observed between enavogliflozin and dapagliflozin. Adverse events were similar between drugs.
Conclusions: This analysis suggests the superior glucose-lowering efficacy of enavogliflozin over dapagliflozin in patients with type 2 diabetes mellitus with mild renal function impairment, attributed to its potent urinary glucose excretion.

Disclosure
Y. Lyu: None. S. Hong: None. S. Lee: None. B. Cho: None. C. Park: None.