bluuebunny/crossref_metadata_2025_split huggingface dataset:
786-P: Effects of Switching from Liraglutide or Dulaglutide to Subcutaneous Semaglutide on Metabolic Parameters in Older People with Type 2 Diabetes Mellitus—SWITCH-SEMA1 Subgroup Analysis
Authors: TAKAHASHI YUKA , NOMOTO HIROSHI , YOKOYAMA HIROKI , MIYA AIKA , MIYAZAKI ASUKA , KAMEDA HIRAKU , ATSUMI TATSUYA , NAKAMURA AKINOBU , MIYOSHI HIDEAKI 
Published: June 2023

Background: Once-weekly treatment with the subcutaneous glucagon-like receptor-1 receptor agonist (GLP-1RA) semaglutide has been reported to have potent beneficial effects on metabolic abnormalities. However, little is known about the usefulness of switching from other GLP-1RAs to semaglutide, especially in older people with type 2 diabetes.
Methods: This study is a subgroup analysis of the SWITCH-SEMA1 study, a multicenter, prospective, open-label, parallel-group, randomized controlled study in which people with type 2 diabetes continued liraglutide or dulaglutide therapy or switched to semaglutide for 24 weeks (jRCTs1011200008). One hundred people enrolled in this study were divided into two groups: an aged group consisting of people 65 years or older (n = 49; 72.8 ± 4.4 years old) and a non-aged group (n = 51; 51.2 ± 6.8 years old). The changes of metabolic parameters between the two treatment arms (continuation vs switching to semaglutide) were compared between an aged and a non-aged group.
Results: At baseline, BMI, fatty liver index (FLI), C-peptide index (CPI), HOMA2-β, HOMA2-R, eGFR, and triglyceride levels were significantly lower in the aged group (all P &lt; 0.05). After 24 weeks, switching to semaglutide significantly ameliorated HbA1c in both groups (aged: −0.7%, P&lt;0.001; non-aged: −0.7%, P &lt; 0.01). In the aged group, FLI; CPI; HOMA2-β; AST, γ-GTP, and uric acid (UA) levels; and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) score significantly improved after switching to semaglutide (all P &lt; 0.05). The magnitude of changes in BMI and UA levels after switching to semaglutide was greater in the aged group than in the non-aged group (BMI: −1.1 vs. −0.5 kg/m2, P &lt; 0.01; UA: −0.4 vs. −0.1 mg/dL, P &lt;0.05).
Conclusions: The effects on metabolic parameters of switching from other GLP-1RAs to once-weekly semaglutide might be greater in aged people than in non-aged people.

Disclosure
Y.Takahashi: None. H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. H.Yokoyama: None. A.Miya: None. A.Miyazaki: None. H.Kameda: None. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. H.Miyoshi: Research Support; Abbott, LifeScan Diabetes Institute, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Kowa Company, Ltd., MSD Life Science Foundation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation.
787-P: Glucose and Weight Outcomes Associated with Oral Semaglutide in the Real-World—Initial Results from the Association of British Clinical Diabetologists’ (ABCD) Audit
Authors: CRABTREE THOMAS S.J. , ADAMSON KAREN , KRISHNASAMY SENTHILKUMAR , THIN KHINE MAY , DE PARIJAT , PETER RAJESH , RYDER ROBERT E. 
Published: June 2023

Semaglutide is the first glucagon like peptide-1 receptor agonist (GLP1-RA) available in an oral preparation. Weight and HbA1c outcomes with injectable semaglutide in the real-world are well established. The aim of this analysis is to assess weight and HbA1c response to oral semaglutide.
Methods: Data were extracted from the secure online ABCD audit tool. Individuals were included if baseline and follow-up weight and/or HbA1c data were available. Change in HbA1c, body mass index (BMI) and weight from baseline was assessed using a multivariate linear regression model and change in the numbers achieving an endpoint HbA1c≤7.5% [58mmol/mol] were assessed using Chi2 tests in Stata 16.
Results: Data were available for 350 individuals with baseline mean±SD HbA1c 9.2%±1.7 [76.6mmol/mol±18.3], weight 101.8kg±21.9, BMI 34.3kg/m2±6.9, median diabetes duration 11years (IQR 6-16) and age 59 years (IQR 51-68); 63.0% were male and 79.7% were white. Median follow-up was 0.5years (IQR 0.3-0.8). Significant reductions in HbA1c of 0.7% (95%CI 0.4, 0.9; P&lt;0.001) [7.4mmol/mol; 95%CI 4.7, 10.0; P&lt;0.001] were observed. Weight decreased by 3.3kg (95%CI 2.3, 4.3; P&lt;0.001) and BMI fell by 1.1kg/m2 (95%CI 0.6, 1.6; P&lt;0.001). Twice as many people achieved a HbA1c≤7.5% at follow-up compared to baseline (28.6% [52/182] vs 14.3% [26/182]) - this change was statistically significant (P&lt;0.001).
Conclusion: In the real-world, oral semaglutide is associated with statistically significant and clinically meaningful reductions in HbA1c, weight and BMI. The numbers achieving a HbA1c≤7.5% also increased. In the light of this, further data collection and analysis should be undertaken, including comparisons between oral and injectable GLP1-RAs and analysis of switches between them

Disclosure
T.S.J.Crabtree: Speaker's Bureau; Abbott Diabetes, Novo Nordisk, Lilly, Sanofi, Insulet Corporation. K.Adamson: None. S.Krishnasamy: Other Relationship; Novo Nordisk, Sanofi, Eli Lilly and Company, AstraZeneca. M.Khine: None. P.De: Speaker's Bureau; Novo Nordisk, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Takeda Canada, Daiichi Sankyo, Napp Pharmaceuticals Limited, Lilly Diabetes. R.Peter: None. R.E.Ryder: Other Relationship; Novo Nordisk, Speaker's Bureau; GI Dynamics, BioQuest.

Funding
Novo Nordisk
790-P: An Indirect Treatment Comparison of the Cardiovascular Protective Effect of Semaglutide vs. Liraglutide in Subjects with Type 2 Diabetes
Authors: CHUBB BARRIE , BØG MARTIN 
Published: June 2023

Background: In the absence of head-to-head evidence, an indirect treatment comparison (ITC) using individual-level participant data was conducted to provide evidence of the comparative cardiovascular (CV) protective effect of liraglutide vs semaglutide in subjects with type 2 diabetes.
Methods: CV outcomes trials (CVOTs) were identified for comparators of interest. LEADER was a randomised controlled trial studying the CV protective effect of liraglutide vs placebo. Similarly, two CVOTs comparing semaglutide with placebo were identified: SUSTAIN 6 and PIONEER 6. Time to first 3-point major adverse CV events (3P-MACE) (adjudicated) was the primary outcome in all trials and was chosen as the primary outcome for the ITC. Potential effect modifiers (baseline indicators of prior CV disease, albumin:creatinine ratio, estimated glomerular filtration rate) were identified in the literature and adjusted for in the ITC. A fixed-effects ITC using individual participant data was conducted in a Bayesian setting. Missing data for potential effect modifiers were imputed using multiple imputation (20 imputations). Comparisons were summarised as cause-specific hazard ratios (HRs). Population-average relative treatment effects between liraglutide and semaglutide were reported for each of the three populations corresponding to the three studies.
Results: The ITC showed that the relative risk of semaglutide vs liraglutide for the occurrence of 3P-MACE in the LEADER population favoured semaglutide: HR 0.73 (95% credible interval [CrI]: 0.56;0.94); results also favoured semaglutide in the SUSTAIN 6 (HR 0.76 [95% CrI: 0.59;0.97]) and PIONEER 6 (HR 0.78 [95% CrI: 0.60;1.00]) populations.
Conclusion: The results demonstrated a risk reduction of CV events (3P-MACE) for semaglutide vs liraglutide of 22-27% depending on the population studied. These results may have implications for clinical practice.

Disclosure
B.Chubb: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. M.Bøg: Employee; Lundbeck, Novo Nordisk.
8-LB: Adipocyte-Derived ANGPTL2 Regulates Abnormal Lipid Metabolism and Inflammation through PirB in Diabetic Kidney Disease
Authors: YIN RUILI , YANG LONGYAN , ZHAO DONG 
Published: June 2023

Diabetic kidney disease (DKD) is a disorder of glycolipid metabolism caused by diabetes mellitus, which leads to hemodynamic and inflammatory processes. The aim of this study is to investigate the mechanism of adipocyte-derived angiopoietin-like protein 2 (ANGPTL2) in promoting the progression of DKD. Patients with DKD were included, and plasma ANGPTL2 was detected by ELISA. Type 2 diabetic mouse model induced by HFD and STZ, systemic Angptl2 knockout mouse model and adipose-specific AAV-Angptl2 were constructed. HKC cells stimulated with high glucose and PA in vitro. ELISA was used to measure the levels of IL-6, IL-1β, TNF-α and ANGPTL2 in plasma. RT-qPCR and Western blot were used to detect PirB, lipid metabolism indicators and inflammation, and the proteomics of kidney was performed. HE, oil red O staining and inflammatory factor staining were used to evaluate the degree of renal lipid metabolism and inflammation. The plasma level of ANGPTL2 in DKD patients is significantly higher than that in normal controls. Compared with the normal mice, the DKD mice had increased lipid accumulation and severe inflammation in kidney tissues, with increased PirB, Cybb and pro-inflammatory factors, and decreased CD36 and FATP2 in kidney. Similarly, overexpression of adipose-derived ANGPTL2 in mice caused the same abnormal lipid metabolism and increased inflammation levels, while Angptl2 ko mice significantly improved lipid deposition and inflammation levels and fatty acid transport. Knockdown of ANGPTL2 in HKC cells also inhibited the reduction of CD36 and FATP2, the increase of its receptor PirB, and the increase of Cybb /Nox2-mediated inflammatory cytokines induced by high glucose and high lipid in HKC cells. Adipose-derived ANGPTL2 may play an important role in lipid metabolism and Cybb/ NOX2-regulated inflammatory through its receptor in DKD, suggesting that ANGPTL2 may serve as a potential treatment for preventing the progression of DKD.

Disclosure
R. Yin: None. L. Yang: None. D. Zhao: None.

Funding
National Natural Science Foundation of China (82170454)
804-P: Similar Hypoglycemia Duration with Once-Weekly Icodec vs. Degludec or Glargine U100 in Insulin-Treated T2D—A Post Hoc CGM Analysis from ONWARDS 2 and 4
Authors: BAJAJ HARPREET S. , ÁSBJÖRNSDÓTTIR BJÖRG , CARSTENSEN LISBETH , LANG LEHRSKOV LARS , MATHIEU CHANTAL , PHILIS-TSIMIKAS ATHENA , BATTELINO TADEJ 
Published: June 2023

Once weekly (OW) icodec is a basal insulin in development. Hypoglycemia duration during the switch (weeks 0-4) and steady state (weeks 22-26) periods from two phase 3, randomized, treat-to-target trials in T2D was investigated, using double-blinded Dexcom G6 CGM. Insulin-treated individuals were randomized to OW icodec or once-daily (OD) degludec (ONWARDS 2), or OW icodec or OD glargine U100 with mealtime insulin aspart (ONWARDS 4). When switching, a one-time only additional 50% icodec dose was administered. Basal insulins were titrated weekly. Median hypoglycemia &lt;70 mg/dL duration for episodes lasting ≥ 15 minutes and the proportion of such episodes spent &lt;54 mg/dL were assessed. Median duration of hypoglycemia &lt;70 mg/dL was similar between icodec and comparators during switch and at steady state (Figure), with no apparent clustering in either time-period. At steady state (icodec/degludec and icodec/glargine U100), of the episodes &lt;70 mg/dL, 66.6/63.9% and 60.4/60.0% spent no time &lt;54 mg/dL; 23.2/26.6% and 29.2/28.8% included episodes &lt;54 mg/dL for ≥15 minutes; and 10.2/9.5% and 10.4/11.2% included episodes &lt;54 mg/dL for &lt;15 minutes, respectively. In insulin-treated T2D, the duration of hypoglycemic episodes &lt;70 mg/dL was similar, with no apparent clustering, during switch and at steady state for OW icodec versus OD degludec or glargine U100.

Disclosure
H.S.Bajaj: Research Support; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Anji Pharmaceuticals, Eli Lilly and Company, Kowa Company, Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Tricida, Inc. B.Ásbjörnsdóttir: Employee; Novo Nordisk. L.Carstensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L.Lang lehrskov: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. T.Battelino: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Consultant; Indigo Diabetes, Research Support; Novo Nordisk, Sanofi, Medtronic, Novartis, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Dexcom, Inc.

Funding
Novo Nordisk A/S
808-P: Pharmacokinetic Properties of Once-Weekly Insulin Icodec in Individuals with Renal Impairment vs. Normal Renal Function
Authors: HAAHR HANNE , KRISTENSEN NIELS R. , LARSEN JONAS H. , WAGNER FRANK-DIETRICH H. , IGNATENKO STANISLAV 
Published: June 2023

Insulin icodec is a once-weekly basal insulin in development. This trial investigated if renal impairment affects the pharmacokinetics (PK) of icodec. In an open-label, parallel-group trial, 58 individuals (39 males; mean±SD age 50±13 yrs, BMI 26.5±3.1 kg/m2) were allocated to five groups according to renal function based on measured glomerular filtration rate (GFR): normal renal function (NRF; ≥90 mL/min; N=12), mild (60 to &lt;90 mL/min; N=12), moderate (30 to &lt;60 mL/min; N=12), severe (&lt;30 mL/min; N=12) renal impairment and end‑stage renal disease (N=10). A single s.c. icodec dose (1.5 U/kg) was administered and blood was sampled for PK until 840 h (35 days) post-dose. A minor increase was observed in total exposure (AUC0-840h,SD) with decreasing GFR, but the estimated effect of GFR on AUC0-840h,SD did not differ statistically significantly from zero (-0.069; 95% CI [-0.150;0.013]; p=0.099). Pairwise group comparisons showed numerically slightly higher AUC0-840h,SD and Cmax,SS for renal impairment vs NRF (Figure). AUC0-840h,SD was statistically significantly higher for moderate renal impairment vs NRF. In conclusion, icodec exposure trended to be slightly higher for renal impairment vs NRF. The clinical relevance is however limited as icodec should be dosed according to individual need. Thus, no specific dose adjustment of icodec is required in individuals with renal impairment.

Disclosure
H.Haahr: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. N.R.Kristensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. J.H.Larsen: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. F.H.Wagner: None. S.Ignatenko: None.

Funding
Novo Nordisk
811-P: Initiation of Once-Weekly (QW) Basal Insulin Fc (BIF) in Three Patient Populations in Phase 2 Studies Using a One-Time Loading Dose (LD) Minimizes Transient Hyperglycemia and Is Not Associated with Excess Hypoglycemia Risk vs. Degludec
Authors: BUE-VALLESKEY JULIANA M. , KAZDA CHRISTOF M. , ZHANG QIANYI , HAUPT AXEL , DAHL DOMINIK , FRIAS JUAN P. 
Published: June 2023

BIF is a fusion protein combining a novel single chain insulin variant with a human IgG Fc domain.
The safety population from 3 randomized, open-label, phase 2 treat-to-target studies included 942 people with T2D previously treated with basal insulin (T2D-Switch) or new to insulin therapy (T2D-Naïve), or with T1D on multiple daily injections (T1D). QW BIF was compared to once daily (OD) DEG for 26 or 32 wks.
Given BIF's slow accumulation and extended PK profile, initiation of or transition from prior OD basal insulin to BIF was managed by “boosting” initial exposure with a one-time ~ 3-fold LD strategy to achieve therapeutic concentration more quickly. In the absence of a definitive mg to unit conversion factor, determination of the starting QW dose differed by study and was based on PK/PD modelling and individual patient characteristics. Fasting glucose and patient reported hypoglycemia &lt;70 mg/dL were compared during the first 6 wks of treatment and showed no clinically significant differences between treatments (Table). T2D-Switch and T1D studies included CGM and data during first 6 wks of the study were reviewed; no severe hypoglycemia was reported during this time.
These data suggest that the BIF LD strategy is safe and effective in reducing transient hyperglycemia, especially in T2D.

Disclosure
J.M.Bue-valleskey: Employee; Eli Lilly and Company. C.M.Kazda: Employee; Eli Lilly and Company. Q.Zhang: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. D.Dahl: Research Support; Lilly, Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim Inc., Amgen Inc. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi.

Funding
Eli Lilly and Company
82-LB: Effectiveness of Coordinated and Centralized Care for Insulin Pump Users—A Multiple-Year Cohort Study
Authors: LATIF KASHIF , LI QINGFENG , SHAIKH YAHYA , CHEEMA FAISAL H. , HYDER ADNAN 
Published: June 2023

Background: With &gt;13000 children diagnosed with type 1 diabetes each year, it imposes a tremendous burden on US healthcare. However, data are scarce on management models for pump users.
Methods: In this observational cohort study, patients (pts) were systematically monitored for 4 years at our centralized & coordinated pump center. Data on both outcome measures (percentage of glycated hemoglobin, or A1C) & pt characteristics were routinely documented.
Results: For all study pts (n=219), a statistically significant reduction in A1C was observed (-0.4% A1C; 95% CI: -0.7-0.1%). And this is true for all three groups of pts disaggregated by initial A1C (7.5-10, 8.0-10, ≥10). The reduction was -0.6 (95% CI: -0.8-0.3) for ps with a starting A1C between 7.5-10; -0.8 (95% CI: -1.1-0.5) for pts with a starting A1C of 8.0-10; and -2.4 (95% CI: -3.4 -1.3) for pts with a starting A1C above 10. A majority of pts reached their target A1C levels, and most of them achieved that in first quarter after the installation of insulin pumps (See Fig 1).
Conclusions: Through centralized and coordinated care, a pump center is effective in assisting diabetes patients in properly using insulin pumps and quickly achieving their target A1C levels. Given the heavy burden of diabetes and large number of insulin pumps, the model of a pump center may be able to help confront the disease burden, and therefore needs to be made available to more patients.

Disclosure
K. Latif: Research Support; Medtronic, Senseonics. Board Member; Bigfoot Biomedical, Inc. Q. Li: None. Y. Shaikh: None. F. H. Cheema: None. A. Hyder: None.
84-OR: Structure–Function Analysis of p57KIP2 in the Human Pancreatic Beta Cell Reveals a Canonical Bipartite Nuclear Localization Sequence (NLS)
Authors: CHOLEVA LAURYN , WANG PENG , LIU HONGTAO , WOOD OLIVIA , LAMBERTINI LUCA , KARAKOSE ESRA , STEWART ANDREW F. 
Published: June 2023

p57KIP2 is a canonical cell cycle inhibitor encoded by the CDKN1C gene on chromosome 11. Mutations in CDKN1C underlie multiple pediatric endocrine syndromes including Beckwith-Wiedemann Syndrome (BWS), the Focal Variant of Congenital Hyperinsulinism (FoCHI), Insulinoma, Russel-Silver Syndrome and IMAGe Syndrome. Despite this central role in disease, little is known about the function of p57KIP2 in any cell type, including the human pancreatic beta cell. We hypothesized that p57KIP2 has functions that extend beyond cell cycle control and are unique to the human beta cell. We prepared RIP1 insulin promoter-driven adenoviruses encoding deletions of multiple putatively important and disease-associated but unexplored regions of p57KIP2 (WTp57, p57ΔPAPA, p57ΔCDKI, p57ΔPCNA and p57ΔNLS), and performed the first comprehensive structure-function analysis of CDKN1C/p57KIP2 in the human beta cell. RT-PCR and immunoblot analyses confirmed p57KIP2 overexpression, construct size and beta cell specificity in human islets. By immunocytochemistry, all constructs demonstrated nuclear localization, with the exception of a deletion mutant removing a putative NLS at amino acids 278-281. Unexpectedly, we identified a second NLS at amino acids 312-316. Further analysis showed that each individual NLS is required for nuclear localization of p57KIP2, but neither alone is sufficient to permit nuclear localization of p57KIP2. Finally, constructs containing both the 278-281 and 312-316 sequences were necessary and sufficient to target heterologous proteins to the nucleus of human beta cells.
In summary, we discovered that p57KIP2 contains a classic bipartite NLS characterized by two clusters of positively charged amino acids 278KRKRS281 and 312RKRLR316 separated by a proline-rich linker region. Variants in the sequences encoding these two NLS sequences account for functional p57KIP2 loss and beta cell expansion seen in human disease.

Disclosure
L. Choleva: None. P. Wang: None. H. Liu: None. O. Wood: None. L. Lambertini: None. E. Karakose: None. A.F. Stewart: None.