bluuebunny/crossref_metadata_2025_split huggingface dataset:
789-P: Real-Life Effectiveness of iGlarLixi (Insulin Glargine 100 U/ml and Lixisenatide) in People with Type 2 Diabetes (T2D) according to Prior Insulin Use
Authors: SEUFERT JOCHEN , FREEMANTLE NICK , GUJA CRISTIAN , HALUZIK MARTIN , BIGOT GREGORY , TOURNAY MATHILDE , BONNEMAIRE MIREILLE , KIS JANOS T. 
Published: June 2023

Little is known in real life clinical practice about the effectiveness and safety of iGlarLixi in insulin naïve compared to insulin treated people with T2D. In the European REALI pooled database, we analyzed patient-level data of 1317 people with T2D initiating a 24-week iGlarLixi treatment: 718 were insulin naïve (55%) and 598 insulin treated (45%), with a median treatment duration of 2.5 years. Demographics were similar among groups with an overall mean±SD age of 61±9 years and BMI 32.2±5.5 kg/m². Median T2D duration was 8 years in the naïve group and 10 years in the treated group. At Baseline, mean HbA1c was 9.39% in the naïve and 8.76% in the treated (p&lt;0.001). The least square (LS) mean HbA1c change from Baseline to Week 24 (using MMRM) was -1.57% in the naïve and -1.29% in the treated (Fig 1); the LS mean [95% CI] fasting plasma glucose change was -52.5 [-54.9; -50.1] and -50.4 [-53.4; -47.5] mg/dL, respectively. Mean±SD body weight decreased by 1.8±4.6 kg at Week 24, with no difference between groups. Mean iGlarLixi daily dose at Baseline was 14.3U in the naïve and 24.4U in the treated, and reached 30.7U and 36.4U, respectively, at Week 24. Symptomatic hypoglycemia reports and gastrointestinal side effects were low in both groups. This analysis demonstrated effectiveness and safety of iGlarLixi in both insulin naïve and insulin treated people with T2D in clinical practice.

Disclosure
J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Merck Sharp & Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk. N.Freemantle: Advisory Panel; AstraZeneca, Research Support; Galderma, ALK-Abelló A/S, Ipsen Biopharmaceuticals, Inc., Vertex Pharmaceuticals Incorporated, Thea, Speaker's Bureau; Abbott Singapore, ALK Shanghai. C.Guja: Advisory Panel; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Servier Laboratories, Viatris Inc. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. G.Bigot: None. M.Tournay: None. M.Bonnemaire: Employee; Sanofi, Stock/Shareholder; Sanofi. J.T.Kis: None.

Funding
Sanofi
796-P: Real-World Persistence with GLP-1 RA Treatment in Patients with Type 2 Diabetes Mellitus (T2DM) and Advanced Chronic Kidney Disease (CKD)
Authors: SIDRA FNU , XIE DONGLU , AGARWAL SHUBHAM , LINGVAY ILDIKO 
Published: June 2023

Guidelines (ADA 2023 and KDIGO 2020) recommend treatment with GLP-1RAs in advanced CKD and ESRD because of their cardiovascular benefits, low risk of hypoglycemia, and potential renal benefits. GLP-1RA are vastly under-prescribed in this population, mainly due to concerns related to tolerability. We compared persistence rate with GLP-1RA vs dipeptidyl peptidase 4 inhibitors (DPP-4i) in this population. We extracted EHR data from a university health system from patients with T2DM and GFR &lt;30 treated with either GLP-1RA or DPP-4i (2012- 2022). All charts were manually reviewed to confirm treatment start & stop date and reason for discontinuation. At the time of treatment initiation, those treated with GLP-1RA (N=149) vs DPP-4i (N=87) were younger, more likely to be female (51% vs 44%) and had a higher BMI. Only 12.7% and 9.2% of patients discontinued treatment with GLP-1RA and DPP-4i, respectively, within 180 days of initiation. The average treatment duration was 1036 and 1109 days with 34.9% and 54% having discontinued treatment at the time of data extraction. The maximum tolerated dose of GLP-1RA were comparable to that expected in patients without CKD (Table). Persistence with GLP-1RA treatment in patients with T2DM and advanced CKD is similar to DPP-4i and the vast majority tolerated the highest approved dose of GLP-1RA, confirming their tolerability in this population.

Disclosure
F.Sidra: None. D.Xie: None. S.Agarwal: None. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim.
8-OR: Novel Mechanism of Lipoprotein Lipase Folding and Maturation in Adipocytes
Authors: WU SHUANGCHENG , QI LING 
Published: June 2023

Lipoprotein lipase (LPL) plays a central role in systemic lipid clearance by catalyzing intravascular hydrolysis of lipoprotein triglycerides, hence representing an important target in the treatment of hyperlipidemia in diabetes. Nascent LPL protein undergoes folding and maturation in the endoplasmic reticulum (ER), with only the properly folded ones exiting the ER and reaching to the cell surface. However, the maturation process for nascent LPL in the ER remains largely unknown. Here we show that LPL maturation in the ER is controlled by compensatory actions of two ER protein quality control mechanisms, ER-associated degradation (ERAD) and ER-phagy, in adipocytes. Specifically, we show that LPL is misfolding prone and degraded by ERAD, and when ERAD is compromised, LPL forms aggregates which is cleared by ER-phagy. In adipocytes lacking both ERAD and ER-phagy, ER fragments containing LPL aggregates cluster and fuse to form a novel cellular architecture, termed as Coalescence of ER Fragments (CERFs), where LPL undergo soluble-to-insoluble phase transition catalyzed by disulfide bond-mediated interactions. Lastly, mice with adipocyte specific ERAD and ER-phagy deficiency exhibited postprandial hyperlipidemia. In summary, this study provides novel insights into not only LPL biogenesis, but also the crosstalk between protein quality control pathways in the maintenance of ER homeostasis, as well as the disease pathogenesis, more broadly, associated with protein folding defects in the ER.

Disclosure
S.Wu: None. L.Qi: None.
80-LB: Evaluation of the Pharmacokinetics of Glucagon-Like-Peptide-1 (GLP-1) Receptor Agonist Delivered through the BIOJET Oral Biotherapeutic Delivery Platform in Porcine Model
Authors: LEE SHAOYING N. , STORK CHERYL A. , VALENZUELA-RIVAS RENE O. , WALKER MICHELLE , SMITH BRYAN J. , SMITH JEFFREY A. , QUINTANA NELSON , WAHL CHRIS , SINGH SHARAT 
Published: June 2023

Glucagon-like-peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and suppress glucagon release. Semaglutide is a GLP-1 agonist currently injected subcutaneously or taken orally to treat type 2 diabetes and for weight management. However, oral administration of protein/peptide therapeutics has proven difficult due to the harsh conditions of the upper gastrointestinal tract (GIT) and poor absorption rates in the small intestine. The BIOJET™ oral biotherapeutic delivery platform is an ingestible drug-device combination developed to increase drug bioavailability via needleless jet injection in the proximal small intestine following oral administration. Previous testing of an earlier, autonomously triggered version of the device in animal models was presented at ACG 2022. In this study we evaluated the pharmacokinetics (PK) of semaglutide delivered through the BIOJET device in a porcine model. Due to prolonged and variable gastric residence times in the porcine model, devices filled with semaglutide (~1mg) were administered by intraduodenal (ID) endoscopic placement and activated in the proximal small intestine of Yucatan swine. PK blood sampling was performed from 0 to 240 hours post-dose to evaluate systemic exposure of semaglutide. Seven of eight (7/8) devices were successfully placed and activated in the duodenum. All seven animals showed detectable drug levels up to ten days post-dosing and had an oral bioavailability average of 37% ± 15% (CV: 40%), ranging from 19%-60% compared to IV control. No significant clinical signs were observed in the animals. This study demonstrated that administration of the BIOJET device has the potential to achieve a magnitude greater bioavailability than the currently marketed oral semaglutide (&lt; 1%). The BIOJET device could provide an alternative for the oral administration of large molecules and may improve patient compliance.

Disclosure
S. N. Lee: Employee; Biora Therapeutics. C. A. Stork: Employee; Biora Therapeutics. R. O. Valenzuela-rivas: Employee; Biora Therapeutics. M. Walker: Employee; Biora Therapeutics. B. J. Smith: Employee; Biora Therapeutics. J. A. Smith: None. N. Quintana: None. C. Wahl: Employee; Biora Therapeutics. S. Singh: None.
80-OR: A New Cytoskeleton-Based Mechanism for Regulating Brown Adipose Tissue Physiology
Authors: AGUILLARD ASHLEY , ARRICASTRES JUNE , TZENG JOYCE , LORENZO DAMARIS 
Published: June 2023

Human genetic variants in ANK2, encoding the scaffold protein ankyrin-B (AnkB), increase risk for T2D. We characterized the role of AnkB in white adipose tissue (WAT) in mice with AnkB deficiency in both WAT and brown adipose tissue (BAT) (AT-AnkB KO). We found that AnkB loss led to obesity and insulin resistance driven by its role in clathrin mediated endocytosis of GLUT4 in WAT. AT-AnkB KO mice also had lipid accumulation in BAT. However, the cell-autonomous roles of AnkB in BAT and its contribution to energy balance is unknown. To elucidate AnkB’s roles in BAT, we developed mice lacking AnkB in BAT (BAT-AnkB KO). Histology and TEM revealed lipid accumulation in BAT of 4-month-old BAT-AnkB KO mice housed at thermoneutrality. Consistent with this finding, brown adipocytes from AnkB deficient mice also have enlarged lipid droplets, suggesting an AnkB cell-autonomous role in BAT lipid homeostasis. Proteomic-MS revealed that AnkB forms complexes with lipolysis factors Atgl, Hsl and Plin1, and regulators of the PKA pathway, suggesting AnkB plays a role regulating BAT lipolysis. Interestingly, Hsl and Plin1 are elevated in BAT despite the enlarged LDs of BAT-AnkB KO mice, implying either lipolytic deficits or compensatory effects. These findings support RNA sequencing that revealed downregulation of PKA signaling genes, ATPase subunits, and mitochondrial calcium signaling genes in BAT of BAT-AnkB KO mice. Last, peri-droplet mitochondria (PDM), a mitochondria subpopulation with reduced beta-oxidation capacity that contacts LDs, form longer contact sites with BAT LDs from BAT-AnkB KO mice. Together, these findings suggest that early alterations in mitochondrial bioenergetics and lipolysis contribute to BAT LD accumulation. Along with this data, we will present findings on thermogenic regulation in vivo and physiological assays evaluating lipolysis and its major regulators.

Disclosure
A.Aguillard: None. J.Arricastres: None. J.Tzeng: None. D.Lorenzo: None.

Funding
American Diabetes Association (1-19-JDF-081 to D.L.); National Science Foundation; Burroughs Wellcome Fund (1022069)
801-P: Short-Acting Exenatide Added Three Times Daily to Insulin Therapy Improves Fatty Liver Index in Type 1 Diabetes
Authors: JOHANSEN NICKLAS , DEJGAARD THOMAS F. , LUND ASGER , NIELSEN CASPER K. , VILSBØLL TINA , KNOP FILIP K. 
Published: June 2023

Fatty liver index (FLI), a marker of hepatic fat content, has been reported as an independent risk factor for all-cause mortality and major cardiovascular events in type 1 diabetes. How short-acting glucagon-like peptide 1 receptor agonists (GLP-1RA) influence FLI in type 1 diabetes remains unknown. We analyzed FLI post-hoc in a phase 2, double-blind, randomized (1:1), clinical trial (NCT03017352) that assessed the efficacy of short-acting GLP-1RA exenatide 10 μg added three times daily to insulin therapy as compared with placebo over 26 weeks of treatment in 108 individuals with type 1 diabetes (76/32 men/women, age 50 (14) years (mean (standard deviation)), diabetes duration 21 (12) years, BMI 28 (4) kg/m2, glycated hemoglobin A1c 8.2 (0.7) % / 66 (7) mmol/mol). Exenatide significantly reduced FLI by 23 % (95 % confidence interval -44; -10, P = 0.001) (Table 1) as compared with placebo after 26 weeks’ treatment. In conclusion, short-acting exenatide reduced FLI-assessed hepatic fat content in patients with long-standing type 1 diabetes and inadequate glycemic control, alluding to potential beneficial effects of this GLP-1RA on both morbidity and mortality in type 1 diabetes.

Disclosure
N.Johansen: Other Relationship; AstraZeneca, Novo Nordisk, Research Support; JDRF. T.F.Dejgaard: Advisory Panel; Novo Nordisk, Research Support; Novo Nordisk, Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk, AstraZeneca. A.Lund: Speaker's Bureau; Novo Nordisk. C.K.Nielsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.

Funding
AstraZeneca
809-P: The Effect of Various Degrees of Hepatic Impairment on the Pharmacokinetic Characteristics of Once-Weekly Insulin Icodec
Authors: HAAHR HANNE , CIESLAROVA BLANKA , DONATSKY ANDERS M. , JOSEPH JOSMIN R. , KRISTENSEN NIELS R. , KUPCOVÁ VIERA , HINGST JANNE R. 
Published: June 2023

Insulin icodec is a novel basal insulin being developed for once-weekly administration. This study investigated if the pharmacokinetic characteristics of icodec are affected by hepatic impairment. In an open-label, parallel-group trial, 25 individuals (13 females/12 males; mean±SD age 54±9 yrs, BMI 28.3±5.2 kg/m2) were allocated to four groups based on hepatic function: normal hepatic function (n=6), mild (Child-Pugh Classification grade A; n=6), moderate (Child-Pugh grade B; n=6), and severe (Child-Pugh grade C; n=7) hepatic impairment. Icodec was administered as a single s.c. dose (1.5 U/kg) followed by blood sampling for pharmacokinetics until 840 h (35 days) post-dose. Total exposure of icodec (AUC0-∞,SD) was greater for mild (by 13%) and moderate (by 15%) hepatic impairment vs normal hepatic function, while no difference was observed for severe hepatic impairment vs normal hepatic function (Figure). Maximum concentration of icodec was not affected by hepatic impairment after a single dose (Cmax,SD) or at simulated steady state (Cmax,SS). In conclusion, the slightly greater total exposure of icodec for mild and moderate hepatic impairment vs normal hepatic function is considered of limited clinical relevance as icodec should be dosed according to individual need. No specific dose adjustment of icodec is required in individuals with hepatic impairment.

Disclosure
H.Haahr: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. B.Cieslarova: None. A.M.Donatsky: Employee; Novo Nordisk. J.R.Joseph: None. N.R.Kristensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. V.Kupcová: None. J.R.Hingst: Employee; Novo Nordisk, Research Support; Pfizer Inc.

Funding
Novo Nordisk
81-LB: Novel Microsphere Technology Reducing Injection Site Reaction in the Development of Long-Acting GLP-1 RA Formulation
Authors: KIM YEJIN , SEOL EUNYOUNG 
Published: June 2023

Microspheres are typically used for long-acting injectable formulation, but often the injection site reactions are reported as side effects. This can reduce patient compliance with medication despite the benefit of reducing the number of administrations. Side effects at the injection site are mostly derived from inflammatory reactions. Therefore, it is necessary to minimize inflammatory reactions for the successful development of long-acting diabetes treatments, including GLP-1 receptor agonists. The purpose of this study is to evaluate the injection site reaction in the placebo, semaglutide and tirzepatide microspheres manufactured using the conventional microsphere technology and to investigate the injection site reaction improvement in the placebo, semaglutide and tirzepatide microspheres manufactured using novel technology by adding anti-inflammatory agent, dexamethasone. Skin samples were collected from the injection site of SD rats on days 3 and 8 after the administration of microspheres with or without dexamethasone. The collected skin was stained with H&E to determine infiltration of inflammatory cells, angiogenesis, and fibrosis and was graded. When microspheres manufactured using the conventional method were subcutaneously administered to rats, infiltration of inflammatory cells and fibrous tissue formation occurred on both days 3 and 8. Higher dexamethasone content in the microsphere showed a tendency for the lesser occurrence of inflammation and greater anti-inflammatory effect in the test group. Surprisingly, improvement in the injection site reaction for microspheres containing dexamethasone was observed even at systemic dexamethasone concentrations much lower than the therapeutic level.
In conclusion, this novel microsphere containing a small amount of dexamethasone shows potential for the development of a long-acting GLP-1 microsphere injectable for diabetes treatment with reduced injection site reaction.

Disclosure
Y. Kim: None. E. Seol: None.

Funding
Ministry of Health & Welfare, Republic of Korea (HI21C1732)
814-P: Intensive Insulin Therapy within One Week Can Improve ß-Cell Function in T2D Patients
Authors: JIANG WEI , CHEN XUANRONG , LIU ZHIGU , LIN BEISI , XU WEN , ZENG LONGYI 
Published: June 2023

Objective: Short-term intensive insulin therapy (IIT), usually over 2 weeks, can improve β-cell function in T2D. However, whether shorter duration of IIT could also have impact on β-cell function remained unclear. This study was thus designed to explore this question.
Methods: One hundred and ninety-two T2D patients who received continuous subcutaneous insulin infusion within 1 week and underwent comprehensive evaluation of β-cell function before and after IIT were included. β-cell function indices including HOMA-β, insulinogenic index, disposition index (DI), fasting and postprandial C-peptide index (CPI), AUC of insulin and C-peptide were adopted. In a subset patients underwent CGM, the correlation of glucose variability and β-cell function were analyzed.
Results: The patients were 56.2±13.7 (mean±SD) years old, with diabetic duration of 6.0 (12.1) [median (interquartile)] years, HbA1c of 9.3±2.0%. After 3-7 days (median: 5 days) of IIT, insulinogenic index [3.6 (5.3) mU/mmol vs. 2.9 (4.4) mU/mmol, p=0.005], DI [358.3 (398.5) vs. 233.3 (275.5), p&lt;0.001], fasting CPI [1.2 (0.8) nmol/mmol vs. 1.0 (0.8) nmol/mmol, p&lt;0.001], postprandial CPI [1.8 (1.5) nmol/mmol vs. 1.4 (1.2) nmol/mmol, p&lt;0.001] and AUC of C-peptide [113.0 (67.1) nmol∙min/L vs. 103.7 (55.9) nmol∙min/L, p=0.002] were significantly improved compared with baseline. Among these patients, 45 subjects underwent CGM. It was found that changes in DI from baseline (ΔDI) were negatively correlated with TAR (r=-0.417, P=0.004), standard deviation (r=-0.366, P=0.013), MAGE (r=-0.295, P=0.049), glucose coefficient of variation (r=-0.321, P=0.031) and positively correlated with TIR (r=0.359, P=0.004). Multiple linear regression revealed that duration of IIT (β=0.453, P=0.009) and TIR (β=0.527, P=0.006) were independent factors of ΔDI.
Conclusions: IIT within 1 week can also improved β-cell function in T2D patients. Duration of IIT and TIR could be the independent factors responsible for the improvement of β-cell function.

Disclosure
W.Jiang: None. X.Chen: None. Z.Liu: None. B.Lin: None. W.Xu: None. L.Zeng: None.
816-P: Predictors of Adherence and Persistence to Basal Insulin Therapy in Adults with Type 2 Diabetes
Authors: ARODA VANITA R. , NIELSEN NICK F. , MANGLA KAMAL K. , WANG YI , NAMVAR TARLAN , RAJPURA JIGAR R. 
Published: June 2023

Objectives: Treatment adherence and persistence lead to gaps in achieving glycemic control in type 2 diabetes (T2D). We sought to identify predictors of adherence and persistence to basal insulin therapy among adults with T2D initiating therapy.
Methods: Commercially insured US adults with T2D initiating basal insulin treatment between January 1, 2016 and December 31, 2018 were identified using IQVIA PharMetrics® Plus claims data. Adherence and persistence were quantified based on basal insulin claims in the one-year follow-up period and established definitions. Logistic regression models were developed to identify predictors of adherence and persistence based on baseline clinical and demographic information.
Results: Among the 64,953 patients sampled, medication adherence and nonadherence (42% and 58%) and medication persistence and non-persistence (57% and 43%) were identified. Older age at baseline, oral and injectable antidiabetic medicine use, and physician office visits were associated with increased persistence and adherence; baseline hospitalization and emergency room visits were associated with decreased levels.
Conclusions: Multiple predictors of adherence and persistence with basal insulin therapy were identified. These findings may help guide therapeutic choices and research priorities to bridge the gap between achievable efficacy of insulin therapy and real-world effectiveness.

Disclosure
V.R.Aroda: Consultant; Applied Therapeutics Inc., Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Applied Therapeutics Inc., Eli Lilly and Company, Fractyl Health, Inc., Novo Nordisk, Sanofi. N.F.Nielsen: Employee; Novo Nordisk A/S, Coloplast A/S. K.K.Mangla: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Y.Wang: None. T.Namvar: None. J.R.Rajpura: Employee; Novo Nordisk.