bluuebunny/crossref_metadata_2025_split huggingface dataset:
817-P: Identifying Modulators of Treatment Benefits of Albiglutide (GLP-1 RA) in Preventing Major Adverse Cardiovascular Events (MACE) among Individuals with Type 2 Diabetes in the HARMONY Trial Using Machine Learning
Authors: KIANMEHR HAMED , LIN YILU , SHI LIZHENG , FONSECA VIVIAN , GUO JINGCHUAN , SHAO HUI 
Published: May 2022

This study aimed to identify patient characteristics associated with the effectiveness of albiglutide in preventing MACE among patients with type 2 diabetes (T2D) in the HARMONY trial. The HARMONY trial was a randomized, double-blind, placebo-controlled trial to examine the effectiveness of albiglutide in reducing the risk of cardiovascular disease in 9,463 individuals with T2D. We used the causal forest (CF) and causal tree (CT) algorithm to identify participant characteristics that modulate the effectiveness of albiglutide in preventing MACE from a list of 16 candidate variables (demographics, disease histories, medications, and biomarkers) at the study baseline. A computer-driven approach identified that study participants with baseline A1c level above 8.0% (absolute risk change (ARC) : -2.77%, 95% confidence interval [-4.21% to -1.28%]; relative risk (RR) : 0.74 [0.62 to 0.87]) , or diabetes duration less than 15 years (ARC: -2.55% [ -3.85% to -1.04%]; RR: 0.70 [0.58 to 0.85]) , or DBP higher than 70 mmHg (ARC: -2.40% [-3.68% to -1.21%]; RR: 0.73 [0.62 to 0.86]) , or heart rate below 70 per hour (ARC: -2.88% [-4.76% to -1.04%]; RR: 0.70 [0.56 to 0.88]) , or ALP level below 70 U/L (ARC: -3.10% [-3.10% to -1.30%]; RR: 0.65 [0.52 to 0.81]) , or serum creatinine level below 90 umol/L (ARC: -1.99% [-3.33% to -0.81%]; RR: 0.74 [0.61 to 0.88]) benefited from albiglutide in reducing the risk of MACE. In contrast, their counterparts who did not have these characteristics did not receive statistically significant MACE risk reduction from albiglutide. Our study identified clinical features that may result in greater benefits of albiglutide on MACE than what would be expected from a population average. Clinicians may consider these individualized characteristics for better-targeted albiglutide treatment. However, future GLP-1 trials may help to confirm this approach to optimize outcomes.

Disclosure
H.Kianmehr: None. Y.Lin: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
821-P: Randomized Clinical Trial on the Renoprotective Effect of CU01-10in Patients with Diabetic Kidney Disease (DKD)
Authors: MOON JUN SUNG , WON KYU CHANG , KIM MIN-JI , LEE IN-KYU , KWON SO HEE , PYO JUNG-IN , KANG JI-HYE , KWON YOUNG-GUEN , SEO HEEWON 
Published: May 2022

Background: One of the leading causes of chronic kidney disease, DKD is associated with increased oxidative stress and chronic inflammation. CU01-10is dimethyl fumarate (DMF) which being developed for treatment of DKD. DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-b/Smad3 signaling in an antioxidant response element independent manner in preclinical model, suggesting that DMF can be potentially effective against kidney damage. In this study, we investigated the efficacy and safety of CU01-10in patient with DKD.
Methods: For this randomized, double-blinded phase 2a clinical trial for the efficacy and safety assessment, we enrolled 42 adults with DKD (estimated glomerular filtration rate (eGFR) 30 to 89 ml/min/1.73m2) with albuminuria to be treated with CU01-10 (120mg twice a day) or placebo. We measured the change from baseline in urine albumin creatinine ratio (uACR) and eGFR at 12 weeks for primary outcomes.
Results: A total of 39 patients were evaluated for primary efficacy analysis. CU01-10group showed significant increase of eGFR (+ 3.80±8.72 ml/min/1.73m2at week 12, from baseline) , and there was a significant intergroup difference of eGFR at 6 and 12 weeks (p=0.0349 and p=0.0121, respectively) . CU01-10group was statistically significantly decreased in the mean ACR (p=0.0441) but not for placebo group (p=0.1336) , and after 12 weeks, CU01-10group (-39.65 mg/g) showed lower median uACR from the baseline than placebo (-16.90 mg/g) . In DMF group, no severe adverse events were reported during the trial and the most common adverse events were nausea (n=3) and skin flushing (n=3) .
Conclusion: CU01-10showed an improvement of uACR and eGFR compared to placebo for patients with DKD, with no major drug-related adverse events.

Disclosure
J.Moon: None. K.Won: None. M.Kim: None. I.Lee: n/a. S.Kwon: None. J.Pyo: None. J.Kang: None. Y.Kwon: None. H.Seo: None.
822-P: The Harmine and Exendin4 Combination Markedly Expands Human Beta-Cell Mass In Vivo in Diabetic Mice
Authors: BELIARD KARA A. , ROSSELOT CAROLINA , LI YANSUI , ALVARSSON ALEXANDRA , WANG PENG , THAKKAR KEYA , GUEVARA DANIELA , DEVITA ROBERT J. , STEWART ANDREW F. , STANLEY SARAH , GARCIA-OCANA ADOLFO 
Published: May 2022

Diabetes results from diminished functional β-cell mass. Small molecule inhibitors of Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A (DYRK1A) markedly increase human β-cell replication in vitro and in vivo. Furthermore, combination of DYRK1A inhibitors such as Harmine (H) with widely clinically used glucagon-like peptide 1 receptor agonists such as Exendin-4 (E) further enhance human β-cell proliferation. However, whether H+E combination increases human β-cell mass and improves glucose homeostasis in diabetic immunosuppressed mice transplanted with a marginal number of human islets is unknown. Human islets from 5-6 different adult healthy donors were transplanted under the kidney capsule (200 islets per kidney) of streptozotocin-induced diabetic immunodeficient Rag1-/- mice. At the time of transplantation, osmotic Alzet minipumps were implanted for continuous delivery of vehicle V, H, E and H+E for a period of 12 weeks. At the end of the study, human islet-bearing kidneys were harvested, labeled with insulin antisera and cleared using a modification of the iDISCO+ method. Imaging and analysis of the β-cell volume was done using the Light-sheet Ultramicroscope II and Imaris software. Transplanted diabetic mice who received the combination of H+E showed a significant increase of human β-cell volume up to 600% compared with mice treated with V or the drugs alone. This increase correlated with a significant increase in plasma human insulin levels, sustained normalization of blood glucose levels and significantly improved glucose tolerance. Our studies provide unequivocal documentation that treatment with the harmine and exendin-4 combination can lead to actual increases in human β-cell mass in diabetic conditions suggesting that β-cell replenishment might be possible in humans with diabetes.

Disclosure
K.A.Beliard: None. S.Stanley: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. C.Rosselot: None. Y.Li: None. A.Alvarsson: None. P.Wang: None. K.Thakkar: None. D.Guevara: None. R.J.Devita: None. A.F.Stewart: None.

Funding
NIH/NIDDK 1R01DK105015-05.
828-P: Preservation of ß-Cell Function in Pancreatic Insufficient Cystic Fibrosis (CF) with Highly Effective CFTR Modulator Therapy
Authors: FLATT ANNELIESE , SHEIKH SABA , PELECKIS AMY J. , GALLAGHER KATHRYN , ALVARADO PAOLA , HADJILIADIS DENIS , STEFANOVSKI DARKO , GALLOP ROBERT J. , RUBENSTEIN RONALD C. , RICKELS MICHAEL R. , KELLY ANDREA 
Published: May 2022

CF related diabetes is common with pancreatic insufficient CF (PI-CF) . Highly effective modulator therapy enhances aberrant CF transmembrane conductance regulator (CFTR) function and improves pulmonary and nutritional status. Ivacaftor therapy for indicated CFTR mutations enhanced insulin secretion to glucose-potentiated arginine (GPA) testing; however the effects of elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) on β-cell function have not been assessed. We retrospectively compared changes in GPA measures performed on two visits in individuals with PI-CF without diabetes and who were 1) initiated on ETI after the baseline visit (ETI group) vs. 2) not treated with CFTR modulator therapy (controls) .
ETI participants (mean±SD age 27±9 years) and 8 matched controls were followed up after a median (IQR) 5.8 (3.7-6.7) and 2.7 (1.9-3.0) years, respectively (p=0.001) , with ETI initiation 1.1 (0.2-1.2) years before the follow-up visit. Weight increased in both groups, but by more in the ETI group (p&lt;0.01) . No differences in lung function or HbA1c were observed; however, improvement in oral glucose tolerance test 2-hour glucose was observed in the ETI group (p&lt;0.05) that was different by trend from the change seen in controls (p=0.09) .
Acute insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls (p&lt;0.05) but not in the ETI group, while C-peptide changes differed between groups (p&lt;0.05) . A trend towards lower acute proinsulin response was seen in the ETI group (p=0.07) with the change different between groups (p&lt;0.05) . Deterioration in the proinsulin secretory ratio was observed in the control (p&lt;0.05) but not the ETI group (between group change, p=0.01) .
ETI therapy appears to preserve β-cell function in CF through effects on glucose-dependent insulin secretion and proinsulin processing. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.

Disclosure
A.Flatt: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.Kelly: Research Support; vTv Therapeutics. S.Sheikh: None. A.J.Peleckis: None. K.Gallagher: None. P.Alvarado: None. D.Hadjiliadis: Advisory Panel; AstraZeneca, Research Support; Mylan N.V. D.Stefanovski: None. R.J.Gallop: None. R.C.Rubenstein: None.

Funding
Public Health Service research grants (RDK97830; K23 DK107937; UL1 TR001878) and National Institutes of Health (P30 DK19525) .
83-OR: The LDIFLARE Method Predicts the Development of Incipient Diabetes Polyneuropathy: Results of the Five-Year Longitudinal Ipswich NeuroDiab Study
Authors: SHARMA SANJEEV , CROSS JEN , RAYMAN GERRY 
Published: May 2022

Aims: The LDIFLARE method has been previously shown to be a sensitive measure of small fibre function. In this longitudinal 5-year study, we evaluated the LDIFLARE as a method to predict the development of DPN.
Methods: From the cohort of 160 people with type 1 and 2 diabetes recruited at baseline, 58 patients who did not have DPN at onset and completed 5 years of follow up were studied. Incident DPN was defined as progression to a Neurology Disability Sore (NDS) of ≥3. All subjects underwent comprehensive neurological review including electrophysiology. We used duration-dependent receiver operating characteristic (ROC) curves to calculate the predictive validity of the baseline LDIFLARE for the development of a NDS of ≥3.
Results: Of the 58 subjects without DPS who completed 5yr follow up, 34 had Type-1 and 24 had Type-2 diabetes; 35 females. Mean age (±SD) was 47.1±8.8 years. Mean follow up time was 5.4 years. Of these, 24 (T1Dm & 14 T2DM) progressed to a NDS of ≥3 (41%; 7.7 events per 100 subject-years) . There was a strong correlation with older age, longer duration of diabetes, raised HbA1c and raised triglycerides (significance: p&lt;0.05) but no effect of BMI or blood pressure. The linear rate of fall of LDIFLARE from baseline in newly diagnosed DPN was 0.16 cm2/yr for T1DM and 0.22cm2/yr for T2DM. The area under the ROC curve for LDIFLARE ranged between 0.66 and 0.75. The optimal diagnostic threshold for a baseline LDIFLARE of 5.05cm2 was associated with 71% sensitivity, 74% specificity, and a hazard ratio of 3.73 (95% CI 2.14-6.73; P &lt; 0.01) for new-onset DPN.
Conclusions: We conclude that the LDIFLARE method with a cut-off of 5.cm2 showed good predictive validity for identifying people with diabetes who are at risk of developing DPN. We suggest that as a measure of small fibre function, the LDIFLARE method may be preferred over conventional large fibre methods in predicting the later development of clinical DPN.

Disclosure
S.Sharma: None. J.Cross: None. G.Rayman: None.
851-P: Oral Long-Acting Menin Inhibitor Normalizes Type 2 Diabetes Mellitus (T2DM) in Two Rat Models
Authors: BUTLER THOMAS , LI WEIQUN , LAW BRIAN , ARCHER TENLEY , KINOSHITA TAISEI , SOMANATH PRIYANKA 
Published: May 2022

Menin is a scaffold protein that has been recognized for its role in T2DM as a key regulator of β-cell proliferation. Menin inhibition has previously been shown to improve glycemic control in diabetic mice. Herein, we report the first evidence that BMF-219, an orally bioavailable, selective, irreversible menin inhibitor, restores glycemic control in Zucker Diabetic Fatty (ZDF) Rat and Streptozotocin-induced Rat (STZ) models of T2DM. Rats were treated daily with BMF-219, vehicle, or pioglitazone for 16 days. BMF-2was well tolerated throughout the conduct of the study. BMF-2treatment resulted in a significant 50% reduction in fasting and non-fasting blood glucose levels, reduced serum insulin and c-peptide levels (p&lt;0.05) , and reduced HOMA-IR (p&lt;0.001) after two weeks of treatment in ZDF rats. BMF-2decreased glucose levels at all timepoints during an oral glucose tolerance test at Day 15 (AUC reduction of 54%, p&lt;0.001) and at Day 29 (AUC reduction of 40%, p&lt;0.05, ∼2 weeks after the last dose) in the ZDF model, indicating prolonged glycemic control. Strikingly, BMF-219, but not pioglitazone, reduced blood glucose levels during an OGTT in STZ animals (AUC reduction of 41%, p&lt;0.05, see figure) . Significant reductions in blood lipemic levels (p&lt;0.01) and body weight were observed in both models. Collectively, our data indicate the novel and marked potential of BMF-2as an oral, long-acting treatment for T2DM.

Disclosure
T. Butler: Employee; Biomea Fusion Inc. W. Li: None. B. Law: Stock/Shareholder; Biomea Fusion Inc., Mirum Pharmaceuticals. T. Archer: Employee; Biomea Fusion. T. Kinoshita: None. P. Somanath: Employee; Biomea Fusion, Inc. Stock/Shareholder; Biomea Fusion, Inc.
852-P: Precision of the Afinion HbA1c Dx Point-of-Care Test in CLIA Waived Settings
Authors: CLENDENIN MARTA , KUPFER KENNETH , GREEN CHRISTOPHER L. , FORTNER KYLE S. , BAILEY TIMOTHY S. , BRICK STEPHEN , SMILEY SARAH I. , STRAUSS GUY S. , THORSELL ASHLEY A. , AHMED NASEER 
Published: May 2022

There is limited data on the performance of point of care HbA1c assays when fingerstick samples are tested by intended users in CLIA waived settings.
This study evaluated the precision of the Afinion HbA1c Dx (Afinion) when performed at CLIA waived sites (N=5) by operators with no laboratory training. The operators (N=12) self-trained using the materials provided with test purchase, had no prior Afinion system experience, and did not observe one another during testing. For each subject enrolled in the study (N=115) , 2 operators each obtained 2 fingerstick samples (4 total fingersticks per subject) and tested one sample on each of 2 Afinion instruments. The repeatability, between-operator, and between-instrument components of variance were calculated using the REML method for each of 4 HbA1c concentration intervals. The total imprecision was calculated as a composite of 6 relevant components of variance, including a) the components of variance estimated here (repeatability, between-operator, and between-instrument) , and b) components of variance estimated in prior studies (between-run, between-day, and between-lot) .
The repeatability was the dominant component, ranging from 0.83-1.14% CV across the HbA1c concentration intervals. The between-operator component was 0.00% CV for 3 out of the 4 HbA1c intervals, and was only 0.19% CV in the remaining interval, indicating the precision of the test is not operator dependent. The between-instrument component ranged from 0.22-0.39% CV. When combined with the other components of variance estimated in prior studies, the total imprecision does not exceed 1.80% CV, which is below the National Academy of Clinical Biochemistry’s (NACB) recommendation for a single method, interlaboratory CV of &lt;3%. The results were similar to those obtained by trained operators testing fingerstick samples with the Afinion system.
These results indicate that the precision of the Afinion is comparable to many laboratory HbA1c assays, and suitable for use in CLIA waived settings.

Disclosure
M.Clendenin: Employee; Abbott. N.Ahmed: Employee; Abbott. K.Kupfer: Employee; Abbott. C.L.Green: Employee; Abbott Diagnostics, Siemens. K.S.Fortner: Employee; Abbott. T.S.Bailey: Advisory Panel; Abbott Diabetes, CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Consultant; LifeScan, Sanofi, Research Support; Abbott Diabetes, Abbott Diagnostics, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Livongo, MannKind Corporation, Medtronic, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita Medical, Senseonics, ViaCyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker's Bureau; Becton, Dickinson and Company, Medtronic, Sanofi. S.Brick: None. S.I.Smiley: None. G.S.Strauss: None. A.A.Thorsell: None.
857-P: Mechanisms of Dapagliflozin to Reduce Intraglomerular Pressure in Patients with Type 2 Diabetes
Authors: BARKHORDARIAN MARYAM , TRIPLITT CURTIS L. , SOLIS-HERRERA CAROLINA , ADAMS JOHN M. , DEFRONZO RALPH A. , CERSOSIMO EUGENIO 
Published: May 2022

Aim: To examine the renal hemodynamic effects of SGLT-2i therapy in type 2 diabetes patients [T2D].
Design & Methods: T2D (n=20) with normal GFR measured with 24-hour creatinine clearance [CrCl&gt;100ml/min/1.73m2], who were not receiving ACEi or ARB, had renal blood flow (RBF) measured using PAH clearance divided by (1-Hct) and mean arterial pressure [MAP] to calculate renal vascular resistance [RVR] prior to and 4 months after Dapagliflozin 10mg/day (DAPA, n=10) . Results were compared to T2D treated with metformin ± glipizide to achieve similar glycemic control (Control, n=10) .
Results: HbA1c decreased equally in DAPA (8.6±0.5% to 7.4±0.3%) and CONTROL (8.7±0.3 to 7.5±0.2%) . There was a non-significant increase in RBF (ml/min) in DAPA compared to Control. MAP (mmHg) decreased by 8.5% from 98.4±2.9 mmHg to 90.0±2.0 mmHg and RVR by 21.4% from 87.9±5.1 mmHg/l/min to 69.1±5.2 mmHg/l/min in the DAPA group, while MAP & RVR remained unchanged in CONTROL group. Data at baseline [Pre-Rx] and after 4 months of therapy [Post-Rx] are shown in the table.
Conclusion: These findings show that, with equivalent glycemic control, dapagliflozin, but not metformin/glipizide, is accompanied by a decrease in renal vascular resistance, without significant change in RBF. Unlike studies in T1D, our results suggest that in T2D patients post-glomerular vasodilatation is the primary reno-protective mechanism of SGLT-2i therapy.

Disclosure
M.Barkhordarian: None. C.L.Triplitt: Consultant; Bayer AG, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. C.Solis-herrera: Speaker's Bureau; Novo Nordisk. J.M.Adams: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. E.Cersosimo: Research Support; AstraZeneca.

Funding
AstraZeneca
858-P: Predictors of HbA1c and Weight Response to Sodium–Glucose Cotransporter 2 Inhibitors (SGLT2i) in the Association of British Clinical Diabetologist (ABCD) UK Nationwide Audit
Authors: CRABTREE THOMAS S.J. , GALLAGHER ALISON , SIVAPPRIYAN SIVA , DHATARIYA KETAN , RAGHAVAN RAJEEV P. , BICKERTON ALEX , ELLIOTT JACKIE , CULL MELISSA L. , RAYMAN GERRY , GALLEN IAN W. , IDRIS ISKANDAR R. , RYDER ROBERT E. 
Published: May 2022

SGLT2i treatment is associated with weight and Hba1c reduction. Previous work has demonstrated clinical predictors of HbA1c and weight reduction with canagliflozin. We aim to analyse predictors of HbA1c and weight change across the class.
Methods: People with type 2 diabetes treated with any SGLT2i in the ABCD nationwide audit and available baseline and follow-up data were included. Multiple linear regression model was used to assess independent predictors of Hba1c and weight change. Analysis was performed using Stata 16.
Results: Data for 275individuals were included (n=13925 Empagliflozin, n=106Dapagliflozin, n=2976 Canagliflozin) . Baseline (mean±SD) were: age 59.8±10.5 years, baseline Hba1c 9.1±1.6%, weight 97.7±22.2kg, BMI 33.8±6.9kg/m2 and eGFR 81.8±13.6. Median (IQR) diabetes duration was 8.3 years (4.4-12.7) and follow-up time 1.5 years (0.7-2.7) . 61.3% were men. HbA1c fell by 0.87% (95%CI 0.85-0.89; p&lt;0.01) . Factors associated with greater Hba1c reductions include: older age (ß=0.01, p&lt;0.01) ; shorter diabetes duration (ß=-0.01, p&lt;0.01) ; higher HbA1c (ß=0.65, p&lt;0.01) ; greater weight loss (ß=0.02, p&lt;0.01) ; higher alanine aminotransferase (ALT) (ß=0.005, p&lt;0.01) ; higher baseline eGFR (ß=0.002, p&lt;0.01) and canagliflozin or empagliflozin use (vs. dapagliflozin; p&lt;0.05) . Weight fell by 3.0kg (95%CI 2.2-3.8; p&lt;0.01) . Predictors of greater weight reductions include: older age (ß=0.05, p&lt;0.01) ; lower HbA1c (ß=-0.29, p&lt;0.01) ; higher weight (ß=0.03, p&lt;0.01) or BMI (ß=0.17, p&lt;0.01) and larger HbA1c reductions (ß=0.41, p&lt;0.01) . Empagliflozin was superior to dapagliflozin (p=0.01) - no other differences between drugs were noted.
Conclusion: Our models demonstrate that baseline characteristics can help predict clinical outcomes with SGLT2i. Individual patient levels factors appear to provide only weak predictive value but may still be useful in assisting therapeutic choices.

Disclosure
T.S.J. Crabtree: Other Relationship; Abbott Diabetes, Novo Nordisk, Sanofi. A. Gallagher: Other Relationship; Dexcom, Inc. S. Sivappriyan: None. K. Dhatariya: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH. R.P. Raghavan: Speaker's Bureau; Novo Nordisk. Other Relationship; Lilly Diabetes, Novo Nordisk. A. Bickerton: None. J. Elliott: Advisory Panel; Abbott. Speaker's Bureau; Abbott, Dexcom, Inc., Insulet Corporation, Novo Nordisk. G. Rayman: None. I.W. Gallen: None. I.R. Idris: None. R.E. Ryder: None.

Funding
The ABCD SGLT2 audits are funded by unrestricted grants from Boehringer Ingelheim, AstraZeneca and Napp Pharmaceuticals