bluuebunny/crossref_metadata_2025_split huggingface dataset:
938-P: The Relationship between Timing of Initiation on a Glucagon-Like Peptide-1 Receptor Agonist and HbA1c among Patients with Type 2 Diabetes
Authors: MALIK RALEIGH E. , MODY REEMA , LAGE MAUREEN J. , BOYE KRISTINA 
Published: June 2020

Onjective: Examine the relationship between timing of initiation on a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and HbA1c.
Methods: The IBM MarketScan databases from 1/1/13 through 12/31/17 were used to identify adults with type 2 diabetes (T2D) who initiated on a GLP-1 RA in 2015 (first such date = index date) and had ≥1 HbA1c result in the last 6 months of the 2 year pre-period and another HbA1c in the last 6 months of the 2 year post-period. Time to GLP-1 RA initiation was proxied by the number of classes of glucose-lowering agents (GLAs) prescribed in the pre-period, with fewer GLAs indicating earlier GLP-1 RA initiation. Paired t-tests were used to examine differences in HbA1c from pre-period to post-period. Multivariable analyses examined the relationship between time to GLP-1 RA initiation and post-period HbA1c.
Results: The cohort (N=1,122) was 54% female with mean age of 55 ± 8.5 [SD] years. Initiation on a GLP-1 RA was associated with a significant reduction in HbA1c (8.5% ± 1.9% pre-period v 7.9% ± 1.8% post-period; P&lt;0.0001). Earlier initiation on a GLP-1 RA was associated with significantly lower post-period HbA1c and a significant increase in the likelihood of a patient achieving post-period HbA1c &lt; 7% (Figure 1).
Conclusions: Earlier initiation on a GLP-1 RA was associated with significantly lower HbA1c and an increased likelihood of achieving HbA1c &lt; 7%.

Disclosure
R.E. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. M.J. Lage: Consultant; Self; Eli Lilly and Company. Consultant; Spouse/Partner; Eli Lilly and Company. K. Boye: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Eli Lilly and Company.
939-P: HD-7671, a Nonpeptide Small Molecule for Orally Available GLP-1 Receptor Agonist, Improves Glucose Tolerance by Increasing Insulin Secretion
Authors: BAEK MYOUNGKI , KIM DAEHOON , KIM CHUN HWA , KIM DOO YOUNG , CHOI HYO SUN , KANG SEUNG JUN , LEE HANKYU , LEE KYUHWAN 
Published: June 2020

Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Currently, GLP-1R agonists comprise a growing class of agents that deliver unprecedented efficacy in diabetes. We discovered a new small molecule GLP-1R agonist, HD-7671, and examined its efficacy in cynomolgus monkeys. The in vitro potency of HD-7671 was evaluated by measuring cAMP accumulation in cells with stable expression of human GLP-1R. HD-7671 stimulated cAMP accumulation and its EC50 value was 2.0 nM. In the cells transfected with human or cynomolgus monkey GLP-1R, HD-7671 promoted cAMP accumulation and its EC50 values for human and cynomolgus monkey GLP-1Rs were 4.5 nM and 7.1 nM, respectively. In contrast, HD-7671 showed no stimulatory activity on other animal species GLP-1Rs. In pharmacokinetic properties, the elimination half-life following oral administration(T1/2) was 0.99 hr in rats and 5.62 hr in cyno monkeys and Cmax was 10,183 ng/ml in rats and 1,423 ng/ml at 10mg/kg, respectively. To evaluate the in vivo insulinotropic effects of HD-7671, glucose stimulated insulin secretion was measured in compound treated in cyno monkeys undergoing an IVGTT. HD-7671 (dosed at 10mg/kg) decreased the blood glucose level and increased insulin secretion. These results demonstrate that HD-7671 has full agonistic activity on human and cynomolgus GLP-1R and improves glucose tolerance by stimulating insulin secretion.
In conclusion, HD-7671 has potential as an orally active, non-peptide GLP-1R agonist for the treatment of type 2 diabetes.

Disclosure
M. Baek: None. D. Kim: None. C. Kim: Employee; Self; Hyundai Pharmaceutical Co., Ltd. D. Kim: Employee; Self; Hyundai Pharm. H. Choi: Employee; Self; Hyundai Pharm. corp. S. Kang: Employee; Self; Hyundai pharm.corp. H. Lee: Employee; Self; Hyundai Pharm. K. Lee: Employee; Self; Hyundai Pharm.
94-LB: Long-Term Clinical Benefits of Early Combination Approach in Latin American Subpopulation of VERIFY Study
Authors: VENCIO SERGIO , MANOSALVA JUAN , MATHIEU CHANTAL , PROOT PIETER , PALDANIUS PAIVI M. 
Published: June 2020

The VERIFY study showed long-term clinical benefits of the early combination therapy of vildagliptin with metformin (EC) vs. traditional stepwise approach initiating with metformin monotherapy (MET) in a multinational population of newly diagnosed adult patients with T2D (HbA1c 6.5-7.5%). This sub-analysis evaluated the outcomes in Latin American population. The primary endpoint was time to initial treatment failure (TF), defined as HbA1c ≥7.0% at two consecutive scheduled visits after randomization. The time to second TF was tested when patients in both groups were receiving and failing on the combination. A total of 537 eligible patients, 58.8% females, were randomly assigned to either receive the EC (n=266) or MET (n=271). EC significantly reduced the relative risk (RR) of time to initial TF by 47% vs. MET (HR [95% CI] 0.53 [0.4, 0.7]; p&lt;0.0001). A total of 66.3% vs. 46.4% of patients achieved the primary endpoint in the MET and EC groups, with a median (interquartile range: IQR) time to TF of 33.4 (12.2, 60.1) and 59.8 (27.5, not estimable) months, respectively. The RR for time to secondary TF was reduced by 31% with EC (p&lt;0.0092). With EC, HbA1c levels were consistently lower and higher proportion of patients maintained HbA1c &lt;7.0%. Both treatment approaches were well tolerated, and only 3.2% participants discontinued the study due to adverse events. Seven patients in EC vs. three in MET, reported mostly one mild hypoglycemic episode, none leading to discontinuation. Similar to the global population, the long-term clinical benefits were achieved more frequently and without tolerability issues with the strategy of EC vs. standard-of-care MET in this Latin American population.

Disclosure
S. Vencio: None. J. Manosalva: None. C. Mathieu: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intrexon, MannKind Corporation, Medtronic, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk Inc., Pfizer Inc., Roche Diagnostic USA, Sanofi. Research Support; Self; Intrexon, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk Inc., Sanofi. P. Proot: None. P.M. Paldanius: Other Relationship; Self; Novartis AG.

Funding
Novartis AG
943-P: Role of Model-Informed Drug Development in Confirming Additional Clinical Benefits of Dulaglutide
Authors: THAM LAI-SAN , GEISER JEANNE , TANG CHENG CAI , SCHNECK KAREN , COX DAVID , MILICEVIC ZVONKO , BETHEL ANGELYN 
Published: June 2020

Throughout the development cycle of dulaglutide, model-informed drug development (MIDD) was applied to facilitate and accelerate decision-making. Currently, dulaglutide 0.75 mg and 1.5 mg given subcutaneously once weekly (QW) is approved for the treatment of type 2 diabetes. Post-approval, pharmacokinetic/pharmacodynamic (PKPD) exposure-response and mechanistic quantitative system pharmacology (QSP) models which leveraged accrued phase 1 data led to the hypothesis that additional glycemic control was possible with higher dulaglutide doses of 3.0 mg and 4.5 mg. MIDD was utilized to design a phase 2 study which explored the safety and efficacy for 3.0 mg and 4.5 mg versus 1.5 mg QW doses and tested a dose escalation approach for mitigating gastrointestinal (GI) nausea/vomiting effects for the investigational doses. Phase 2 data enriched understanding of benefit-risk of the extended doses and refined the dose escalation scheme for the pivotal phase 3 trial (AWARD-11). Efficacy and GI tolerability from AWARD-11 closely resembled model-predictions. While MIDD has been most commonly applied in dose-selection, novel MIDD approaches were also adopted for the dulaglutide program to design a dose escalation scheme and evaluate drug-drug interactions (DDI). Acetaminophen PK from previous gastric emptying studies covering a wide range of dulaglutide doses was used to characterize the extent of gastric-emptying delay (GED) related to 4.5 mg of dulaglutide and this extent of GED was then applied to physiologically based pharmacokinetic (PBPK) models of individual commonly co-administered oral agents to simulate effect of delayed gastric emptying on their PK profiles. Overall, a range of quantitative models were successfully employed to predict effects of and inform clinical trial design for higher dulaglutide doses for patients needing additional glycemic control.

Disclosure
L. Tham: Employee; Self; Eli Lilly and Company. J. Geiser: Employee; Self; Eli Lilly and Company. C. Tang: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Novartis Pharmaceuticals Corporation. K. Schneck: Employee; Self; Eli Lilly and Company. D. Cox: Employee; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. A. Bethel: Employee; Self; Eli Lilly and Company.
949-P: Dulaglutide Improves Kidney Fibrosis Biomarker Levels in Patients with Type 2 Diabetes and Moderate-to-Severe Chronic Kidney Disease
Authors: TUTTLE KATHERINE R. , WILSON JONATHAN M. , LIN YANZHU , QIAN HUI-RONG , KELLY-BORUFF KATHLEEN , GENOVESE FEDERICA , KARSDAL MORTEN A. , DUFFIN KEVIN L. , BOTROS FADY T. 
Published: June 2020

The AWARD-7 clinical trial demonstrated that once-weekly dulaglutide slowed the decline in estimated glomerular filtration rate (eGFR) and decreased urine albumin/creatinine ratio compared to insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD). Lower levels of urinary C3M, a marker for type III collagen degradation, and increased level of plasma PRO-C6, a marker for type VI collagen formation, have been reported to correlate with CKD progression and lower eGFR. This exploratory analysis evaluated changes in urinary C3M and plasma PRO-C6 in response to treatment with dulaglutide 1.5 mg compared to insulin glargine in AWARD-7. At baseline, urinary C3M and serum PRO-C6 levels were comparable between the dulaglutide 1.5 mg and insulin glargine groups. At week 26 and 52 of treatment, urinary C3M levels were significantly higher and serum PRO-C6 levels were significantly lower in the dulaglutide 1.5 mg group compared with insulin glargine group, respectively (Table).
In conclusion, dulaglutide was associated with decreased levels of biomarkers for type VI collagen formation and increased type III collagen degradation, suggesting a potential effect to reduce kidney fibrosis. These anti-fibrotic effects could be a potential mechanism for the beneficial effects observed with dulaglutide treatment on CKD in type 2 diabetes.

Disclosure
K.R. Tuttle: Consultant; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Goldfinch Bio, Novo Nordisk Inc. J.M. Wilson: Employee; Self; Lilly Diabetes. Y. Lin: None. H. Qian: Employee; Self; Eli Lilly and Company. K. Kelly-Boruff: Employee; Self; Eli Lilly and Company. F. Genovese: None. M.A. Karsdal: Stock/Shareholder; Self; Nordic Bioscience. K.L. Duffin: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Pfizer Inc. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Funding
Eli Lilly and Company
95-LB: Control-IQ Technology in the Real World: The First 30 Days
Authors: MUELLER LARS , CONSTANTIN ALEXANDRA , SINGH HARSIMRAN , HABIF STEPHANIE 
Published: June 2020

The t:slim X2 insulin pump with Control-IQ technology from Tandem Diabetes Care, Inc. was cleared by the Food and Drug Administration in December 2019. This study examined the commercial introduction of Control-IQ technology in the U.S. We performed a retrospective analysis of users who uploaded at least 30 days of pre and 30 days of post Control-IQ software update usage data to Tandem’s t:connect® web application as of March 11, 2020 and had ≥75% CGM use during this time (n=1,659). Outcomes included total daily insulin and sensor glucose values during open and closed-loop use of Control-IQ technology. Changes in glycemic outcomes were analyzed using the Wilcoxon signed-rank test. The mean age of patients was 43 years, 52% female, and mean diabetes duration was 21 years. Ninety percent of patients reported type 1 diabetes, 4% type 2 diabetes, and 6% “other” or unknown. The Control-IQ software update led to a 10% increase (p&lt;0.001) of median sensor time in range (70-180 mg/dL) to 78% (IQR =69%-85%) due to a 10% decrease in sensor time &gt;180mg/dL to 21% (IQR= 13%-30%) and a 0.1% decrease of sensor time &lt;70mg/dL to 1.1.% (IQR=0.5%-2.2%). Improvements in sensor time in range were consistent across age groups. Mean sensor glucose fell from 161 mg/dL to 148 mg/dL while the median total daily insulin increased from 48u to 49u. Median time in closed-loop was 96% (IQR = 93%-98%). These real-world data demonstrate improved sensor time in range without increasing hypoglycemia.

Disclosure
L. Mueller: Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. A. Constantin: Employee; Self; Tandem Diabetes Care. Other Relationship; Self; Bigfoot Biomedical. H. Singh: Employee; Self; Tandem Diabetes Care. S. Habif: Employee; Self; Tandem Diabetes Care.
962-P: Impacts of Different Hypoglycemic Agents on Adipokines and Inflammatory Markers in Newly Diagnosed T2D Patients
Authors: DENG HONGRONG , YANG XUBIN , XU WEN , LV JING , ZENG LONGYI , YAO BIN , WENG JIANPING 
Published: June 2020

Background: Adipokines and inflammatory markers contribute to the pathogenesis of T2D. This study investigated the impacts of T2D and different hypoglycemic agents on the important adipokines and inflammatory markers in newly diagnosed T2D patients.
Methods: The clinical parameters, leptin, adiponectin, resistin, fibroblast growth factor21, betatrophin, IL-1β and IFNγ were assessed in 41 normal-glucose controls and 416 newly diagnosed T2D patients. Then the patients were randomly assigned to receive exenatide, insulin or pioglitazone, with the above adipokines and inflammatory factors evaluated at 48 weeks.
Results: As shown in Table 1, compared with the controls, T2D patients had significantly higher IL-1β, lower leptin, adiponectin and IFNγ levels. Among the 416 patients, 342 patients completed the 48-week study. The HbA1c change (ΔHbA1c) were similar among groups. Exenatide significantly decreased the BMI and IL-1β, while increased IFNγ and adiponectin. Insulin markedly increased IL-1β and IFNγ. And pioglitazone only increased adiponectin. Multiple linear regression showed that Δleptin and Δadiponectin were associated with ΔBMI, but not with ΔHbA1c, fasting insulin or fasting C-peptide.
Conclusions: Exenatide has better impacts on improving IL-1β, IFNγ, and adiponectin levels than insulin and pioglitazone in T2D patients, which may probably due to decreasing BMI.

Disclosure
H. Deng: None. X. Yang: None. W. Xu: None. J. Lv: None. L. Zeng: None. B. Yao: None. J. Weng: None.

Funding
National Natural Science Foundation of China (81770821 to W.X.); National Key Research and Development Program of China (2016YFC1304801); Eli Lilly and Company
97-OR: Randomization to a Higher–Complex Carbohydrate vs. Conventional Diet in GDM Improves Glucose Tolerance and Results in Similar Cord Blood Insulin and Newborn Adiposity
Authors: HERNANDEZ TERI L. , FARABI SARAH S. , ARBET JARON , HIRSCH NICOLE , DUNN EMILY Z. , HEISS KRISTY P. , CARLI JAYNE MARTIN , KREBS NANCY F. , POWELL THERESA L. , REYNOLDS REGINA , VAN PELT RACHAEL E. , FRIEDMAN JACOB E. , BARBOUR LINDA (LYNN) A. 
Published: June 2020

Robust evidence for specific nutrition therapy for gestational diabetes (GDM) is lacking. Preliminary data suggested our CHOICE diet, higher in complex carbohydrate (60%) and lower in fat (25%) reduced fasting glucose (FBG), free fatty acids (FFA), and newborn adiposity (NB%fat). We tested the hypothesis that 7-8 wks of CHOICE would improve insulin resistance, reduce FFA and NB%fat (2-wk PeaPod; 1° powered outcome) vs. a conventional low-carbohydrate (40%), higher fat (45%) diet (LC/CONV). After diagnosis (∼28-30 wks), 59 BMI-matched diet-controlled GDM women (mean±SD; BMI 32±5) were randomized to a eucaloric CHOICE or LC/CONV diet (7.2±1 wks; ALL MEALS PROVIDED). At baseline, a 2-hr 75g OGTT (with insulins) was performed and diet initiated. On day-4, a breakfast meal was given (30% of total calories) with fasting and hourly blood drawn x5 (gluc, insulin, FFA, triglycerides[TG]) for area-under-the curve (AUC). Measures were repeated at 36-37 wks. Of 59, 13 met exclusions (4 diet failures, 2/group). By ANCOVA (n=23/group), total and weight gain during diet were similar (CHOICE 1.9 vs. LC/CONV 1.8 kg) as was delivery wk (39.2 vs. 39.3 wks). At 37 wks, the meal gluc (p=0.001) and insulin AUCs (p=0.013) were lower for LC/CONV, though fasting gluc/insulin were similar. TG increased similarly. The FFA AUC decreased from 30-37 wks on CHOICE but rose on LC/CONV (p=0.016), and was lower for CHOICE at 37 wks (p=0.009). By the 37-wk OGTT, FBG decreased within both groups (CHOICE -7.2, LC/CONV -3.5 mg/dL, both p&lt;0.01) but CHOICE led to improved (p=0.001) and lower gluc AUC (p&lt;0.05)(similar insulin AUCs). Birthweight (3293 vs. 3303 g), anthropometrics, NB%fat (10.8±4 vs. 10.3±4%), and cord blood gluc, C-peptide, FFA and TG were similar. This RCT shows that complex carbohydrate can be liberalized by 20% above conventional recommendations and may improve gluc tolerance and similarly normalize fetal growth, expanding nutrition options in GDM.

Disclosure
T.L. Hernandez: None. S.S. Farabi: None. J. Arbet: None. N. Hirsch: None. E.Z. Dunn: None. K.P. Heiss: None. J. Martin Carli: None. N.F. Krebs: None. T.L. Powell: None. R. Reynolds: None. R.E. Van Pelt: None. J.E. Friedman: None. L.A. Barbour: None.

Funding
National Institutes of Health (R01DK101659, UL1TR002535); Janssen Research & Development, LLC
970-P: Comparative Assessment of the Effect of Vildagliptin and Metformin on Pancreatic Beta-Cell Function and Insulin Sensitivity in Newly Diagnosed Asian Indians with Type 2 Diabetes
Authors: SATHEESH KRISHNAMOORTHY , SNEHALATHA CHAMUKUTTAN , NANDITHA ARUN , RAGHAVAN ARUN , VINITHA RAMACHANDRAN , SUSAIRAJ PRISCILLA , RAMACHANDRAN AMBADY 
Published: June 2020

Aim: To compare the effect of vildagliptin versus metformin on pancreatic beta-cell function among newly diagnosed, non-obese Asian Indians with type 2 diabetes (T2D) in 2 years.
Methods: Randomized, multicentric, controlled, parallel-group study of 2 years treatment with vildagliptin or metformin in drug-naïve T2D persons (baseline HbA1c - 7.0 - 8.5% and body mass index (BMI) &lt; 25kg/m2). Plasma glucose, insulin, HbA1c and C-peptide were measured at intervals of 6 months for 2 years. We randomised 203 (104 men and 99 women) T2D persons in two groups. Group 1 was treated with metformin, 500mg - 2000mg (n = 100), and group 2, with vildagliptin 100mg (n = 103).
Results: In the metformin group 36% and in the vildagliptin group 27.2 % required only monotherapy for a median duration of 48 weeks (25 - 70 weeks). At the end of the study, changes in the area under the curve of insulin to glucose were non-significant in both groups. There were no changes in the postprandial C-peptide. Reduction in insulin resistance (HOMA-IR) was similar in both groups. Insulin sensitivity (Matsuda Index) increased significantly at 6 and 12 months with metformin but no change was seen in the vildagliptin group. The HbA1c level decreased significantly in both groups until 18 months. The fasting plasma glucose decreased significantly till 12 months in both groups. Postprandial plasma glucose decreased only with vildagliptin till 12 months. Occurrences of adverse events were similar in both groups. Higher C-peptide and lower HbA1c values at the baseline predicted better glycemic control with vildagliptin. Lower baseline HbA1c predicted good glycemic control with metformin.
Conclusion: Both metformin and vildagliptin had similar protective effects on the beta-cell function, reduced insulin resistance and glycemic levels. Improved insulin sensitivity was seen with metformin.

Disclosure
K. Satheesh: None. C. Snehalatha: None. A. Nanditha: None. A. Raghavan: None. R. Vinitha: None. P. Susairaj: None. A. Ramachandran: None.

Funding
India Diabetes Research Foundation
971-P: Renal Impairment Has No Impact on the Clinical Pharmacokinetics of Tirzepatide
Authors: URVA SHWETA , QUINLAN TONYA , LANDRY JOHN , MARTIN JENNIFER , LOGHIN CORINA 
Published: June 2020

Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics (PK) and tolerability of TZP in subjects with renal impairment (with or without T2DM) vs. healthy subjects with normal renal function. Subjects in this single-dose study were categorized by renal impairment defined by baseline estimated glomerular filtration rate (eGFR, MDRD equation): 14 with normal renal function (≥90 mL/min/1.73m2), 8 with mild impairment (60-89 mL/min/1.73m2), 8 with moderate impairment (30-59 mL/min/1.73m2), 7 with severe impairment (&lt;30 mL/min/1.73m2) and 8 with end stage renal disease (ESRD) requiring dialysis. All subjects received a single subcutaneous dose of 5 mg TZP. Blood samples were collected to determine TZP plasma concentrations to estimate PK parameters. Adverse events were monitored to assess safety and tolerability. Log-transformed AUC0-∞, AUC0-tlast, and Cmax were evaluated by analysis of variance and 90% CI of the ratio between groups was estimated. Additionally, relationship between TZP PK parameters and eGFR (MDRD and CKD-EPI) and creatinine clearance (Cockcroft-Gault) was assessed by regression analysis. PK parameters were similar between subjects with severe renal impairment and healthy subjects (geometric LSM ratios [90% CI] of 1.03 [0.836, 1.27], 1.04 [0.841, 1.28] and 1.23 [0.966, 1.56] for AUC∞, AUC0-tlast, and Cmax, respectively). Similar results were observed when comparing the PK parameters of mild, moderate and ESRD groups vs. healthy subjects. There was no statistically significant relationship at the two-sided 10% significance level between exposure and eGFR. No notable differences in safety profiles were observed. There were no clinically relevant effects of renal impairment on TZP PK. Thus, patients with renal impairment treated with tirzepatide may not require dose adjustments.

Disclosure
S. Urva: None. T. Quinlan: None. J. Landry: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Martin: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company.

Funding
Eli Lilly and Company