bluuebunny/crossref_metadata_2025_split huggingface dataset:
1094-P: A Major Source of Hypoglycemia in Patients with Type 2 Diabetes Using Insulin
Authors: BISGAIER STANLEY G. , ISAMAN DEANNA J. , BASHAN ERAN , HODISH ISRAEL 
Published: June 2019

Insulin requirement is highly dynamic, causing unpredictable reductions in insulin needs. Therefore, frequent dosage titration is needed to achieve and maintain therapy goals. Hypoglycemia is the primary risk in insulin management. We sought to determine if reductions in insulin requirements are associated with hypoglycemia frequency, by using data from a technology-based insulin titration service. To keep glycemia stable, the service adjusts insulin dosage at least weekly. Therefore, insulin dosage reacts quickly to both hyper- and hypo- glycemia, and as a result closely tracks insulin requirement. Outcome was defined as events of considerable and persistent decrease in insulin requirements as identified by reductions in daily dose ≥25%. Patients (N=246) were followed for 2.8±0.9 years. Insulin titrations occurred every 6.4±1.9 days. Considerable decrease in insulin requirement was experienced by 70.3% of the patients, every 15.0±7.5 months, lasted 10.0±7.7 weeks, and insulin requirements declined by 39.9%±12.6%. Hypoglycemia (&lt;54mg/dl) occurred 6.0±7.2 times per year, and was 6.5 times more prevalent during reductions in insulin needs (Figure). In total, 39.9% of hypoglycemic events occurred during the 10.5% of time when insulin requirements declined. Substantial reduction in insulin needs explains a significant part of the hypoglycemic burden, which demands frequent titration to preserve treatment safety.

Disclosure
S.G. Bisgaier: Employee; Self; Hygieia. D.J. Isaman: Consultant; Self; Hygieia. E. Bashan: Employee; Self; Hygieia. I. Hodish: Stock/Shareholder; Self; Hygieia.
11-OR: What Has Contributed to the Increase in the National Spending on Antidiabetic Drugs: 2005-2016?
Authors: ZHOU XILIN , SHRESTHA SUNDAR , SHAO HUI , ZHANG PING 
Published: June 2019

Spending on antidiabetic drugs is the fastest growing component of the medical cost of diabetes in the U.S. What factors have contributed to the increase remains unclear. Using Medical Expenditure Panel Survey, we (1) estimated the increase in the national spending on antidiabetic drugs from 2005 to 2016; (2) examined magnitudes of contributing factors to the increase using a full decomposition method. The contributing factors were first grouped into insulin verse non-insulin, the former was grouped into human, analog, and premixed insulin and later was grouped into metformin, older drugs (sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and meglitinides), newer drugs (dipeptidyl peptidase-4 inhibitor, amylin analog, glucagon-like peptide-1, and sodium-glucose contransporter-2), and combinations. Spending on insulin and non-insulin was also decomposed into number of users and expenditure per user. National spending increased by $38.7 billion from 2005 to 2016 (Figure). Most of the increase was due to insulin, mainly analog insulin. Increases in noninsulin was a net effect of an increase in newer drugs and a fall in older drugs. Higher spending per user was the main driver for insulin and both more users and lower expenditure per user led to the increase on noninsulin. Understanding the driving factors can help identify ways to slow down the growth in antidiabetic drug expenditures.

Disclosure
X. Zhou: None. S. Shrestha: None. H. Shao: None. P. Zhang: None.
1103-P: Glucose-Responsive Insulin: An Unprecedented Cleavable Linker Concept
Authors: MANNERSTEDT KARIN , ENGHOLM EBBE , MISHRA NARENDRA KUMAR , LUNDH MORTEN , BUCH-MÅNSON NINA , FINK LISBETH N. , PEDERSEN SØREN LJUNGBERG , PEDERSEN PHILIP J. , LE-HUU PRISKA , LAI JOHNATHAN , JENSEN KNUD J. , FOSGERAU KELD 
Published: June 2019

Achieving the optimal combination of multiple glucose measurements and insulin injections provides a complex daily situation for most insulin-dependent diabetes patients with currently available insulin products. To date, several fast-acting and long-acting insulins have been developed. However, while the pharmacokinetic profiles have been optimized, it has remained an elusive goal for decades to develop a Glucose Responsive Insulin (GRI), which can be responsive to the fluctuations in blood glucose concentrations during the day. Here we present an unprecedented GRI concept. The concept is based on the hydrolysis of a cleavable linker that is covalently bound to insulin. The chemical nature of this central linker is designed to rapidly release active insulin when glucose rises above euglycemia (5 mM), and this release of active insulin will increase with increasing blood glucose concentration. The second element of the concept is an albumin-mediated inactivation of the GRI by lipidation. After injection, the GRI will bind to albumin and circulate as a depot, resulting in a slow release of insulin like seen with other basal insulins such as insulin Detemir. At the linker level, we have tested three concentrations of glucose, and glucose responsiveness was demonstrated by a decrease in reaction time with increasing glucose concentration. Moreover, fully conjugated GRI molecules were tested in 90% pancreatectomized rats, a model of type 1 diabetes, demonstrating significant and long-lasting glucose lowering effect as compared to control. Overall, we have demonstrated the feasibility of providing a GRI approach, which combines the properties of a basal insulin with that of a bolus insulin. With the circulating depot approach the concept also holds a promise for liver preference. Ultimately our approach could provide a safe insulin for the treatment of insulin-dependent diabetes with very low risk of side effects.

Disclosure
K. Mannerstedt: Employee; Self; Gubra. E. Engholm: Employee; Self; Gubra. N.K. Mishra: Employee; Self; Gubra. M. Lundh: Employee; Self; Gubra. N. Buch-Månson: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. S.L. Pedersen: None. P.J. Pedersen: Employee; Self; Gubra. P. Le-Huu: Employee; Self; Gubra, Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. J. Lai: Employee; Self; Gubra. K.J. Jensen: Consultant; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Fosgerau: Stock/Shareholder; Self; Gubra.
111-LB: Oral Semaglutide vs. Sitagliptin: Efficacy by Baseline HbA1c and Background OAD in PIONEER 3
Authors: ROSENSTOCK JULIO , ALLISON DALE C. , BIRKENFELD ANDREAS L. , BLICHER THALIA MARIE , DEENADAYALAN SRIKANTH , KOUSHOLT ASTRID , DAVIES MELANIE J. 
Published: June 2019

Exploratory analyses of PIONEER 3 (NCT02607865) assessed the efficacy (HbA1c change from baseline [BL], achievement of HbA1c &lt;7.0%) of oral semaglutide (sema; 3, 7, or 14 mg), a novel oral GLP-1 receptor agonist, vs. sitagliptin (sita) 100 mg at week 26 by BL HbA1c and background OAD in pts with T2D uncontrolled on metformin ± sulfonylurea.
HbA1c was reduced across all BL HbA1c and OAD groups in all treatment arms; reductions were greater with higher BL HbA1c. HbA1c reductions were significantly greater with oral sema 7 and 14 mg vs. sita in all groups, except for 7 mg in the HbA1c ≤8.0% group (Figure 1). Achievement of HbA1c &lt;7.0% was greater with oral sema 7 and 14 mg vs. sita in all groups (Figure 2).
In conclusion, oral sema 7 and 14 mg significantly improved glycemic control vs. sita across most HbA1c groups, and irrespective of background OAD use.

Disclosure
J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck & Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. D.C. Allison: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Sanofi. A.L. Birkenfeld: None. T.M. Blicher: Employee; Self; Novo Nordisk A/S. S. Deenadayalan: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. A. Kousholt: Employee; Self; Novo Nordisk A/S. M.J. Davies: Advisory Panel; Self; Eli Lilly and Company, Janssen Global Services, LLC., Novo Nordisk A/S, Sanofi-Aventis, Servier. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk Foundation. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited.

Funding
Novo Nordisk A/S
1111-P: The Qualitative and Quantitative Effect of IDegLira Compared with the Nonfixed Administration of Degludec and Liraglutide
Authors: KOUTSOVASILIS ANASTASIOS , SOTIROPOULOS ALEXIOS , ANTONIOU ANASTASIA , PAPPA MARIA , BOUSBOULAS STAVROS , PEPPAS THEODOROS 
Published: June 2019

Background: The efficacy and safety of IDegLira and the benefits of its complementary mode of action have been examined in the large global DUAL clinical trial program.
Aim: The aim of this study is to examine the effect of the IDegLira on the glycemic control and the cardiometabolic risk factors compared to the non-fixed adiministration of degludec and liraglutide.
Material and Methods: 473 patients with type 2 diabetes mellitus (T2DM) were included in the study. 158 patients on oral antidiabetic drugs (OADs) switched to OADs and IDegLira (Group A), 163 under OADs and liraglutide treatment added degludec to their regimen (Group B) and in 152 patients using degludec and OADs, liraglutide was added (Group C). Follow-up period was 52 ±2 weeks and changes in HbA1c, cardiometabolic risk factors and treatment adherence (with the 8-item Morisky Medication Adherence Scale (MMAS-8)) were recorded.
Results: There was no difference at baseline between the three groups as to age (61.88 ± 9.98 years, p =0.212), diabetes duration (12.08 ± 5.83, p = 0.332), HbA1c (mean HbA1c: 8.59± 1.13, p = 0.118) καιΒΜΙ (BMI 32.08 ± 3.22, p = 0.144). Mean HbA1c levels after the follow-up period was 6.79 ± 0.77, 7.14 ± 1.19, 7.18 ± 1.07 (p = 0.033) for Group A, B and C, respectively. Most of patients in Group A reached the treatment target for HbA1c (p = 0.041). Weight change was -3.2 ± 1.2 kg for Group A, -1.2 ± 1.1 kg for Group B and -4.3 ± 1.7 kg for Group C (p &lt; 0.001). There was no difference in the hypoglycemic episodes between the groups (p = 0.251). The highest levels of adherence were noticed in Group A compared to Group B and C (7.58 ± 1.08, 6.38 ± 1.28 and 6.44 ± 1.16, p = 0.031, respectively) while total insulin dose was lower for Group A compared to the other groups (p=0.041).
Conclusion: Uncontrolled patients on oral antidiabetic drugs when switched to an IDegLira regimen achieved a significant improvement in their glycemic control and a more significant adherence compared the non-fixed combination of degludec and liraglutide.

Disclosure
A. Koutsovasilis: None. A. Sotiropoulos: None. A. Antoniou: None. M. Pappa: None. S. Bousboulas: None. T. Peppas: None.
1113-P: Six Months Comparative Evaluation of Efficacy and Safety of Wockhardt’s Biosimilar Insulin Glargine (Glaritus®) with Reference Insulin Glargine (Lantus®) in Type 2 Diabetes Mellitus in India
Authors: SHARMA SURENDRA , AJMANI AJAY KUMAR , KHOSLA POOJA , MUKHOPADHAYAY PRADIP , BHATIA GIRISH , KG PRAKASH , CHHAYA GAURAV , SUPE PRAVIN , PAVITHRAN VINODKUMAR , BORA HRISHIKESH , SHAH AGAM , INGOLE SHAHU ASHOK , JAIN RISHI 
Published: June 2019

Introduction: Glaritus® has been found comparable to reference insulin glargine in physico-chemical characteristics, pre-clinical studies and treatment of type 1 diabetes mellitus (DM).
Objective: To compare the immunogenicity, HbA1c reduction and safety of Glaritus® to Lantus® over 6 months treatment in type 2 DM.
Methods: This is an ongoing prospective, open-label, randomized, multicentre Phase IV study. Total 180 patients of type 2 DM, who were inadequately controlled on oral antidiabetic drugs, were randomized in 1:1 ratio to Glaritus® and reference insulin glargine treatment. Analysis of 144 patients, who completed 6 month comparative phase, is presented herewith.
Results: Baseline characteristics of both the treatment arms were comparable in terms of age, gender distribution and body mass index. Over the treatment period, mean anti-insulin antibody titre increased marginally, mean HbA1c reduced significantly and substantial percentage of patients attained HbA1c value &lt;7% within each treatment arm. However, both arms were comparable (P&gt;0.05) in terms of these changes. Both glargine treatments were found to be safe in terms of hypoglycemic events.
Conclusion: Glaritus® was found to be equally effective and safe in patients with inadequately controlled T2DM compared to reference insulin glargine.

Disclosure
S. Sharma: None. A. Ajmani: None. P. Khosla: None. P. Mukhopadhayay: None. G. Bhatia: None. P. Kg: None. G. Chhaya: None. P. Supe: None. V. Pavithran: None. H. Bora: None. A. Shah: Employee; Self; Wockhardt. S.A. Ingole: Employee; Self; Wockhardt. R. Jain: Employee; Self; Wockhardt.

Funding
Wockhardt Pharmaceuticals Ltd.
1114-P: Feasibility Study of a Novel Way to Initiate Insulin Treatment in Persons with Type 2 Diabetes
Authors: ARADÓTTIR TINNA , BENGTSSON HENRIK , JENSEN MORTEN L. , POULSEN NIELS KJØLSTAD , BOIROUX DIMITRI , SCHMIDT SIGNE , NØRGAARD KIRSTEN 
Published: June 2019

Introduction: Insulin initiation in type 2 diabetes (T2D) can be a complex process. In U.S., more than 60% of T2Ds treated with insulin do not reach recommended glycemic targets.
Aim: To investigate the feasibility of using a simple dose response model for predicting the basal insulin dose needed to reach glycemic target for a person with T2D.
Methods: To support initiation of a long acting insulin (insulin Degludec), we used CGM and injection data during insulin initiation to create an individual dose response model. Insulin naïve persons with T2D were included. Patients wore a CGM until the glycemic target was reached. CGM data from the first two weeks were used to identify the lowest glucose value of a day. The estimated safe and effective insulin dose (the 2-week dose estimates) were obtained by combining these lowest daily glucose periods with corresponding insulin doses, and extrapolating to a target range of 4-6 mmol/L. At end of study, the 2-week dose estimate was compared to the actual dose needed for glycemic control to assess how safe and effective the initial estimate would have been.
Results: Of the first 7 of 10 patients who completed the study, 5 were males of average age 60.3 (9.1) years, BMI 30.5 (4.1) kg/m2 and diabetes duration 15.8 (8.8) years. The observed actual dose for reaching the glycemic target was 49.9 (31.4) IU, and the 2-week dose prediction for reaching 4 and 6 mmol/L was 31.4 (12.6) IU and 45.5 (17.7) IU, respectively. At the end of study, a dose range for reaching the 4-6 mmol/L range was estimated using all the collected data, and all estimates were within or below this range.
Conclusion: Preliminary results from this feasibility study show that the insulin Degludec dose predicted two weeks after initiation was within or below the dose range needed for optimal control, thus the prediction errors were on the safe side in all cases. The results indicate that linear glucose and insulin extrapolation can be a safe and effective way to support initiation of insulin Degludec for people with T2D.

Disclosure
T. Aradóttir: None. H. Bengtsson: None. M.L. Jensen: Employee; Self; Novo Nordisk A/S. N.K. Poulsen: None. D. Boiroux: None. S. Schmidt: Speaker's Bureau; Self; Novo Nordisk A/S. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic, Novo Nordisk A/S. Speaker's Bureau; Self; Bayer US, Medtronic, Roche Diabetes Care, Rubin Medical, Sanofi, Zealand Pharma A/S. Stock/Shareholder; Self; Novo Nordisk A/S.

Funding
Novo Nordisk A/S; Innovation Fund Denmark (5189-00033B); Novo Nordisk Foundation
112-LB: Melatonin and DPP-IV Inhibitor: A Novel Combinatorial Approach for ß-Cell Regeneration
Authors: PATEL ROMA , PRAMANIK SAYANTANI , RATHWA NIRALI NANDUBHAI , PARMAR NISHANT R. , DHIMMAR HEMANGINI , PANCHOLI DHARA ASHWINKUMAR , A.V. RAMACHANDRAN , BEGUM RASHEEDUNNISA 
Published: June 2019

Progressive deterioration of β-cell function and mass is a central parameter to the development of type-1/2 diabetes (T1/2D). Over the last decade, many studies have explored the potential benefits of incretin-based therapies on β-cell preservation and/or regeneration. In this context, DPP-IV inhibitor is known to improve GLP-1 and GIP longevity besides increasing β-cell mass. Melatonin, a pineal hormone is shown to ameliorate oxidative stress and bring about insulin secretion via MT1 receptor activation. Our aim was to evaluate the additive therapeutic effect of melatonin and DPP-IV inhibitor (sitagliptin) on β-cell regeneration in chemically (streptozotocin) induced T1D young and old mouse models, and on insulin resistance in high-fat diet (HFD)-induced T2D mouse model. Our results on pancreatic β-cell regeneration in T1D young and old mice suggest that the combinatorial treatment significantly increased insulin levels thereby lowering FBG levels and increasing glucose tolerance. In young diabetic mice, sitagliptin and melatonin work in an additive manner by increasing β-cell mass (replication and neogenesis) and decreasing apoptosis thus, ameliorating TID manifestations. However, in old diabetic mice, melatonin treatment alone was not as effective as sitagliptin treatment but a significant additive effect was observed in S+M group on β-cell regeneration. In HFD-induced T2D mice the combination therapy was superior to monotherapies in reducing FBG levels, and increasing glucose tolerance. Further, the combination treatment showed increased glucose metabolism, glycogen synthesis, and insulin sensitivity. There was no significant change in β-cell mass in HFD-induced T2D mice.
In conclusion, combinatorial therapy is able to ameliorate T1D and T2D in mouse models by β-cell regeneration and increasing insulin sensitivity. Melatonin promotes β-cell proliferation whereas sitagliptin promotes β-cell neogenesis and in concert, they enhance β-cell regeneration.

Disclosure
R. Patel: None. S. Pramanik: None. N.N. Rathwa: None. N.R. Parmar: None. H. Dhimmar: None. D.A. Pancholi: None. R. A.v.: None. R. Begum: None.

Funding
Department of Biotechnology, New Delhi, India (BT/PR12584/MED/31/289/2014)
1121-P: Metformin Intolerance, Proton Pump Inhibitors, and OCT1 Variation: A Recruit-by-Genotype, Randomised Controlled Trial (ImpOCT)
Authors: MCCREIGHT LAURA J. , HAPCA SIMONA M. , PEARSON EWAN 
Published: June 2019

Aims: Metformin uptake is transporter-dependent. Observational data indicates that reduced-function variants in organic cation transporter 1 (OCT1) and OCT1-inhibiting drugs increase risk of metformin intolerance. The ImpOCT study investigated impact of OCT1 genotype and use of omeprazole (an OCT1-inhibiting drug) on an individual’s metformin tolerance.
Methods: This recruit-by-genotype, double-blind, randomised, placebo-controlled, crossover study recruited 61 nondiabetic individuals with homozygous reduced-function (null) or wild type (WT) OCT1 genotype. During two 4-week treatment periods, participants received metformin and concurrent omeprazole or placebo. Metformin was titrated weekly according to tolerance, assessed by interview and symptom severity scoring. The primary outcome was maximum tolerated dose of metformin (MTD) in each treatment period. Results were analysed using mixed effects modelling, assessing effect of genotype, treatment and gene x drug interaction on MTD.
Results: Participants were well matched for age and gender. Median BMI was higher in OCT1 null (26.3 [IQR 24.1 - 28.1] vs. 29 [IQR 26.5 - 31.8], p&lt;0.001), though these OCT1 variants are not associated with obesity. Frequency of tolerance was comparable (WT 60% vs. null 64.5%, p=0.7). We identified a significant gene x drug interaction (p=0.04) - OCT1 WT individuals have improved MTD whilst taking omeprazole, compared to placebo, p=0.008, whereas OCT1 null individuals show no improvement in MTD with omeprazole compared to placebo, p=0.87. BMI was not significant in the model of MTD, p=0.27.
Conclusions: Reduced function SNPs in OCT1 are relatively common and can affect transporter efficacy. This study identified a gene x drug interaction, between OCT1, metformin and omeprazole. Our data indicates that OCT1 WT individuals may benefit from PPI treatment to improve symptoms of metformin intolerance - this benefit is lost in those with reduced OCT1 function.

Disclosure
L.J. McCreight: None. S.M. Hapca: None. E. Pearson: None.

Funding
UK Wellcome Trust (to E.P.)
1134-P: Efficacy of iGlarLixi in Adults with Type 2 Diabetes Inadequately Controlled on Two or More Oral Antidiabetic Agents
Authors: SKOLNIK NEIL , NIEMOELLER ELISABETH , SOUHAMI ELISABETH , MENEGHINI LUIGI 
Published: June 2019

LixiLan-O, a randomized, 30-week, open-label study compared the fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) with insulin glargine (iGlar) or lixisenatide in patients inadequately controlled on metformin alone or combined with a second OAD. This exploratory subgroup analysis examines the efficacy and safety of iGlarLixi vs. iGlar in patients with baseline HbA1c ≥8.0% receiving metformin plus a second OAD at screening; the second OAD was a sulfonylurea in 93.8% of patients. Mean age was 59.2 years, mean BMI was 31.5 kg/m2, mean diabetes duration was 10.0 years, and mean duration of second OAD use was 4.5 years. Compared with iGlar alone, the iGlarLixi-treated group demonstrated greater mean reductions from baseline in HbA1c, 2-h PPG, and weight, greater proportions achieving HbA1c &lt;7.0%, or a composite endpoint of HbA1c &lt;7.0% with no weight gain (Table). There were no differences between the groups in change in FPG, or in insulin dose at Week 30 (40.7 vs. 40.2 U/day, respectively; p=0.8664). Incidences of documented symptomatic hypoglycemia (plasma glucose ≤70 mg/dL) were similar between groups (29.0% and 27.9%, respectively). Patients in this difficult-to-treat subgroup with advanced T2D and higher baseline HbA1c achieved better glycemic control without increased risk of hypoglycemia when intensified with iGlarLixi compared with iGlar.

Disclosure
N. Skolnik: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Mylan, Sanofi, Teva Pharmaceutical Industries Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. E. Niemoeller: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. E. Souhami: Employee; Self; Sanofi Research & Development. L. Meneghini: Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. Consultant; Self; Sanofi-Aventis. Other Relationship; Self; American Diabetes Association.

Funding
Sanofi