bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antidiabetes Drug Prescription in Indian Scenario—A Cross-Sectional Analysis from a Large, Pan India Database of the Apollo Sugar Clinics
Authors: SESHADRI KRISHNA G. , VENKATARAMAN S. , RM MANIKANDAN , CS DWARAKANATH , TS BOOCHANDRAN , NK NARAYANAN , GOPAL JAYASREE , DUVURU SHANTHARAM , AYYAGARI USHA , BEHL ANISH ,   APOLLO SUGAR RESEARCH GROUP
Published: June 2018

Aim: Our objective was to determine nature of antidiabetes prescriptions across the Apollo Sugar Ecosystem, India, a healthcare organization with more than 30 centres (as standalones, secondary and tertiary institutions) that provide care to patients with diabetes
Methods: An eligible 206prescriptions with a diagnosis of T2DM from Jan 2016 to June 2017 were included in this analysis to determine the choice of therapy, frequency of usage of different class of anti-iabetes medications, types of insulin, combination and of number of OHAs with insulin. Descriptive analysis was used to report the results.
Results: The mean age of the patients was 53.2 years, 63% males and 37% females. The majority of the patients were on OHAs (68.2%) with 22.8% of patients on OHAs+insulin and 9.0% on insulin alone. Biguanides (55.7%) were most commonly prescribed in combination with other OHAs followed by DPP-4 inhibitors (DPP-4i) (35%). 63% of patients requiring insulin were using at least one oral drug. The most common drugs used along with insulin included biguanides (50.5%) followed by DPP-4i (46.7%). Among Insulins short acting insulin was most commonly prescribed followed by Insulin glargine (22.5%) and premixed insulin and analogues (13.55).
Conclusions: Several observations stand out from this large cross sectional analysis. 1 A significant number of patients are on monotherapies other than MF. 2. Use of DPP-4i as the most common drug after MF when two drugs are used reflects a significant shift from a SU dominated practice system in India. 3. SGLT2i and insulin find progressive inclusion when three or more drugs are required. 4. A greater adoption of basal and short acting insulin as opposed to premix insulin in a country that was traditionally considered a premix market. The data provided here give a snap shot of the changing trends in adoption of therapeutic practices with availability of newer medications, physician education and patient ability to afford care.

Disclosure
K.G. Seshadri: None. V. S.: None. M. Rm: None. D. Cs: None. B. Ts: None. N. Nk: None. J. Gopal: None. S. Duvuru: None. U. Ayyagari: None. A. Behl: None.
Recombinant Protease Inhibitor Enhances Oral Insulin Pharmacodynamics in Pigs
Authors: NAGARAJU RAMACHANDRA , MADAN SONIA , ARORA KAJAL , ARORA NUPUR M. , KUNDU PRABUDDHA K. , GREENBERG-SHUSHLAV YAEL , KIDRON MIRIAM , HERSHKO AVRAM 
Published: June 2018

Oral insulin delivery is projected to provide both physiologic and technical benefits, and has been the focus of rigorous research efforts in recent years. The ORMD-0801 oral insulin formulation relies on the activities of both protease inhibitors and an absorption enhancer to ensure insulin integrity and bioavailability. In efforts to further improve its efficacy, a recombinant protease inhibitor (rPI), identical in sequence to its naturally sourced (nsPI) counterpart, was cloned and expressed in Pichia pastoris. The enzymatic activity of the isolated and purified protein was then tested in vitro. In addition, the glucose-lowering effect of ORMD-0801 formulated with various doses of rPI was assessed in 8 healthy, fasting pigs administered the preparation directly to the duodenum. rPI effectively inhibited its standard substrate in a dose-dependent manner and demonstrated &gt;2.5-fold higher activity as compared to nsPI. When integrated in the ORMD-0801 formulation, pigs treated with the formulation containing 25 mg rPI experienced a 20% greater change from baseline serum glucose concentrations as compared to those treated with the PI-free formulation (AUC: -6369 mg/dL vs. -2201 mg/dL, respectively). In parallel, the duration of its effect (140±33 minutes) was 75% longer than the duration of the effect of the PI-free formulation (80±37 minutes). Further calibrations of the rPI-supplemented ORMD-0801 formulation promise to enhance oral insulin bioavailability and its salutary effects, subsequently improving its clinical potential and value.

Disclosure
R. Nagaraju: None. S. Madan: None. K. Arora: None. N.M. Arora: None. P.K. Kundu: None. Y. Greenberg-Shushlav: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc. A. Hershko: Advisory Panel; Self; Oramed Pharmaceuticals, Inc..
IMG-1 Lowers Insulin Resistance by Decreasing Hepatic Glucose Production in a DIO Mouse Clamp Test
Authors: POLLETT JONATHAN B. , NOH HYE LIM , KIM JASON K. , THAI NGOC 
Published: June 2018

IMG-1 is a novel therapeutic compound for the treatment of diabetes. IMG-1 has been shown to successfully treat both type 1 mice and rats (STZ models) and type 2 ZDF rats. To test how IMG-1 is able to treat type II diabetes, diet-Induced Obese (DIO) C57BL/6J mice were used in a hyperinsulinemic-euglycemic clamp assay. The hyperinsulinemic-euglycemic clamp is the gold-standard method to assess insulin sensitivity. The euglycemic clamp is widely used in clinics and laboratories to measure insulin action on glucose utilization in humans and animals for clinical and basic science research. Sixteen DIO C57BL/6J mice underwent a 2-hour hyperinsulinemic-euglycemic clamping to assess insulin action and glucose metabolism in IMG-1 treated (2µg IMG-1 administered IV via tail vein 48 and 24hours prior to the clamp test, n=8) or PBS treated animals (n=8). IMG-1 treated animals had significantly higher steady-state glucose infusion rates during clamping than PBS treated animals, indicating that IMG-1 is able to decrease insulin resistance in DIO mice. IMG-1 did not affect whole-body glucose turnover, glycolysis or glycogen synthesis in any of the treated animals. Glucose metabolism in skeletal muscle and adipose tissue was not significantly different in either IMG-1 or PBS treated animals during the clamp assay. However, Hepatic Glucose Production (HGP) was dramatically suppressed in all animals treated with IMG-1 (a decrease from 3.mg/kg/m to -6.16 mg/kg/m). Furthermore, hepatic insulin action (the percent suppression of HGP) was increased in all IMG-1 treated animals&#x2028;during the hyperinsulinemic-euglycemic clamp (from 70.9 control to 99.7 IMG-1). IMG-1 is a novel compound for the treatment of diabetes. These results show that IMG-1 decreases insulin resistance in a type 2 diabetic mouse model by suppressing HGP and increasing hepatic insulin action.

Disclosure
J.B. Pollett: Employee; Self; Imagine Pharma. H. Noh: None. J.K. Kim: None. N. Thai: Board Member; Self; Imagine Pharma.
Role of Vitamin E for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Patients with T2DM—A Randomized, Controlled Trial
Authors: BRIL FERNANDO , BIERNACKI DIANE M. , LOMONACO ROMINA , KALAVALAPALLI SRILAXMI , SUBBARAYAN SREEVIDYA K. , LAI JINPING , TIO FERMIN O. , SUMAN AMITABH , ORSAK BEVERLY K. , HECHT JOAN , CUSI KENNETH 
Published: June 2018

While the use of vitamin E (Vit E) in nondiabetic patients with NASH has proven to be effective in the PIVENS study (NEJM 2010), there is no information about its effect in patients with NASH and T2DM. To examine this, we performed a randomized, double blind, controlled trial assessing the efficacy of Vit E, alone or combined with pioglitazone (PIO) in this population. Patients (n=105) were randomized 1:1:1 to Vit E 400 U BID, Vit E 400 U BID + PIO 45mg QD, or placebo for 18 months. The primary endpoint was histological improvement, defined as a 2-point reduction in the NAFLD activity score from 2 different parameters, without worsening of fibrosis. Secondary outcomes: resolution of NASH, individual histological scores, and metabolic parameters. Based on 2 planned primary comparisons, a p&lt;0.025 was considered to indicate statistical significance. Groups were well matched at baseline. A total of 87 patients completed 18 months of follow-up. More patients on Vit E and PIO combination achieved the primary outcome compared to placebo (65% vs. 22%, p&lt;0.001), but not in the Vit E alone group (36% vs. 22%, p=0.18). The same trend was observed for resolution of NASH, with a significant improvement only in the combination group (57% vs. 18%, p&lt;0.001), but not with Vit E alone (42% vs. 18%, p=0.036). While steatosis grade improved with either combination (p&lt;0.001) or Vit E alone (p=0.018), inflammation (p=0.018) and ballooning (p=0.022) grades only improved with Vit E + PIO. No improvement in fibrosis was observed in any group. Four patients died of cardiovascular causes during the study (2 on Vit E alone and 2 on combination). Weight gain, peripheral edema and hypoglycemia were more frequent in the combination group.
Conclusion: Vit E alone was ineffective to treat NASH in patients with T2DM. While the combination of Vit E and PIO was significantly better than placebo, response rate was similar to that reported for PIO alone in patients with T2DM, suggesting no role of Vit E in this population.

Disclosure
F. Bril: None. D.M. Biernacki: None. R. Lomonaco: None. S. Kalavalapalli: None. S.K. Subbarayan: None. J. Lai: None. F.O. Tio: None. A. Suman: None. B.K. Orsak: None. J. Hecht: None. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..
Long-Term Safety and Tolerability of Dasiglucagon, a Stable-in-Solution Glucagon Analog
Authors: CASTLE JESSICA R. , ELANDER MIKAEL , O'HALLORAN SEAN A. 
Published: June 2018

Several groups are developing fully integrated dual-hormone artificial pancreas systems, which deliver insulin or glucagon in response to changes in glucose to maintain euglycemia. These systems hold the potential to transform management of type 1 diabetes, but in order to be realized these systems require a stable-in-solution glucagon analog suitable for chronic use. Dasiglucagon is a novel glucagon analog stable in liquid formulation. The present studies evaluated safety and tolerability of chronically administered dasiglucagon in rats and dogs.
Rats and dogs were dosed s.c. daily for 26 and 39 weeks, respectively, in 4 groups of 20 rats with 0 (vehicle), 0.5, 2, or 8 mg/kg/day; 4 groups of 4 beagle dogs with 0, 0.02, 0.1, or 0.3 mg/kg/day.
Glucose and insulin levels increased in a dose-dependent manner in all treated animals. In dogs, heart rate increased at the 0.1 and 0.3 mg/kg/day dose level. Liver and kidney weights increased at all dose levels for in both species, and microscopic pathology demonstrated increase in hepatocyte glycogen vacuolation and increase in chronic progressive nephropathy (a normal finding in aging rats). Heart weights increased with no histopathological correlate. All findings showed full/partial recovery after 4-week treatment free periods. Some animals developed anti-drug-antibodies but with no apparent effect on pharmacodynamics. The NOAEL (no observed adverse effect level) dose of 2 mg/kg/day in rats and 0.1 mg/kg/day in dogs represents exposure multiples (AUC) of 22 and 2 compared to anticipated human doses of up to 1 mg/day.
Chronic administration of dasiglucagon multiple times above relevant human doses was well tolerated. All findings were consistent with the known pharmacological effects of glucagon. The risk of glycogen accumulation is not considered relevant for humans treated with dasiglucagon to maintain euglycemia. These findings support long-term human testing of dasiglucagon in dual-hormonal artificial pancreas systems.

Disclosure
J.R. Castle: Consultant; Self; Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk Inc. M. Elander: Employee; Self; Zealand Pharma A/S. S.A. O'Halloran: None.
Effectiveness and Safety of Oral Hypoglycemic Agents as Initial Treatment in Comparison to Insulin Injection in Newly Diagnosed Type 2 Diabetes Mellitus
Authors: CHEN XI , WANG YUFAN , ZHANG AIFANG , WANG NIAN , LI NA 
Published: June 2018

Objective: To explore the effectiveness and safety of oral hypoglycemic agents (OHA) and insulin (INS) therapy as initial treatment in patients with newly diagnosed type 2 diabetes mellitus (T2DM).
Subjects and Methods: An retrospective cohort study was conducted between December 2015 and June 2017 in diabetic clinic in Shanghai General Hospital.195 newly diagnosed T2DM were enrolled. 107 subjects received OHA while 88 subjects received insulin therapy of which 39 switched to OHA in 6 months. The general characteristics, HOMA-B and HOMA-IR, the glycemic control, glucose control rate and hypoglycemia were compared between OHA group and INS group. All of those data were compared between continued insulin group and switch to OHA group.
Results: 1.The baseline A1C levels were higher and HOMA-B was lower in INS group. While the A1C levels was significantly higher and the rates of glycemic control were significantly lower in INS group than in OHA group after 6 months’ treatment. The incidences of hypoglycemia, changes of BMI were similar in both groups. However, Multiple linear regression analysis indicated that baseline A1C was independently associated with glycemic control (P =0.005). 2. 44.32% patients switched to OHA in INS group in 6 months. This subgroup was younger, had better glycemic control and more male subjects compared with patients who still used insulin. There were no significant differences in terms of A1C, BMI and HOMA-B at baseline, the changes of BMI and rates of hypoglycemia.Binary logistic regression showed that age was significantly associated with continuous usage of insulin. (P=0.005).
Conclusion: Our results demonstrate that baseline A1C was negatively associated with glycemic control and the younger the more possibility to switch from insulin to oral hypoglycemic agents in real word setting. Incidences of hypoglycemia were similar in OHA and INS groups.

Disclosure
X. Chen: None. Y. Wang: None. A. Zhang: None. N. Wang: None. N. Li: None.
L-Carnitine and Resveratrol Action on Oxidative Response and Differentiation in H9c2 Rat Cardiomyocytes
Authors: TERRUZZI ILEANA , SENESI PAMELA , MONTESANO ANNA , VACANTE FERNANDA , LUZI LIVIO 
Published: June 2018

Diabetic heart disease (DHD) results in structural and functional deterioration due to progressive loss of cardiomyocytes and cardiac stem cells, leading to a premature aging of the diabetic heart. The causes of DHD development are not completely clarified, but it is evident that higher oxidative stress of diabetes induces cardiac structural alterations. Recently, the use of stem cells or cardiac progenitors have inspired the most promising therapeutic strategies but these approaches are limited in diabetic patients. Herein we investigate L-Carnitine (LC) and Resveratrol (RSV) actions on oxidative stress and differentiation process in H9c2 rat cardiomyocytes. H9c2, during proliferation or differentiation condition, were treated with LC (0.5 or 5mM) or RSV (0.1 or 25μM). LC significantly enhanced anti-oxidative response by increasing (48 and 72h) mitochondrial SOD2 protein expression and STAT3 activation. LC did not induce p21 translocation at the nuclear level, demonstrating not to have an inhibitory effect on the cell cycle. LC decreased protein synthesis of CaMKII, whose activation is associated with hypertrophic process. In addition, the protective LC effect on H9c2 cardiomyocytes in stress condition was evaluated treating cells with LC 48h before exposure to H2O2: LC significantly reduced intracellular ROS concentration in a dose-dependent manner. RSV 0.1μM while increasing CaMKII content, did not show any effect on the proliferative potential of H9c2. RSV 25μM induced a significant proliferation decrease in favor of H9c2 differentiation, as shown by ERKs pathway activation and α-actinin protein synthesis promotion. RSV 25μM significantly reduced ROS generation induced by rotenone in neo cardiomyotubes (72h). The ability to improve the microenvironment damaged by oxidative stress and to stimulate cardiac progenitor differentiation could recognize LC/RSV as valid adjuvant therapies to preserve cardiomyocytes survival and ameliorate heart regeneration.

Disclosure
I. Terruzzi: None. P. Senesi: None. A. Montesano: None. F. Vacante: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew.
Telmisartan Combination with Amlodipine Inhibits RAGE
Authors: SRIRAMOJU SWETHA , GOETZ KERRY 
Published: June 2018

Diabetic Retinopathy (DR) is the leading cause of blindness in the United States corresponding to 20,000 new diagnoses annually (cite this). Hyperglycemia is a major risk factor of type 2 diabetes and leads to the formation of plasma proteins known as Advanced Glycation End Products (AGEs). In the eye, AGES’s bind to the receptor of the Advanced Glycation End Products (RAGEs) eventually leading to DR. The following study analyzed drug targets (single drugs and combination of drugs) that are currently marketed for heart disease, diabetes, and hypertension to understand how they interact with RAGE with the goal of identifying compounds that are predicted to inhibit the ligand-receptor interaction. Docking programs, AutoDock Tools and AutoDock Vina, were used to determine the binding affinity and visual orientation of the drug receptor binding. Cholesterol lowering drugs such as Atorvastatin and Fenofibrate were able to bind to RAGE with a high hydrophobicity and great negative affinity (-7.5 and -7.7). In combination, the hypertensive drugs such as Telmisartan (Angiotensin II receptor blocker) and Amlodipine (calcium channel blocker) bind with the RAGE receptor with a high hydrophobicity and high negative affinity (-9.7). Metformin administered alone or in combination was not shown to bind to RAGE. Overall this analysis shows that a combination of hypertensive drugs and cholesterol lowering drugs may decrease the progression of DR in type II diabetes.

Disclosure
S. Sriramoju: None. K. Goetz: None.
Cost-Effectiveness of Telephone-Delivered Behavioral Skills Intervention for African-American Adults with Diabetes
Authors: EGEDE LEONARD E. , DISMUKE CLARA , EILER CHRISTIAN , WALKER REBEKAH J. 
Published: June 2018

Background: To investigate cost differences between intervention arms of a telephone-delivered self-management training for African Americans with diabetes.
Methods: This RCT used a 2x2 factorial design, randomizing African American adults with poorly controlled diabetes to: 1) knowledge only, 2) skills training only, 3) combined knowledge and skills training, or 4) control group receiving general health education. The primary outcome for cost effectiveness was glycemic control (HbA1c) at 12-months post-randomization. Costs for healthcare utilization were measured using Medical Expenditure Panel Survey (MEPS) estimates and costs for lost wages were estimated using interval regression. All costs were adjusted to 2012 dollars. Cost utility was quality-adjusted life years (QALYs) estimated via the area under the curve technique using utilities obtained from respondents’ answers to SF-12 questions and mortality estimates based on CDC lifetables. Empirical joint distribution of incremental costs, QALYs, and cost effectiveness acceptability curves were generated using non-parametric bootstrapping.
Results: There was no significant difference in cost (p=0.44) or change of QALYs between arms (p=0.36). With no statistically significant difference in cost, the incremental cost effectiveness ratios (ICER) were not significant compared to control, however, the knowledge only arm was $660 less expensive, the behavioral skills arm was $813 more expensive, and the combined arm was $3,630 less expensive than the control arm to achieve a 0.6% decrease in HbA1c.
Conclusions: Combined with the clinical findings, these results suggest telephone-delivered education and behavioral skills training is a cost-effective way to improve glycemic control. In particular, the combined knowledge and skills training intervention arm resulted in costs $3,600 lower than the control, and dropped HbA1c by 0.6%, achieving a clinically significant change for lower cost.

Disclosure
L.E. Egede: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Advisory Panel; Self; Novo Nordisk Inc.. C. Dismuke: None. C. Eiler: None. R.J. Walker: None.
Cost-Effectiveness Analysis of the EndoBarrier Device in Patients with Type 2 Diabetes
Authors: GUPTA PIYA SEN , ARMSTRONG STEPHANIE , AMIEL STEPHANIE A. , RYDER ROBERT E. , PENNINGTON MARK W. 
Published: June 2018

Objective: There are multiple pharmacotherapy options for type 2 diabetes mellitus (T2DM) including injectable glucacon-like peptide-1 receptor agonists (GLP-1RA) e.g., liraglutide. EndoBarrier is an innovative impermeable liner implanted endoscopically into the proximal intestine for up to one year, before removal. We compared the cost effectiveness of three strategies in patients with suboptimally controlled diabetes despite at least 6 months’ liraglutide: EndoBarrier combined with 1.2mg liraglutide (E+L); EndoBarrier without liraglutide (E), and 1.8mg liraglutide without Endobarrier (L) for the treatment of obese patients with T2DM from a National Healthcare perspective.
Methods: Seventy patients were randomised to one of three treatment arms (REVISE-Diabesity ISRCTN00151053) and followed for two years. Quality of life was measured with EQ-5D-5L and Quality Adjusted Life-Years (QALYs) calculated. Treatment costs were estimated including the costs of adverse events related to treatment. The incremental cost-effectiveness ratio (ICER) was calculated over a two-year horizon. The Core Diabetes Model (QuintilesIMS) was used to estimate outcomes and costs beyond two years based on patient physiological data at two years, allowing calculation of the lifetime ICER.
Results: At two years, QALYs were highest in the E group, followed by E+L, after adjustment for baseline differences. Costs were lowest in the L group and highest in the E group. The ICER of E compared with L was £25,130. However, E+L generated the largest reductions in both HbA1c level (-0.6% compared with L) and weight (-2.1 Kg compared with L) at two years. Consequently, over the lifetime of a patient E+L generated the most QALYs and the lowest cost.
Conclusion: Our analysis suggests a role for EndoBarrier along with GLP-1RA therapy for the control of HbA1c and weight in patients with T2DM. Further research to confirm the sustainability of gains in HbA1c and weight following removal of EndoBarrier is recommended.

Disclosure
P. Sen Gupta: None. S. Armstrong: None. S.A. Amiel: Advisory Panel; Self; Medtronic MiniMed, Inc., Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. R.E. Ryder: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; Bioquest, Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. M.W. Pennington: Consultant; Self; Merck Sharp & Dohme Corp..