bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health State Utilities Associated with Attributes of Weekly Injection Devices and Subdermal Implant for Treatment of Type 2 Diabetes
Authors: RENTZ ANNE M. , CUTTS KATELYN , WASHINGTON KELLIE , BEILLAT MAUD , YU-ISENBERG KRISTINA 
Published: June 2018

Cost-utility analyses include health utilities to compare medical treatments. Health utilities, ranging from 0 to 1, represent the strength of a patient’s preference for a drug profile or health-related outcome. Recently glucagon-like peptide-1 (GLP-1) receptor agonists have been used for management of glycemic control in type 2 diabetes (T2DM). Many GLP-1 drugs have similar modes of administration. In contrast, ITCA 650 is an investigational product which is an implantable device that, following subdermal placement, provides continuous delivery of exenatide for 3 or 6 months. The study’s purpose was to estimate health utilities associated with treatment processes of GLP-1s for use in economic models. During a UK-based pilot study, 19 general population (general population) participants completed time trade-off (TTO) interviews to value health states (often called vignettes or scenarios) which were based on literature review, instructions for use, and clinician interviews. A follow-up pilot study was conducted in both general population and T2DM participants to value modified health states. Participants were recruited to ensure equal distribution across gender and education levels. A total of 20 general population and 18 T2DM patients completed face-to-face interviews (general population mean age= 50.7; T2DM mean age = 56.2). Mean utilities (SD) for ITCA-650 were 0.93 (0.06) for T2DM patients and 0.91 (0.11) for the general population. Mean utility scores for injection health states ranged from 0.83-0.92 for T2DM and 0.82-0.91 for general population. Results are higher than others found in the literature for diabetes treatment processes (range: 0.85 to 0.88). A main study with 200 participants will be conducted in early 2018. Results may be useful in cost-utility models comparing the value of treatment processes for patients with T2DM. Findings suggest the TTO method may be used to quantify preferences among different treatment processes.

Disclosure
A.M. Rentz: Other Relationship; Self; Intarcia Therapeutics, Inc., Servier. K. Cutts: None. K. Washington: None. M. Beillat: None. K. Yu-Isenberg: Employee; Self; Intarcia Therapeutics, Inc..
An Allosteric Glucagon Receptor Antagonist, LGD-6972, Displays Biased Receptor Signaling
Authors: VAJDA ERIC G. , ZHI LIN , MARSCHKE KEITH 
Published: June 2018

Glucagon receptor antagonists (GRA) are novel molecules in development for the treatment of type 1 and type 2 (T2DM) diabetes. LGD-6972 recently demonstrated robust efficacy in a 12-week, Phase 2 study in T2DM, reducing HbA1c by 1.2% from baseline, with a safety profile more favorable than other GRAs at this stage of development. LGD-6972 is structurally distinct from other small molecule GRAs, containing a sulphonic acid tail (SAT) rather than a carboxylic acid tail (CAT), potentially explaining this finding. We performed computational modeling of LGD-6972 bound to the glucagon receptor (GCGR) and compared it to x-ray crystallography data with receptor bound MK-0893. The SAT of LGD-6972 creates a larger pocket between helix 6 and 7 in the GCGR transmembrane domain, and alters the orientation of helix 8. Activity of LGD-6972, MK-0893 and other SAT and CAT GRAs were examined in cellular models of glucagon-stimulated cAMP accumulation, β-arrestin recruitment, and receptor internalization. All tested GRAs were full (&gt;95%) antagonists of cAMP accumulation. CAT GRAs were full antagonists of β-arrestin (≥96%) and receptor internalization (≥94%). In contrast, SAT GRAs had reduced antagonism of β-arrestin (58-87%) and receptor internalization (6-52%). The relative potency was also altered with greater potency for CAT GRAs on β-arrestin vs. cAMP, whereas the opposite was true for SAT GRAs. Furthermore, a LGD-6972 analog with a CAT and a MK-0893 analog with a SAT displayed CAT- and SAT-like activity, respectively, indicating a clear structure-activity relationship exists, with LGD-6972 displaying receptor-biased signaling. To further investigate the potential differences among compounds, primary human hepatocytes were treated with glucagon or glucagon with MK-0893 or LGD-6972 and gene expression was analyzed by microarray. Broad differences between glucagon and the GRAs were observed and future studies will investigate the effects of SAT and CAT compounds.

Disclosure
E.G. Vajda: Employee; Self; Ligand Pharmaceuticals, Inc. L. Zhi: Employee; Self; Ligand Pharmaceuticals, Inc. K. Marschke: Employee; Self; Ligand Pharmaceuticals, Inc..
OWL833, an Orally Active Nonpeptide GLP-1 Receptor Agonist, Improves Glucose Tolerance by Increasing Insulin Secretion and Reduces Food Intake of Cynomolgus Monkeys
Authors: KAWAI TAKAHIRO , TANINO FUMIHITO , FUKAZAWA MASANORI , OGAWA KOTARO , NAGAO SHUNSUKE , YOSHINO HITOSHI , KOMATSU SHUN-ICHIRO , SUZUKI YOSHIYUKI , KAWABE YOSHIKI 
Published: June 2018

Activation of glucagon-like peptide-1 receptors (GLP-1R) is a promising approach for the treatment of type 2 diabetes mellitus (T2D), and several peptide analogues of GLP-1 have been successfully developed. Here we identified a new orally active non-peptide GLP-1R agonist, OWL833, and examined its efficacy in cynomolgus monkeys. The agonistic activity of OWL833 was evaluated by measuring cAMP accumulation in cells expressing mammal GLP-1Rs and other glucagon family receptors. In the cells expressing human or cynomolgus monkey GLP-1R, OWL833 promoted cAMP accumulation to the same level achieved by GLP-1, and its EC50 values for human and cynomolgus monkey GLP-1Rs were the same at 1.1 nmol/L. In contrast, OWL833 showed no stimulatory activity on human glucagon, GIP, and GLP-2 receptors. The predicted bioavailability and T1/2 of OWL833 in human based on rodent and non-rodent experimental data are 30% and ∼18 hour, respectively. After OWL833 followed by glucose was intravenously injected in cynomolgus monkeys, OWL833 decreased the blood glucose level via insulin secretion to the same extent as effective concentrations of exenatide, a GLP-1 peptide mimetic, in clinic. Doses of 0.and 0.1 mg/kg OWL833 given orally to cynomolgus monkeys reduced their food intake by 25% and 45%, respectively, as compared with vehicle group, and the effect on food intake was equal to that of 0.3 and 0.6 µg/kg subcutaneous injections of exenatide. No critical finding was observed in the subchronic toxicity studies in rats and cynomolgus monkeys. These findings demonstrate that OWL833 has full agonistic activity on human and cynomolgus GLP-1R and improves glucose tolerance by stimulating insulin secretion, and that it exhibits an anti-feeding activity similar to exenatide.
In conclusion, OWL833 has potential as a once-daily, orally active, non-peptide GLP-1 receptor agonist.

Disclosure
T. Kawai: Employee; Self; Chugai Pharmaceutical Co., Ltd. F. Tanino: Employee; Self; Chugai Pharmaceutical Co., Ltd. M. Fukazawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. K. Ogawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Nagao: Employee; Self; Chugai Pharmaceutical Co., Ltd. H. Yoshino: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Komatsu: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Suzuki: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Kawabe: Employee; Self; Chugai Pharmaceutical Co., Ltd..
Alteration of Gut Microbiota Induced by DPP-4i Treatment Improves Glucose Homeostasis
Authors: LIAO XIAOYU , ZHENG HONGTING 
Published: June 2018

Background and Aims: Emerging evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. While, little is known about the effect of antidiabetic agents on the gut microbiota. In the current study, we investigated the role of DPP-4i and acarbose in modulating the gut microbial community.
Methods: 16S rRNA sequencing was performed to analysis the effect of DPP-4i and acarbose on the gut microbiota in HFD mice. Fecal microbiota transplantation (FMT) from DPP-4i, acarbose, or placebo- treated T2D patients to germ-free (GF) mice was performed to investigate the contribution of the altered microbiota to the antidiabetic effect. Fecal metabolomics were analyzed by untargeted and targeted GC-MS system.
Results: DPP-4i and acarbose changed the gut microbial composition, and the DPP-4i- altered microbiome improved the glucose tolerance, while acarbose- altered microbiome did not. Moreover, DPP-4i primarily reduced the ratio of Firmicutes to Bacteroidetes, and changed the pattern of metabolites in HFD mice, especially the increase of succinate.
Conclusions: Our findings demonstrated that the alterations of the gut microbial composition and metabolites might be a previously unsuspected hypoglycemic mechanism of DPP-4i. It might provide a potential strategy for modulating glucose homeostasis in the future.

Disclosure
X. Liao: None. H. Zheng: None.
Cumulative Delays in Treatment Intensification over Three Typical Stages of Antihyperglycemic Treatment
Authors: VUPPUTURI SUMA 
Published: June 2018

Although delays in treatment intensification (TI) have been documented for anti-hyperglycemic medications, cumulative delays over the life course of diabetes treatment have not been reported. We combined 2005-2016 data from the Northwest and Mid-Atlantic regions of Kaiser Permanente to identify 248 patients who: (1) initiated metformin (MET); (2) then added a sulfonylurea (SU) to existing MET; and (3) initiated insulin (INS) after MET or SU. We used the date of the initiation of each stage of therapy to calculate time between A1C ≥7% and TI, pre-TI A1C, post-TI A1C, and achievement of A1C goal ≤7% within one year of TI. We also measured time to intensification within 6 months prior to TI. Mean or median cumulative measures were summed across the three TI stages. Among patients who experienced each stage of MET, SU, and INS intensification, the mean A1C percentage points outside of goal summed to 5.9 (Table). These patients accrued a median of 191 days of TI delays in the 3 6-month periods preceding TI. Although A1C was lowered after each stage of TI, a minority of patients achieved A1C goals of ≤7% resulting in accumulation of a mean of 3.3 excess A1C percentage points over the 3 one year periods after TI of MET, SU, and INS. TI delays occur at every stage of diabetes therapy. Glycemic burden accumulates over the life course of diabetes and may result in differential complication risks. However, further study is needed.
Cumulative TI ExposuresMET initiationSU add-onINS add-onCumulativeMean distance from goal measured during 1 year after TI1.7%1.7%2.5%5.9 %Median days to intensification measured during 6 months prior to TI27.967.795.3190.9Mean Pre-TI A1c8.7%8.7%9.5%--Mean Post-TI A1c7.7%8.5%8.1%--Post-A1c minus A1c goal measured during 1 year after TI0.7%1.5%1.1%3.3%Achieved A1C goal ≤7%35.1%16.9%26.6%--

Disclosure
S. Vupputuri: Research Support; Self; Sanofi US.
The Comparative Cardiovascular Effectiveness of Six Antidiabetic Medications among Insured Adults with Type 2 Diabetes
Authors: O'BRIEN MATTHEW , KARAM SUSAN L. , WALLIA AMISHA , KANG RAYMOND , COOPER ANDREW J. , LANCKI NICOLA , MORAN MARGARET R. , LISS DAVID T. , PROSPECT THEODORE A. , ACKERMANN RONALD T. 
Published: June 2018

This retrospective cohort study compared the effectiveness of six antidiabetic medication (ADM) classes on major adverse cardiovascular events. Using nationwide U.S. administrative claims data from 2011-2015, we studied 132,737 insured adults with type 2 diabetes who started one of six ADM after taking metformin alone or no prior ADM. The key exposure was the new ADM class, which was filled ≥2 times. The composite primary outcome included hospitalization for one of the following conditions: heart failure, stroke, ischemic heart disease, and peripheral artery disease. Eligibility criteria and outcomes were ascertained using claims data. We used Cox regression to model the association between new ADM class and composite cardiovascular events, adjusting for baseline characteristics of patients, including prior use of metformin and cardiovascular medications, as well as prescribers and health plans. DPP-4 inhibitors (DPP-4) were the comparator given evidence of their cardiovascular neutrality. Overall, 5.5% of patients had a history of prior cardiovascular disease. There were 3,603 cardiovascular events during a mean follow-up of 1.3 years. Compared to DPP-4, the adjusted hazard ratios for each ADM class were: [sulfonylureas (SFU): HR 1.36, 95% CI: 1.23-1.49; basal insulin: HR 2.03, 1.81-2.27; thiazolidinediones (TZD): HR 0.89, 0.73-1.08; SGLT2 inhibitors (SGLT2): HR 0.80, 0.56-1.14; and GLP-1 receptor agonists (GLP-1): HR 0.78, 0.63-0.96]. The GLP-1 benefit was not robust across alternate modeling approaches. Among low-risk patients with type 2 diabetes, we found higher cardiovascular risk associated with SFU and basal insulin compared to newer ADM classes. Cardiovascular outcomes associated with DPP-4, GLP-1, and SGLT2 were similar in this population. Providers may consider prescribing these newer drugs routinely after metformin. Future clinical trials and data describing total costs of care will further inform providers’ choice of second-line ADM.

Disclosure
M. O'Brien: None. S.L. Karam: Research Support; Self; United Healthcare Services. A. Wallia: Research Support; Self; UnitedHealth Group. Consultant; Self; Glytec Systems, Lexicon Pharmaceuticals, Inc.. Research Support; Self; Eli Lilly and Company. R. Kang: Research Support; Self; UnitedHealth Group. A.J. Cooper: Research Support; Self; UnitedHealth Group. N. Lancki: Research Support; Self; United Healthcare Services. M.R. Moran: Research Support; Self; United Healthcare Services. D.T. Liss: Research Support; Self; United Healthcare Services. T.A. Prospect: Employee; Self; UnitedHealth Group. R.T. Ackermann: Consultant; Self; UnitedHealth Group.
Systems Medicine Derived Biomarkers to Assess How Canagliflozin Delays Progression of Diabetic Kidney Disease
Authors: HEERSPINK HIDDO LAMBERS. , PERCO PAUL , LEIERER JOHANNES , HANSEN MICHAEL K. , HEINZEL ANDREAS , MAYER GERT 
Published: June 2018

The SGLT2 inhibitor canagliflozin (CANA) slows progression of kidney function decline in type 2 diabetes. In this translational study, we determined in silico potential mechanisms of action (MoA) and identified representative candidate biomarkers to assess in vivo how CANA may delay progression of diabetic kidney disease (DKD). These biomarkers were then validated in a CANA clinical trial. A CANA MoA network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes of disease progression. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with CANA therapy and may be used to monitor CANA response. These biomarkers were measured in 296 plasma samples of the 2-year CANTATA-SU clinical trial comparing CANA with glimepiride. Forty-four proteins present in the CANA MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates serving as proxy for monitoring impact of CANA on DKD pathophysiology. For ten of these, scientific evidence was available suggesting that they are involved in DKD progression. Of these, CANA 300 mg decreased plasma levels of tumor necrosis factor receptor 1 (TNFR-1; 9.2%, p&lt;0.01), interleukin 6 (IL6; 26.6%, p=0.01), matrix metalloproteinase 7 (MMP7; 24.9%, p=0.01), and fibronectin 1 (FN1; 14.9%, p=0.02) during two years follow-up. Changes in TNFR-1 at 1 year independently associated with eGFR decline over 2 years (p=0.0234). This study successfully applied a network-based systems biology analysis to select biomarkers for monitoring kidney response to CANA. CANA significantly reduced plasma levels of TNFR-1, IL6, MMP7, and FN1 suggesting CANA reverses molecular processes related to inflammation, extracellular matrix and fibrosis.

Disclosure
H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Consultant; Self; Janssen Research & Development, Fresenius SE & Co. KGaA. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. P. Perco: None. J. Leierer: None. M.K. Hansen: Employee; Self; Janssen Research & Development. A. Heinzel: None. G. Mayer: None.
Short-Term Effects of a Sodium-Glucose Linked Transporter 2 Inhibitor on Left Ventricular Relaxation in Nondiabetic Hypertensive Patients
Authors: KRYSTEL KELLY EBO ETOUA , MBANYA JEAN CLAUDE , SOBNGWI EUGÈNE , LILIANE MFEUKEU KUATE 
Published: June 2018

Background: The rapid beneficial effects of Empagliflozin on cardiovascular mortality and hospitalization rate for heart failure in subjects with type 2 diabetes Mellitus raised some questions related to a potential intrinsic effect on the heart. We conducted this study in a population of nondiabetic hypertensive patients in order to look out for short-term effects on left ventricular relaxation.
Methods: We carried out a single arm non-randomized clinical trial. Each patient received 25mg of empagliflozin as add-on therapy once daily for six weeks. We included nondiabetic hypertensive patients on stable anti-hypertensive medication for at least 12weeks with diastolic dysfunction haven given their informed consent. The outcome measures were to evaluate the left ventricular relaxation, to determine changes in the nycthemeral blood pressure profile and to evaluate the electrocardiographic profile before and after the treatment. The primary endpoint was the increase in velocity of the lateral mitral annulus e’ at Doppler echocardiography.
Results: A total of 11 patients were treated. Nine patients had significant improvement of their mitral profiles E/A from 0.71 [0.58-0.75] to 0.82 [0.79-0.93] cm/s (p= 0.008). The velocity e’ that was impaired in 5 patients improved by 22% in 4 patients. The effect of empagliflozin was non-significant on blood pressure at ABPM. On the electrocardiogram we observed a significant decrease in the PR interval from 200 [157-200] to 160 [143-186] ms, p= 0.04.
Conclusion: Daily intake of 25mg Empagliflozin is associated with an early improvement of the left ventricular relaxation in nondiabetic hypertensive patients without significant reduction in blood pressure. This suggests an intrinsic myocardial action of Empagliflozin to investigate.

Disclosure
E. Krystel Kelly: None. J. Mbanya: Advisory Panel; Self; GlaxoSmithKline plc.. Speaker's Bureau; Self; Novo Nordisk A/S, Sanofi, Servier. E. Sobngwi: None. M. Liliane: None.
Dapagliflozin Improves Insulin Sensitivity in the Obese Prediabetic Canine
Authors: PASZKIEWICZ REBECCA L. , BERGMAN RICHARD N. , BEDIAKO ISAAC ASARE , MKRTCHYAN HASMIK J. , SASHI GOPAUL V. , YANG HSIU-CHIUNG , LUNDBORG EVA , KIM STELLA , FORMENTINI IVAN , KOLKA CATHRYN M. 
Published: June 2018

SGLT2 inhibition has positive effects on glucose balance, reducing fasting and postprandial glucose levels, however little is known about the effects of SGLT2 inhibitors on lipid levels. PKPD simulation for this canine model was applied for dose selection of dapagliflozin (dapa). Seven dogs were fed a high fat diet for 6 weeks, then received a single low dose of streptozotocin (18.5mg/kg) to induce mild type 2 diabetes. Animals were exposed to dapa (n=4, 1.25mg/kg) or placebo (n=3) once per day for 6 weeks, while remaining on the high fat diet. Animals were then subjected to the intravenous glucose tolerance test (IVGTT) to assess glucose tolerance and insulin response to glucose, and the euglycemic hyperinsulinemic clamp protocol in conjunction with tracer infusions to evaluate adipose tissue, skeletal muscle and hepatic insulin sensitivity. In the IVGTT, modeling techniques are used to estimate the acute insulin response to a glucose bolus, which was not altered with dapa treatment, but insulin sensitivity was significantly improved compared to placebo-treated animals (dapa 0.54±0.22, control -0.95±0.51mU/l-1.minute-1, p=0.05). The glucose infusion required for euglycemia during steady state in the clamp was decreased with dapa (dapa -3.0±1.05, control 1.53±1.28 mg/minute/kg, change from pre-drug timepoint, P=0.038), supporting the IVGTT results. Urinary glucose disposal rate during the clamp was inconsistent. There is a trend towards higher FFA levels in dapa-treated animals under noninsulin stimulated conditions (P=0.054). These may be a regulator of hepatic glucose production, or reflect a switch towards lipid utilization. We conclude that 6 weeks of dapa treatment improves insulin sensitivity in a canine model of mild type 2 diabetes. Further studies on lipid metabolism, body fat deposition and insulin clearance are on-going.

Disclosure
R.L. Paszkiewicz: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S. I. Asare Bediako: None. H.J. Mkrtchyan: None. V. Gopaul: Employee; Self; AstraZeneca. H. Yang: Employee; Self; AstraZeneca. E. Lundborg: Employee; Self; AstraZeneca. S. Kim: None. I. Formentini: Employee; Self; AstraZeneca. C.M. Kolka: Research Support; Self; AstraZeneca.
Which Is Better? High-Dose Metformin Alone or Combination of Low-Dose Metformin and Linagliptin on Glycemic Variability in Japanese Type 2 Diabetes Patients with Insufficient Glycemic Control with Low-Dose Metformin Alone—A Randomized, Crossover, Pilot Study
Authors: TAKAHASHI HIROSHI , NISHIMURA RIMEI , UTSUNOMIYA KAZUNORI 
Published: June 2018

The aim of this study is to investigate the effect of high dose metformin or combination of low dose metformin and linagliptin on glycemic variability (GV) in Japanese type 2 diabetes (T2D) patients with insufficient glycemic control with low dose metformin alone in a cross-over study using continuous glucose monitoring (CGM). This study was conducted in T2D outpatients (7%&lt; HbA1c &lt;10%) receiving low dose metformin (750-1000 mg) alone. All patients were assigned to metformin 1500 mg monotherapy (high dose metformin; HMET) or combination of metformin 750 mg and linagliptin 5 mg (low dose metformin and DPP-4; LMET+DPP-4) in a cross-over fashion and underwent CGM assessments more than 4 weeks after change of treatment. 24-hour data were collected for comparison after they had had the same retort pouch foods. Mean glucose level, standard deviations of glucose (SD), glucose coefficient of variation (%CV), mean amplitude of glucose excursions (MAGE), pre-meal glucose levels, and 3-hour postprandial glucose area under the curve (AUC, &gt;160 mg/dL) were compared between HMET and LMET+DPP-4 groups by using t-test. The study enrolled a total of 11 patients with T2D (men/women, 8/3; age, 51.9 ± 9.8 years; BMI, 26.3 ± 3.0 kg/m2; HbA1c, 7.6 ± 0.4%; and metformin dose 750/1000 mg, 6/5). Of the CGM-derived GV metrics for the HMET vs. LMET+DPP-4, mean glucose level, SD, MAGE and %CV were not significantly different (p=0.946, 0.394, 0.865, 0.290). Again, while the pre-breakfast glucose level were not significantly different between the groups (p=0.432), the AUC after breakfast was significantly smaller in LMET+DPP-4 vs. HMET (5004 ± 3220 vs. 7712 ± 5177; p=0.047). A comparison of GV with HMET vs. LMET+DPP-4 suggested that LMET+DPP-4 may reduce post-breakfast GV to a greater degree than HMET in Japanese patients with T2D receiving low dose metformin monotherapy.

Disclosure
H. Takahashi: None. R. Nishimura: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Abbott, Medtronic, MSD K.K., Novo Nordisk A/S, Sanofi, Takeda Development Center Asia, Pte. Ltd., Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.. K. Utsunomiya: None.