bluuebunny/crossref_metadata_2025_split huggingface dataset:
680-P: PAID-ing Off through Personalized Chronic Disease Management—Promising Preliminary Analysis in Alleviating Diabetes-Related Distress
Authors: BENOWITZ KYRA , WONG SHIRLEY , YOUNG CLIPPER F. 
Published: June 2024

Objective: To examine whether a personalized chronic disease management approach induces a change in diabetes-related distress (DRD).
Methods: This pilot analysis - embedded in a clinical pharmacy program delivering care via telehealth and home visits, the Pharm2Home Initiative - utilizes a prospective design, comparing outcomes between two time points. DRD is measured using the Problem Areas in Diabetes 5-Item Scale (PAID-5). Inferential statistics were used to detect whether differences existed in each pair of PAID-5 item data and the total score.
Results: The primary and secondary outcomes are summarized below.

Conclusion: This preliminary analysis detected a significant difference in the total PAID-5 score with a 35% reduction from baseline, suggesting the personalized chronic disease management approach positively impacts participants’ DRD. Also, with no significant difference being detected in all measures within the secondary outcome, this intervention potentially induces a legacy effect where participants at least maintained a similar level of DRD three months after the intervention period. The outcomes thus far reflect an interprofessional effort, partnering clinical pharmacists with diabetologists and primary care providers to co-manage chronic diseases. Continuous monitoring is warranted to determine the program's impact on DRD.

Disclosure
K. Benowitz: None. S. Wong: None. C.F. Young: Other Relationship; Abbott.
712-P: Assessing the Relationship between Social Support, Depressive Symptoms, and Type 2 Diabetes Outcomes among Older Adults
Authors: SMALLS BRITTANY L. , TAYLOR ZOE M. , GONZABATO NELSON , SCHAEFER JILL 
Published: June 2024

Type 2 diabetes (T2D) is an epidemic across the U.S. with a 11.6% prevalence for adults nationally, compared to 13.6 -23.6% spanning urban and rural areas in Kentucky. Additionally, older adults are disproportionately affected, where 1 in 4 have T2D. Kentucky also has high rates of depression, which literature has shown a bi-directional relationship with T2D. Therefore, this study sought to evaluate the relationship between social support, depressive symptoms, and T2D outcomes among older adults living in Kentucky. &lt;u&gt;&lt;/u&gt; Social support and depression were assessed using the MOS Social Support Survey and the Geriatric Depression Scale (GDS). Respondents were also asked to name up to 3 individuals in their support network. Mean raw MOS scores were enumerated and subscale means were converted to percentages. Spearman correlation was used to assess associations. There were 55 participants with a mean A1C of 7.02%. Of those, 49.09% reported three social support members, and only 7.27% reported zero social support. MOS revealed generally increasing scores highlighting a robust network size has direct impact on diabetes management. Social network size was negatively correlated with GDS scores (r= -0.13, p=0.38) and positively correlated with all MOS subscales. The overall MOS score was negatively correlated with A1c (r= -0.19, p=0.2) as was network size (r= -0.09, p=0.54). GDS scores showed a weak negative correlation with A1c (r= -0.10 p=0.52). Social support was associated with fewer depressive symptoms and improved glycemic control. Future longitudinal studies with larger and more diverse samples could&lt;u&gt; &lt;/u&gt;further clarify these relationships.

Disclosure
B.L. Smalls: None. Z.M. Taylor: None. N. Gonzabato: None. J. Schaefer: None.

Funding
National Institutes of Diabetes and Digestion and Kidney Disease (5K01DK116923-05)
751-P: Benefits of HR17031, a Fixed-Ratio Combination of INS068 and SHR20004, vs. Its Components Alone in Patients (pts) with Type 2 Diabetes (T2D) Uncontrolled on Oral Antidiabetic Drug(s) (OADs)
Authors: JI LINONG , HUANG DEBING , LIN XIANG , DONG XUE , LI LU , SUN QINGYUAN , SUN XIAODONG , MAO LI , ZHAO SHI , WANG QUANREN , YE ZI 
Published: June 2024

Introduction & Objective: HR17031 is a once-daily, novel combination of basal insulin analogue (INS068) and GLP-1 receptor agonist (SHR20004). This trial assessed efficacy and safety of HR17031 vs INS068 and SHR20004 in pts with T2D.
Methods: In this randomized phase 2 trial, 455 Chinese adults with T2D (HbA1c 7.5%-11.0%; previous metformin±another OAD) were randomized (2:2:1) to daily injections of HR17031 (n = 183), INS068 (n = 182) or SHR20004 (0.12 mg/d; n = 90). Primary outcome was HbA1c change at 26 weeks.
Results: After 26 weeks, greater reduction in HbA1c from baseline was achieved with HR17031 compared with INS068 and SHR20004 (-2.4% vs -1.5% and -1.7%; Fig 1), indicating superiority for HR17031 vs both INS068 (difference [D] = -0.9%) and SHR20004 (D = -0.7%). More pts reached HbA1c target &lt;7% and &lt;6.5% with HR17031 (&lt;7%, 81.4%; &lt;6.5%, 74.3%) than INS068 (47.8%; 26.4%) and SHR20004 (55.6%; 41.1%). HR17031 led to weight loss in contrast to INS068 (-0.1 vs 2.0 kg). Insulin dose of HR17031 was lower than INS068 (30.3 vs 38.1 U/d). All the above results were statistically significant (all P &lt;0.001). Documented &lt;3.0 mmol/L hypoglycemia was similar with HR17031 (5.5%) and INS068 (4.4%). No unexpected safety issues occurred.
Conclusion: HR17031 is effective and well-tolerated in pts with T2D uncontrolled on OAD(s).

Disclosure
L. Ji: None. D. Huang: None. X. Lin: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. X. Dong: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. L. Li: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Q. Sun: None. X. Sun: None. L. Mao: None. S. Zhao: None. Q. Wang: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Z. Ye: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding
Jiangsu Hengrui Pharmaceuticals Co., Ltd (sponsor)
766-P: Long-Term Effectiveness Associated with Maintenance Doses of Once-Weekly Semaglutide in U.S. Adults with Poorly Controlled Type 2 Diabetes
Authors: TAN XI , CAO YIWEN , DUNN TYLER J. , LIANG YUANJIE , NOONE JOSHUA , GAMBLE CORY L. , KING AARON A. 
Published: June 2024

Introduction & Objective: To evaluate long-term effectiveness associated with maintenance doses of once-weekly semaglutide (sema) in US adults with poorly controlled type 2 diabetes (T2D).
Methods: Observational cohort study (Optum Clinformatics® Data Mart, Jan 2017-Dec 2022). Eligibility criteria: confirmed diagnosis of T2D, HbA1c ≥9.0% and newly initiated sema. Exclusion criteria: T1D and pregnancy. HbA1c outcomes were assessed in the 2nd year of follow-up in three groups reaching: 0.5 mg only; ≥0.5 mg; and 1 mg. Time to initiation (TTI) of new glucose‑lowering therapy (GLT) was assessed in patients (pts) reaching 1 mg within 1 year.
Results: Among 2311 pts, the 1 mg group (50.2%) had worse overall health and T2D at baseline vs the 0.5 mg-only group (32.5%). There was a ~2.5% reduction in HbA1c in the second year of follow‑up, across all groups (Table). After reaching 1 mg sema, 29.5% of pts newly initiated any GLT, 14.9% initiated SGLT-2i and 6.9% insulin. Average TTI of any new GLT was 208 days. TTI of insulin or SGLT-2i after dose escalation to 1 mg was 235 days and 234 days, respectively, and from sema initiation was 312 and 310 days, respectively.
Conclusion: In pts with poorly controlled T2D, sema maintenance doses were associated with a considerable reduction in HbA1c and delay in insulin initiation in a 2-year follow-up, highlighting the importance of a maintenance dose in such pts.

Disclosure
X. Tan: Employee; Novo Nordisk, Merck & Co., Inc. Y. Cao: None. T.J. Dunn: Employee; Novo Nordisk. Y. Liang: Employee; Novo Nordisk. J. Noone: Employee; Novo Nordisk. C.L. Gamble: Employee; Novo Nordisk. A.A. King: Speaker's Bureau; Abbott, MannKind Corporation, Novo Nordisk. Advisory Panel; Novo Nordisk. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Dexcom, Inc. Advisory Panel; Dexcom, Inc. Speaker's Bureau; Astellas Pharma Inc.

Funding
Novo Nordisk Inc.
768-P: A Phase 1b/2a Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of PB-718, a GLP-1R/GCGR Dual Agonist in Subjects with Obesity
Authors:   STUDY GROUP PB-718, DING KE 
Published: June 2024

Introduction: PB-718 is a fixed dose combination of PB-119 (GLP-1 receptor agonist) and PB-722 (glucagon receptor agonist in clinical development. Compared with a single molecule approach, PB-718 may offer the balance between GLP-1 and GCGR through adjusting the molar ratio of PB-119 and PB-722 to achieve optimal efficacy and safety. Linear pharmacokinetics, good tolerability and promising effect of weight loss have been demonstrated in a phase 1 study conducted in US. Here we report a phase 1b/2a study in Obesity
Methods: Thirty-six patients with obesity (BMI 30.5-40.0 kg/m2) without diabetes were randomized to this 3-sequential cohorts study (NCT06147544). In each cohort, 12 subjects were randomized (3:1) to receive PB-718 (PB-119/PB-722 600/1560 μg, 900/2340 μg or 1600/4160 μg) or placebo SC. injections once a week for 12-18 weeks. The primary endpoints were safety and PK profile. The secondary efficacy endpoints included changes in body weight (BW), BMI, lipids and HbA1c levels. Liver MRI-PDFF and body composition analysis were also assessed.
Results: Both PB-119 and PB-722 demonstrated dose-proportional increases in AUC0-last and Cmax ,showing linear, and synergic pharmacokinetics. At 12 weeks, BW, FPG, HbA1c, Lipid, insulin level and HOMA-IR all decreased dose-dependently, and significant reduction in BW of over 4-6% were observed. Serum uric acid was also decreased. Liver fat content and visceral fat mass also showed significant and dose-related reduction with PB-718 treatment. Meanwhile, PB-718 groups lost more fat mass than lean mass. GI side effects were the most common AEs, and were all grade 1 in severity.
Conclusions: PB-718 was safe, had predicted PK profile, and led to greater reductions in BW, HbA1c, blood lipids, uric acid, liver fat content and visceral fat mass. These data highlight the potential for PB-718 to provide additional benefit, and support the development of PB-718 as a promising treatment for obesity and NASH.

Disclosure
K. Ding: None.
776-P: Potent Weight Loss and Favorable Glycemic Control Effects of a Novel Long-Acting GLP-1/GIP/GCG Triple Agonist, HM15275, in Animal Models
Authors: HYUN PARK SANG , KIM YOHAN , KUK KIM JUNG , LEE DAHAE , PARK EUNJIN , KIM JEONG A. , HONG SUNGHEE , CHOI JAEHYUK , BAE SUNGMIN , HYUN LEE SANG , YOUNG CHOI IN 
Published: June 2024

Introduction & Objective: The prevalence of obesity is increasing worldwide, urging development of obesity drugs with better efficacies and weight loss qualities. HM15275 is a GLP-1/GIP/Glucagon triple agonist designed to have well-harmonized activities and long-acting property for maximized body weight reduction. To elaborate the effects, a series of studies were conducted to evaluate (1) proper target engagement, (2) pharmacokinetics, and (3) body weight loss effects in DIO mice.
Method: Target receptor engagement of HM15275 was tested by cAMP assay with or without antagonist for each receptor. Plasma concentrations of HM15275 in rat and mouse were measured after a single subcutaneous dosing of HM15275. In DIO mice, body weight loss by HM15275 was compared with semaglutide and tirzepatide after 3 weeks treatment.
Results: Maximal in vitro activities of HM15275 significantly reduced in the presence of selective GLP-1, GIP, or Glucagon antagonist (hGLP-1R: 94.56% to 0.81%, hGIPR: 97.85% to 14.07%, hGlucagonR: 95.16% to 4.14%), indicating proper target engagement. In addition, protracted pharmacokinetic profiles were observed in rodent models, (half-life in mouse: 12 ~ 16 hr and rat: 17 ~ 19 hr). In DIO mice, HM15275 remarkably decreased body weight compared to semaglutide or tirzepatide at week 3 (-39.9%, -15.0%, and -25.3% vs. baseline). Furthermore, pair-fed study showed both food intake inhibition dependent and independent weight loss by HM15275. Energy balance evaluation revealed enhanced energy expenditure by HM15275. ipGTT results indicated favorable glycemic control of HM15275.
Conclusion: As a novel long-acting triple agonist, the molecular characteristics of HM15275 had been elucidated, demonstrating superior weight loss compared to currently available anti-obesity drugs. Therefore, HM15275 could be a valuable therapeutic option for weight control and human study is ongoing to assess clinical relevance of such findings.

Disclosure
S. Park: None. Y. Kim: None. J. Kim: None. D. Lee: None. E. Park: None. J.A. Kim: None. S. Hong: None. J. Choi: None. S. Bae: None. S. Lee: None. I. Choi: None.
785-P: Preclinical Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) Assessments of Sustained-Released Formulation of Once-Monthly Injectable Semaglutide (PT403)
Authors: LEE JIHYANG , CHO JAEPYOUNG , JANG EUNSEO , KIM MIRI , BAE JIHYUN , CHOI MYUNG-JOO , CHANG SEUNG-GU , G JUNG JIN 
Published: June 2024

Objective: Advancements in GLP-1RA research, shifting from daily to weekly injectables, have improved therapeutic outcomes and expanded market potential, paving the way for monthly injectable drug development. This study evaluates the clinical potential of PLGA-encapsulated once-monthly injectable semaglutide through extensive non-clinical assessments, including safety profiling and pharmacokinetic/pharmacodynamic evaluations.
Methods: Semaglutide was solubilized in acetic acid with a diverse biodegradable PLGA polymer mixture and processed using ultrasonic spray-drying to create microspheres encapsulating semaglutide. The optimized formulation, PT403, with a proper drug loading and no initial burst was developed. Subsequent assessments, including PK, PD, and toxicology, were conducted in mouse, rat, and/or minipig.
Results: PT403 exhibits favorable physicochemical properties, including uniform microsphere size (20μm), one-year stability, and extended release up to 70 days in minipigs. In a Single Ascending Dose (SAD) study in mice, PT403 induced a 20% body weight reduction at doses ranging from 24 to 192 mg/kg. No other notable critical signs were observed, ensuring a safe profile even up to 192 mg/kg. Moreover, simulated release profiles suggest PT403's potential as a once-a-month injectable, with a Peak-to-Trough ratio of 1.4. Both semaglutide and PT403 demonstrated consistent reductions in body weight (30%) and cumulative food intake across 28 repeated injections of semaglutide and double injections of PT403.
Conclusion: PT403, featuring uniform microsphere size and favorable drug loading, exhibited safety in mice at the highest dose. Simulations support this formulation, and consistent pharmacodynamic effects across semaglutide and PT403 groups in repeated injections suggest its promise for clinical development as a monthly injectable for diabetes and obesity.

Disclosure
J. Lee: None. J. Cho: None. E. Jang: None. M. Kim: None. J. Bae: None. M. Choi: None. S. Chang: None. J. Jung: None.
800-P: Post Hoc Analysis of Phase III Study of Liraglutide Biosimilar with Reference Biologic in Obese Type 2 Diabetes Mellitus Indians
Authors: JOSHI SHASHANK R. , BARKATE HANMANT V. , MANE ABHISHEK , PETARE ANUP U. , CHOUDHARI SANJAY Y. 
Published: June 2024

Background: Biosimilar of Liraglutide developed in India has demonstrated non-inferiority in terms of safety, efficacy and quality compared to reference biologic. Basis this biosimilar of Liraglutide has been approved in India for management of T2DM. Data generated in Indian obese T2DM was further analyzed to see efficacy & safety with biosimilar of Liraglutide
Methods: This post hoc analysis assessed the efficacy & safety of Liraglutide biosimilar & reference biologic in obese T2DM Indians. Aim of this analysis was to assess mean change in glycemic parameters from baseline to week 24 in both the groups.
Results: Total 179 Obese patients (BMI 25 kg/m2 and above) were included in the post-hoc analysis. As shown in table 1 the change in HbA1c, FPG & PPBG at week 24 was significant compared to baseline in obese patients with biosimilar of Liraglutide & reference biologic (p&lt;0.001). However, there was no significance between the change in glycemic parameters when intergroup comparison done for biosimilar of Liraglutide & reference biologic treatment.
Conclusion: Biosimilar of Liraglutide demonstrated comparable glycemic control with respect to the reference biologic in terms of reduction in HbA1c, FPG and PPBG from baseline to Week 24 in obese T2DM patients.

Disclosure
S.R. Joshi: Consultant; Twin Health, Marico, Franco Indian, Zydus Cadila, Glenmark Pharmaceuticals. Other Relationship; Novo Nordisk, Sanofi, MSD, Abbott Nutrition, Abbott, Biocon, Alkem, USV Private Limited, Boehringer-Ingelheim. H.V. Barkate: Employee; Glenmark Pharmaceuticals. A. Mane: None. A.U. Petare: Employee; Glenmark Pharmaceuticals. S.Y. Choudhari: Employee; Glenmark Pharmaceuticals, Sun Pharmaceutical Industries Ltd.

Funding
Glenmark Pharmaceuticals Ltd.
804-P: Understanding Off-Label Use of GLP-1 (Glucagon-Like Peptide-1 Receptor) Agonists among Providers Participating in the T1D Exchange Quality Improvement Collaborative (T1DX-QI)
Authors: PAT GALLAGHER MARY , BASINA MARINA , OSPELT EMMA L. , RIOLES NICOLE , BREIDBART EMILY , ZUPA MARGARET , ENG DONNA , NG JASON , LEVY CAROL J. , EBEKOZIEN OSAGIE , COLLABORATIVE T1DX-QI 
Published: June 2024

Background: The use of glucagon-like peptide-1 agonists (GLP-1a) as adjunctive therapy to insulin is not yet standard for people with type 1 diabetes (PwT1D) but is being explored.
Methods: T1DX-QI Collaborative administered a Qualtrics survey to providers at 55 centers Jul.-Sept. 2023 to determine current opinions and practices regarding the use of GLP-1a in PwT1D. Descriptive analysis was performed.
Results: Fifty of 55 centers (91%) completed the survey. Fifty percent of pediatric and 75% of adult centers reported that GLP-1a have a role in T1D management as an adjunctive therapy to insulin. Both pediatric and adult centers reported that they would consider adding a GLP-1a to insulin therapy in PwT1D, based on BMI and total daily insulin dose. Adult providers were more likely to consider the PwT1D’s desire to lose weight, personal or family history of early ASCVD, and presence of NAFLD compared with pediatric providers (Fig. 1). Both adult and pediatric centers reported insurance coverage as a barrier even when PwT1D meet criteria for GLP-1a treatment for weight loss based on BMI.
Conclusions: A large percentage of centers report that GLP-1a have a role in T1D management. Providers consider a range of factors when adding GLP-1a to insulin therapy in PwT1D, including data that BMI is an independent risk factor for early ASCVD in PwT1D.

Disclosure
M. Gallagher: None. M. Basina: None. E.L. Ospelt: None. N. Rioles: None. E. Breidbart: None. M. Zupa: None. D. Eng: None. J. Ng: Research Support; Sanofi-Aventis U.S., T1D Exchange. C.J. Levy: Research Support; Dexcom, Inc. Consultant; Dexcom, Inc. Research Support; MannKind Corporation, T1D Exchange, Tandem Diabetes Care, Inc., Abbott, Insulet Corporation. O. Ebekozien: Advisory Panel; Sanofi, Medtronic. Research Support; Vertex Pharmaceuticals Incorporated. Speaker's Bureau; Vertex Pharmaceuticals Incorporated. Research Support; Medtronic, Lilly Diabetes, Abbott, Dexcom, Inc.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust
805-P: Development of a Semaglutide-Releasing Long-Acting Injectable, IVL3021, and Its Physicochemical and Pharmacokinetic Studies
Authors: KIM MINSUNG , LEE SLGIRIM , HEE KIM JU 
Published: June 2024

For many chronic conditions, microsphere-based long-acting injectables (LAIs) have been employed to replace repetitive daily or weekly therapies with long-term therapies (e.g. 1 month). The key technology to develop LAIs is controlling release profiles since it is significant not only to patient adherence and efficacy but also to the safety of the medications by minimizing the burst exposure of the drug and keeping its drug level within the therapeutic range. The focus of the current study is on semaglutide (Sema), an FDA-approved glucagon-like peptide-1 (GLP-1) receptor agonist for managing diabetes and obesity. Most annoying adverse events that Sema induces are gastrointestinal AEs, which can be mitigated by using LAIs. However, encapsulating it into microparticles and controlling the release have presented challenges, given its physicochemical properties. In this study, we introduce a novel one-month LAI of Sema, named IVL3021, developed using IVL-DrugFluidics® technology. This microfluidics-based manufacturing approach enables precise control of drug release through size and morphology-regulated microspheres. Our study demonstrates the smooth uniform spherical morphology of IVL3021 microspheres, with an encapsulation efficiency exceeding 97.0%. Importantly, in preclinical pharmacokinetic studies, IVL3021 maintains plasma concentrations of Sema within the therapeutic range over 4 weeks without an initial burst release.
In conclusion, IVL3021 showed its potential to be used as a 1-month LAI of Sema for obesity and diabetes management. The current study also suggested the potential of IVL-DrugFluidics® Technology in creating size-controlled peptide-encapsulating microspheres. Based on the positive results, further preclinical evaluation is ongoing.

Disclosure
M. Kim: Employee; Inventage Lab Inc. S. Lee: Employee; Inventage Lab Inc. J. Kim: Board Member; Inventage Lab Inc.
814-P: What Are the Early Selection Predictors of GLP-1 Receptor Agonists in Real-World Data for Japanese Individuals with Type 2 Diabetes?
Authors: SUGANUMA YUKA , ISHIGURO MIZUKI , OHNO TAKAYUKI , NISHIMURA RIMEI 
Published: June 2024

Introduction & Objective: The objective of this study is to elucidate the prescription order of GLP-1 receptor agonists (GLP-1RA) and predictors affecting their selection in Japanese type 2 diabetes (T2D) using real-world data.
Methods: The subjects were extracted from individuals with T2D attending our 4 hospitals (approximately 10,000/month in outpatient attendance) newly prescribed GLP-1RA between 2016 and 2019, excluding those initiated during hospitalization. Using clinical information databases, we examined patient backgrounds and changes over time in selection orders of GLP-1RA among antidiabetic drugs, as well as concurrent drugs. To identify predictors for GLP-1RA being the first or second choice, multiple regression analysis was performed with variables such as age, gender, prescription year, medical history, BMI, HbA1c, presence of chronic kidney disease (CKD), and insulin use as independent variables.
Results: We included 671 participants (259 females) with a median age [25-75 percentile] of 61.0 [50.0-72.0] years and BMI of 27.3 [23.8-31.6] kg/m2. Among GLP-1RA, 62.6% were dulaglutide, while 36.1% were liraglutide. GLP-1RA remained third new prescription from 2016 to 2019, with no changes over time. Switching from other medications accounted for 76.5% (1st: DPP4i, 2nd: rapid-acting insulin), while adding to current treatments constituted 23.5%. When prescribed as the third choice, the most common pre-prescribed combination was biguanide + insulin throughout the study period. The predictors for the early selection of GLP-1RA were older age, given the popularity of low-dose dulaglutide, and presence of CKD.
Conclusion: GLP-1RA was the third choice among antidiabetic drugs, with frequent switches from DPP4i or insulin. It was considered that older age or the presence of CKD were predictors for early selection of GLP-1RA. We will monitor for changes in predictors with introduction of semaglutide and tirzepatide.

Disclosure
Y. Suganuma: None. M. Ishiguro: None. T. Ohno: None. R. Nishimura: Speaker's Bureau; Abbott. Advisory Panel; Abbott Japan Co., Ltd. Speaker's Bureau; Boehringer-Ingelheim, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Medtronic, Sanofi, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Eli Lilly and Company, Novo Nordisk A/S. Consultant; Terumo Corporation.