bluuebunny/crossref_metadata_2025_split huggingface dataset:
1060-P: The Effect of FGF21/GLP-1 Fusion Protein on Glucose and Lipid Metabolism Using Diabetic Mice Models
Authors: GUO LIXIN , PAN QI , CHEN CHAO , LIN SHUSHAN , LI YU , LI XIAOPING , CHEN XIAOFENG , LIU LIANG , LI WENJIA , TANG XINFA 
Published: June 2020

Objective: Fibroblast growth factor 21 (FGF-21) is an endocrine factor playing important role in energy metabolic pathways and might be a potential therapeutic target for metabolic disorders such as type 2 diabetes (T2D) and NASH. However, Wild type FGF-21’s clinical application is hindered due to its limited bio-activity. To enhance the medicinal properties, this study mutated FGF-21 to improve its bio-activity. And based on potential synergistic effect of GLP-1 and FGF-21, a FGF-21/GLP-1 fusion protein was constructed to develop a potential T2D/NASH effective drug.
Methods: FGF-21-Fc was mutated to enhance its receptor interaction and stability. FGF-21 mutants’ blood glucose reduction capability were compared on db/db mice. Moreover, by constructing a dual agonist from FGF-21 and GLP-1, the bio-activity was further enhanced. Using HFD ob/ob mice, the dual agonist was evaluated by measuring multiple indicators such as blood glucose level, body weight, liver function, and the NAS score.
Results: Results from db/db mice (n=9, single SC injection, 40nM/kg) show that the mutated FGF-21-Fc possesses significantly stronger blood glucose lowering effect than the wild type (P&lt;0.01). Results from HFD ob/ob mice (n=8, SC injection, BIW, 4 weeks) show that the dual agonist reduces the blood glucose level by 60% or more (P &lt;0.001), reduces ALT levels by more than 70%, and reduces NAS scores by more than 3 points. The dual agonist is more effective than dulaglutide on T2D and NASH (P&lt;0.001).
Conclusions: According to this study, FGF-21 and GLP-1 can synergistically enhance the metabolic regulation through multiple mechanisms. The mutated dual agonist possesses optimized bio-activity and shows significant improvements for T2D and NASH. It is a very promising drug for both T2D and NASH treatment.

Disclosure
L. Guo: None. Q. Pan: None. C. Chen: None. S. Lin: None. Y. Li: None. X. Li: None. X. Chen: None. L. Liu: None. W. Li: None. X. Tang: None.
1061-P: Effects of Long-Term Vitamin D and Omega-3 Fatty Acid Supplementation on Inflammatory and Cardiac Biomarkers in Patients with Type 2 Diabetes
Authors: LIMONTE CHRISTINE , ZELNICK LEILA , HOOFNAGLE ANDY , THADHANI RAVI , MELAMED MICHAL , RUZINSKI JOHN , LEE I-MIN , SESSO HOWARD , BURING JULIE E. , MANSON JOANN E. , DE BOER IAN 
Published: June 2020

Background: Immune system activation contributes to the development of microvascular and macrovascular complications in diabetes. Identifying interventions that reduce inflammation may delay progression of diabetes complications.
Methods: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1,312 adults with type 2 diabetes were randomized to vitamin D3 (2000 IU/d) versus placebo and omega-3 fatty acids (EPA+DHA;1g/d) versus placebo in a 2x2 factorial design. We measured serum interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after two and five years, then used linear mixed models to test treatment effects.
Results: Participants were on average 67.6 years old (46% women). Overall, baseline geometric means of IL-6, hsCRP, and NT-proBNP were 1.2 pg/mL, 1.9 mg/L, and 262 pg/mL, respectively. After five years, mean IL-6 and hsCRP remained within 5% of their baseline values while mean NT-proBNP increased by 56% in the full population. Compared with placebo, participants assigned to vitamin D3 had a larger increase in NT-proBNP over time (ratio of change compared with placebo at five years 1.25; 95%CI 1.09-1.43; p=0.005), while there was no significant difference in change in IL-6 (ratio 0.97; 95%CI 0.80-1.18) or hsCRP (ratio 0.90; 95%CI 0.79-1.02). Comparing omega-3 fatty acids to placebo, there was no significant difference in change in IL-6 (ratio 1.11; 95%CI 0.92-1.34), hsCRP (ratio 0.88; 95%CI 0.77-1.00), or NT-proBNP (ratio 1.03; 95%CI 0.90-1.17) at five years. No heterogeneity was observed in subgroup analyses accounting for pre-specified clinical and demographic features.
Conclusions: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids did not reduce IL-6, hsCRP, or NT-proBNP long-term.

Disclosure
C. Limonte: None. L. Zelnick: None. A. Hoofnagle: None. R. Thadhani: None. M. Melamed: Other Relationship; Self; American Board of Internal Medicine, ICON plc. J. Ruzinski: None. I. Lee: None. H. Sesso: None. J.E. Buring: Advisory Panel; Spouse/Partner; Pharmavite. J.E. Manson: None. I. de Boer: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Consultant; Self; George Clinical, Goldfinch Bio, Ironwood Pharmaceuticals.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088762); National Institutes of Health (U01CA138962, R01CA138962)
1064-P: The Human Recombinant REG3A Protein ALF-5755 Restores Glucose Homeostasis and Insulin Sensitivity in High-Fat Fed Mice and in Ob/Ob Mice
Authors: DARNAUD MARION , CRUCIANI-GUGLIELMACCI CÉLINE , GONZALEZ PATRICK , AMOUYAL PAUL , AMOUYAL GILLES , JAMOT LAURE , MONIAUX NICOLAS , ANDREELLI FABRIZIO , BRÉCHOT CHRISTIAN B. , MAGNAN CHRISTOPHE , FAIVRE JAMILA 
Published: June 2020

Introduction: REG3A (Regenerating islet-derived protein 3A) is a carbohydrate-binding protein belonging to the family of C-type lectins. REG3A has antioxidant and anti-inflammatory properties modulating glucose and lipid homeostasis. We report a study of the effects of the administration of the human recombinant REG3A protein ALF-5755 on glucose and lipid homeostasis in insulin-resistant mice.
Materials and Methods: 4-week-old C57Bl/6N male mice were fed HFD for 12 weeks. The control group received a standard chow diet. 12-week-old Ob/Ob mice were used. Mice were given ALF-5755 (43µg/day, ALF group) or a formulation buffer (buffer group) by subcutaneous infusion for 28 days. We measured: body weight, blood glucose, fasting insulin, glucose tolerance and insulin sensitivity, glucose turnover and uptake during hyperinsulinemic/euglycemic clamps and AMPK activity.
Results: In both models, ALF-5755 administration significantly decreased basal blood glucose with no change in basal insulin levels. The changes in blood glucose levels in response to an oral glucose load in the ALF and buffer groups were similar in HFD-fed mice but were lowered by ALF-5755 in Ob/Ob mice. Insulin secretion at 15 and 30 min was significantly reduced in the ALF group compared to Buffer group in both models. During clamp, glycolytic muscles exhibited an increase in glucose uptake in HFD-fed mice, and an increase in AMPK activity in both models treated with ALF-5755. Insulin sensitivity was increased in ALF group. The plasma TG was significantly decreased in the ALF compared to Buffer group. No difference in body weight was observed whatever the administered molecules.
Conclusion: Administration of ALF-5775 improves blood glucose and insulin sensitivity in insulin-resistant mice. This effect is mediated by an increase of skeletal muscle glucose uptake through AMPK activation. REG3A is a potential therapeutic drug for the management of insulin resistance syndrome.

Disclosure
M. Darnaud: None. C. Cruciani-Guglielmacci: Consultant; Self; The Healthy Aging Company. P. Gonzalez: None. P. Amouyal: None. G. Amouyal: None. L. Jamot: None. N. Moniaux: None. F. Andreelli: Consultant; Self; Lilly Diabetes, THAC. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; Lilly Diabetes. C.B. Bréchot: Consultant; Self; Romark. Employee; Self; The Healthy Aging Company. C. Magnan: None. J. Faivre: None.
1067-P: Development of Novel Modulators of the GABAA Receptor for Diabetes Therapy
Authors: HASSE BIRGIT , BELGARDT BENGT-FREDERIK , HECHT MARION , WÖRDENWEBER ROBIN , PIECHOT ALEXANDER , RODEN MICHAEL , ECKEL JÜRGEN 
Published: June 2020

Accumulating data suggest that the GABAergic system may play a key role in beta-cell survival and regeneration in both type 1 and type 2 diabetes. Therefore, the development of new positive allosteric modulators of the GABAA receptors (GABAA-Rs) provides an interesting strategy for an antidiabetic therapy, although central nervous system side effects mediated by α1-GABAA-Rs are a potential concern. Here we synthesized and functionally analyzed a series of low molecular weight thioacrylamides (ThAcs), designed to both positively modulate GABAA-R signalling and show low blood brain barrier penetration. Beta-cell proliferation was increased by several ThAcs at nanomolar concentrations in a rat beta-cell line in vitro (i.e., ∼82% increased EdU incorporation after 24 hours treatment with ThAc HK-4 at 100 nM). The most effective candidate, HK-4, was further characterized. By using radio ligand competition assays and functional patch clamp experiments we analyzed the interaction between HK-4 and GABAA-Rs. In competition assays, we observed a dose-dependent affinity of HK-4 for GABAA-Rs in rat cortical neuron membranes. In electrophysiological patch clamp assays, we determined the modulating activity of HK-4 to individual human GABAA-Rs using HEK293 cells stably expressing different subunit combinations. HK-4 induced very strong potentiation of the current elicited by the natural ligand GABA on GABAA receptors containing combinations of α2β3γ2 (current ∼300% of GABA alone), α3β3γ2 (∼770%) and on α1β3γ2 (∼580%) subunits, respectively. Minimal blood brain barrier penetration of HK-4 was verified by mass spectrometry-based analyses of brain and plasma samples of rats. Additionally, HK-4 shows no major toxicological effects as determined in a 90-day toxicity study with daily dosing, has a favorable pharmacokinetic profile and demonstrates good oral bioavailability. Our data reveal the potential of HK-4 and other ThAcs for further development into antidiabetic drugs.

Disclosure
B. Hasse: Stock/Shareholder; Self; Algiax Pharmaceuticals GmbH. B. Belgardt: None. M. Hecht: None. R. Wördenweber: None. A. Piechot: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. J. Eckel: None.

Funding
EFRE; NRW; European Union
1077-P: De-escalation Treatment (DET): A Personalized Pharmacological Intervention to Stop Disease Progression in Patients with Type 2 Diabetes
Authors: PFÜTZNER ANDREAS , MANESSIS ANASTASIOS , DO LINDA , HANNA MINA 
Published: June 2020

Type 2 diabetes is a chronic progressive disease with increasing drug demands. It is comprised of a hereditary ß-cell dysfunction, (ßCD), insulin resistance (IR), and chronic systemic inflammation (CSI), which can be present with different degrees of severity. We have tested an alternative approach to the common drug escalation programs. DET (De-Escalation Treatment), temporary, multi-drug intervention targets to improve ß-Cell function and reverse disease progression. A personalized drug combination for a three-month treatment is determined based on a biomarker panel consisting of classic and new biomarkers. 22 patients (8 women, 14 men, age: 62±8 yrs., disease duration: 12±7 yrs., HbA1c: 7.8 %, BMI: 33.2±2.4 kg/m², treatment with 1 or 2 oral drugs) were treated with follow-up periods of up to 12 years. DET consisted of low doses each of basal insulin to address ßCD, treatment of IR (exercise and/or pioglitazone), a drug to reduce CSI (diet, GLP-1, or SGLTII) and a hypoglycemic intervention (metformin, or DPP-IV). The DET approach was well tolerated (nausea: 4 cases, edema: 1 case). All patients experienced a normalization or pronounced improvement of glycemic control without report of hypoglycemia. Mean HbA1c after 3 months was 5.9±0.4 %. Intact proinsulin decreased from 9.3±2.1 pmol/L to 2.3±0.6 pmol/L, adiponectin improved from 3.4±1.2 to 8.6±2.4 mg/dL, and mean body weight decreased by 2.4±1.1 kg (all: p&lt;0.01). After the DET, treatment was continued with lifestyle only or a drug monotherapy targeting the major component of their individual diabetes phenotype. This DET “honeymoon“ effect lasted in the mean for about 2 years (range until next DET: 6 months to &gt;11 years). Regeneration of ß-cell function by means of DET resulted in a temporary stop of chronic disease progression. A formal prospective clinical study to investigate the practicability of this approach in routine clinical practice is currently ongoing.

Disclosure
A. Pfützner: Consultant; Self; LifeCare, Inc., Novo Nordisk A/S. Research Support; Self; CNOGA Medical, Esperion Therapeutics, Inc. Speaker’s Bureau; Self; Sanofi-Aventis. A. Manessis: Research Support; Self; Novo Nordisk Inc., Sciema GmbH. L. Do: Research Support; Self; Sciema GmbH. M. Hanna: None.

Funding
Diabetes Treatment Centers International
1079-P: Engineered Silica Particles Reduce HbA1c in Persons with Prediabetes
Authors: JOHNSTON ERIC V. , IQBAL MUHAMMAD N. , ROBERT-NICOUD GHISLAINE , LINDGREN MARIA Z. , WAARA ERIK R. , UDDEN ANNA , PIETILÄINEN KIRSI , BENGTSSON TORE 
Published: June 2020

The standard of care for persons with prediabetes is lifestyle intervention, however in real-life less than 20% of people are able to adopt a healthier living. There is an unmet need for safe and effective treatment options for persons with prediabetes.
We have developed unique mesoporous silica particles (MSP) with tailored characteristics (SiPore15) that sequesters pancreatic amylase and lipase locally in the gut, resulting in decreased digestion of carbohydrates and fats. A first-in-man safety-trial in healthy and obese volunteers (clinicaltrials.org ID no. NCT03667430) showed a good safety profile for SiPore15 and an exploratory analysis revealed a reduction in HbA1c.
In the present efficacy-trial 43 subjects were enrolled, 33 persons with prediabetes (HbA1c 39 mmol/mol or above) and 10 persons newly diagnosed with diabetes type 2. All subjects were treated with SiPore15, 3 gm-TID with meals, for 12 weeks (clinicaltrials.org ID no. NCT03823027). A manufacturing error resulted in 26 subjects receiving the correct MSP for half of the treatment period and 9 subjects for the full period. An exploratory analysis revealed that the long-term blood glucose marker HbA1c was statistically reduced after 6 weeks (1 mmol/mol) and further reduced at 12 weeks (1.4 mmol/mol). Among the subjects who received the correct material, 0 subjects had a serious AE and the AEs reported were mild to moderate, indicating a favorable safety profile. The magnitude in HbA1c reduction was comparable to what has been observed with metformin in prediabetic clinical trials, translating to significant risk reduction in developing diabetes type 2.
SiPore15’s novel ingestible device concept, combined with the preliminary demonstration of efficacy and safety indicates that SiPore15 is an exciting approach for prevention and treatment of diabetes and merits further clinical investigation.

Disclosure
E.V. Johnston: None. M.N. Iqbal: None. G. Robert-Nicoud: Employee; Self; Sigrid Therapeutics. M.Z. Lindgren: None. E.R. Waara: None. A. Udden: None. K. Pietiläinen: None. T. Bengtsson: Board Member; Self; Atrogi, Sigrid Therapeutics.
1084-P: Postmarketing Real-World Effectiveness of Hydroxychloroquine (HCQ) in Treatment of Patients with T2D
Authors: PAREEK ANIL , DHARMADHIKARI SHRUTI , MEHTA RAVI T. , NAIDU KUMAR B. 
Published: June 2020

Real-world data is important in providing evidence of treatment effectiveness in clinical practice. This real-world analysis included 1523 patients of T2D uncontrolled (A1c≥7%) on metformin-SU combination to additionally receive HCQ 400 mg/day for 24 weeks. Mean age of patients was 51.3 years and 53.25% were males. Of the 1523 enrolled patients, 1297 patients who completed 24 weeks of therapy were analyzed for effectiveness. Treatment with HCQ resulted in significant reduction in A1c (change from baseline at Week 12 and 24 was 1.10% and -1.41%, respectively; p&lt;0.0001) and other glycemic and lipid parameters. At Week 24, 81% and 62% of patients reported a fall of ≥0.5% and ≥1% in A1c, respectively. Target A1c of &lt;7% and &lt;8% was achieved by 34% and 73% of patients, respectively at Week 24. Overall, HCQ was well tolerated. Majority of the 148 AEs were GI related (25%), mild in intensity (85%) and unlikely related (66%) to HCQ. Ten patients reported hypoglycemia; all were ADA Level 1. Nine NPDR cases were reported, all were mild and 8 were unlikely related to HCQ. Of 8 SAEs reported, 7 were not related to HCQ. Causality was assessed by investigator. Low-grade inflammation is a common feature in T2D. HCQ, an anti-inflammatory agent, significantly improved glycemic profile (comparable to other OHAs) with added benefits on lipids. Thus, HCQ could be an effective and well-tolerated therapeutic option for treatment of T2D.

Disclosure
A. Pareek: Employee; Self; Ipca Laboratories. S. Dharmadhikari: Employee; Self; Ipca Laboratories. R.T. Mehta: Employee; Self; Ipca Laboratories. K.B. Naidu: Employee; Self; Ipca Laboratories.

Funding
Ipca Laboratories Limited
1087-P: Hospital and Emergency Department Utilization in U.S. Veterans with Hyperkalemia
Authors: KOVESDY CSABA P. , GOSMANOVA ELVIRA , WOODS STEVEN D. , FOGLI JEANENE J. , ROWAN CHRISTOPHER G. , HANSEN JARED L. , SAUER BRIAN C. 
Published: June 2020

Background: Patiromer (PAT) is a sodium-free, non-absorbed potassium (K+) binder (KB) approved for the treatment of hyperkalemia (HK). HK is common in older pts with cardiorenal comorbidities and often leads to increased Healthcare Resource Utilization (HRU). Here we aim to describe electrolyte-related HRU in Veterans with HK who initiated PAT or discontinued RAAS inhibitor (RAASi DC) therapy and were not receiving a KB (1/1/2016−8/30/2018).
Methods: Using retrospective, observational data, pts utilizing the hospital or ED during the 6 months (mos) prior to the index date were assessed at 1, 3, and 6 mos post-index. The index date was the date of PAT initiation or the date of RAASi DC in pts not receiving a KB (RAASi DC/no KB). All pts had a baseline serum K+ ≥5.1mEq/L and HF, DM, or non-dialysis CKD. Pts with continuous exposure (CE) to PAT and those who did not restart RAASi were analyzed.
Results: 288 and 26,543 pts were included in the PAT and RAASi DC/no KB groups, respectively. Following CE to PAT at 1, 3, and 6 mos post-index, no electrolyte related ED or hospital utilization was observed. In the RAASi DC group, 2-5% of pts reutilized the ED or hospital within 6 mos (Figure).
Conclusion: Of the pts who experienced an electrolyte-related hospitalization or ED visit within the 6 mos prior to PAT dispensing, no pts reutilized these services in the following 6 mos. Given the limited number of PAT users, additional investigation is warranted.

Disclosure
C.P. Kovesdy: Consultant; Self; Amgen, AstraZeneca, Bayer AG, Cara Therapeutics, Reata, Takeda Pharmaceutical Company Limited, Tricida. E. Gosmanova: None. S.D. Woods: Employee; Self; Relypsa, Inc. Stock/Shareholder; Self; Vifor Pharma Group. J.J. Fogli: Employee; Self; Relypsa, Inc. Stock/Shareholder; Self; Vifor Pharma Group. C.G. Rowan: Consultant; Self; AbbVie Inc., Covidia, Halozyme, Keryx, Relypsa, Inc., Vifor Pharma Group. Other Relationship; Self; COHRDATA. J.L. Hansen: Research Support; Self; COHRDATA. B.C. Sauer: Research Support; Self; COHRDATA.

Funding
Relypsa, Inc.
1092-P: Treatment Changes Post–Second-Line Medication Initiation, a Real-World Retrospective Cohort Study
Authors: PASRICHA SANYA , CHERUPALLY MANISHA , KOEP ELEENA , ACKERMANN RONALD T. , AIKMAN CASSANDRA , COOPER ANDREW J. , O’BRIEN MATTHEW , WALLIA AMISHA , LISS DAVID T. , PARKER EMILY D. 
Published: June 2020

Objective: This study used real-world data to describe treatment patterns in second-line antidiabetic medication (ADM) regimen (Sulfonylureas, DPP-4 inhibitors, GLP-1 RAs, SGLT2 inhibitors, or TZDs) over a fixed 12 month follow-up period.
Methods: Medical and pharmacy claims were used to identify adult commercial and Medicare Advantage Part D health plan enrollees with T2DM initiating second-line ADMs between 2013-2016. The primary outcome was the first pharmacy claim indicating a change in regimen: switch to a new ADM class; treatment discontinuation (gap ≥30 days); or intensification (≥doubling of dose, adding a new ADM class, or switching to/adding insulin). Patients were classified as adherent if no change was observed.
Results: Of 73,290 study subjects with 2LADM, 53% were Sulfonylurea, 26% were DPP-4, 7% were GLP-1 RA, 9% SGLT2, and 5% TZD. Changes in treatment within 1 year were observed for over 70% of all patients (Table). There was little switching, about 50% discontinued their 2LADM with the highest rate of discontinuation among those receiving GLP-1 RAs and lowest among those receiving TZDs. About 20% of patients intensified medication regimen.
Discussion: The very high rate of observed treatment changes, in particular discontinuation, may indicate that patients face multiple barriers to treatment adherence. Real-world studies can inform patient-centered treatment selection.

Disclosure
S. Pasricha: None. M. Cherupally: None. E. Koep: Employee; Self; UnitedHealth Group. R.T. Ackermann: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, UnitedHealth Group. C. Aikman: None. A.J. Cooper: None. M. O’Brien: Research Support; Self; UnitedHealth Group. A. Wallia: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., UnitedHealth Group. D.T. Liss: None. E.D. Parker: None.

Funding
UnitedHealth Services (SP0036847)