bluuebunny/crossref_metadata_2025_split huggingface dataset:
1150-P: Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers on Renal Outcomes in Patients with Type 2 Diabetes and Proteinuria
Authors: COLEMAN CRAIG I. , WEEDA ERIN R. , KHARAT AKSHAY A. , BOOKHART BRAHIM , BAKER WILLIAM L. 
Published: June 2019

Background: The impact of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) on renal outcomes in patients with type 2 diabetes (T2D) and proteinuria remains unclear.
Methods: A search of Medline, Embase and the Cochrane Databases through 11/2/2018 was performed. We included randomized controlled trials (RCTs) of T2D patients and micro- or macroalbuminuria; comparing an ACEI or ARB with placebo, placebo+background antihypertensives or non-ACEI or ARB containing antihypertensives; randomizing ≥100 subjects; and following subjects for ≥12 months. Endpoints included doubling of serum creatinine (SCr), end-stage renal disease (ESRD), all-cause and cardiovascular (CV) mortality and progression and regression of proteinuria. A Hartung-Knapp random-effects model producing a risk ratio (RR) with 95% confidence interval (CI) was employed, with between-study variance calculated using the Paule-Mandel estimator.
Results: The use of an ACE inhibitor or ARB was not associated with a significant reduction in the risk of a doubling in SCr (n=7 trials, RR=0.77, 95% CI=0.50-1.21). ACE inhibitors or ARBs reduced the risk of progressing to ESRD (n=8, RR=0.79, 95CI=0.75-0.83). No difference in all-cause (n=11, RR=0.98, 95% CI=0.89-1.08) or CV mortality (n=6 trials, RR=1.08, 95% CI=0.92-1.28), nor the composite outcome of doubling SCr, development of ESRD or mortality (n=3 trials, RR=0.87, 95% CI=0.72-1.06) were observed. The risk of progression of patients’ proteinuria was decreased when an ACE inhibitor or ARB was used versus control (n=10, RR=0.49, 95% CI=0.33-0.74). The chance of regression of patients’ proteinuria was not significantly improved with an ACE inhibitor or ARB (n=11, RR=1.55, 95% CI=0.93-2.58).
Conclusion: ACEIs and ARBs may reduce the risk of ESRD and slow progression of nephropathy, but do not appear to decrease all-cause or CV mortality in T2D patients with proteinuria.

Disclosure
C.I. Coleman: Research Support; Self; Janssen Scientific Affairs, LLC. E.R. Weeda: None. A.A. Kharat: Consultant; Self; Janssen Scientific Affairs, LLC. B. Bookhart: Employee; Self; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Janssen Pharmaceuticals, Inc. W.L. Baker: None.

Funding
Janssen Scientific Affairs, LLC
1154-P: Genetic and Pharmacological Suppression of Cathepsin K Promotes Wound Healing in Diabetic Mice
Authors: GUO RUI , ZHANG LIPING , THAKAR AMIT , BROWN TRAVIS E. , REN JUN , ZGHEIB CARLOS , XU JUNWANG , LIECHTY KENNETH W. , NAIR SREEJAYAN 
Published: June 2019

Background and Hypothesis: Impaired wound healing is a serious complication of diabetes and accounts for over 70,000 amputations annually in the United States. Accumulating evidence suggests that wounds with poor healing process display persistently elevated protease activity. Here we tested the hypothesis that genetic knockout or pharmacological inhibition of cathepsin K, a cysteine protease with potent collagenolytic and elastolytic activity, accelerates wound closure in diabetic mice.
Methods: Diabetes was induced in cathepsin K knockout (Ctsk-/-) and wild type litter-mates by intraperitoneal injection of streptozotocin (STZ, 120 mg/Kg). Two weeks following STZ injection, a full thickness 8-mm excisional wound was created on the dorsum of the mice. In a separate set of experiments, excisional skin wounds were created in genetically diabetic (db+/db+) and their normoglycemic litter-mates. The wounds were treated with cathepsin K inhibitor II (0.35μg/d on days 0, 3, and 5), or vehicle, given as intradermal injections along the circumference of the wound. Wound healing was evaluated by measuring the wound closure rate, CD31 expression, and histological analysis.
Results: In the STZ-induced diabetic model, wounds in the cathepsin K-knockout mice closed significantly earlier than the vehicle-treated wounds. Similarly, pharmacological inhibition of cathepsin K in db/db mice resulted in near complete resolution of the wound in 22 days compared to about 29 days in vehicle-treated mice. Histological evaluations demonstrated that topical delivery of cathepsin K inhibition resulted in higher levels of collagen deposition and increased angiogenesis. In an in vitro scratch-assay using cultured human fibroblasts, cell migration, which was significantly impaired by high-glucose concentrations, was restored by cathepsin K inhibitor-II.
Conclusion: Cathepsin K may represent a potential treatment-target to facilitate diabetic wound healing.

Disclosure
R. Guo: None. L. Zhang: None. A. Thakar: None. T.E. Brown: None. J. Ren: None. C. Zgheib: None. J. Xu: None. K.W. Liechty: Consultant; Spouse/Partner; Cell research. S. Nair: None.

Funding
National Institute of General Medical Sciences (2P20GM1034320); University of Wyoming
1156-P: Duodenal Mucosal Resurfacing (DMR) Combined with GLP-1 RA May Eliminate Insulin Therapy and Improve Metabolic Health in Type 2 Diabetes
Authors: SMEELE PAUL , VAN BAAR ANNIEKE C. , VRIEND TESSA M. , HOLLEMAN FRITS , SOETERS MAARTEN , NIEUWDORP MAX , TIJSSEN JAN , BERGMAN JACQUES J. 
Published: June 2019

Background: Duodenal mucosal resurfacing (DMR) is an endoscopic intervention in which the duodenal mucosa is ablated by hydrothermal energy. DMR improves glycemic control in type 2 diabetes (T2D) through altered metabolic signaling from the duodenum causing insulin sensitization. We studied the feasibility of eliminating insulin therapy in T2D by combining DMR with GLP-1r agonism (liraglutide) and lifestyle counseling.
Methods: Single arm, single center study in 16 insulin treated T2D patients (HbA1c ≤64 mmol/mol; basal insulin &lt;1U/kg/day, c-peptide ≥0.5 nmol/l). Day 1, DMR is administered and insulin therapy discontinued. Day 14, liraglutide is introduced (titrated to 1.8 mg/day) and life style counseling is administered throughout. Primary endpoint: percentage of patients free of insulin and HbA1c ≤59 mmol/mol at 6 months.
Results: Enrolment has been completed and 9 patients have reached 6 months with 8/9 (89%) insulin-free and able to maintain glycemic control with improvement across multiple metabolic parameters (Table 1).
Conclusion: Single endoscopic DMR, combined with liraglutide and lifestyle counseling, may effectively eliminate the need for insulin therapy in T2D while improving overall metabolic health. This treatment approach is a promising alternative that appears to shift insulin-treated T2D patients to a state of better overall metabolic health.

Disclosure
P. Smeele: None. A.C. van Baar: None. T.M. Vriend: None. F. Holleman: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi. M. Soeters: None. M. Nieuwdorp: Advisory Panel; Self; Caelus health. J. Tijssen: None. J.J. Bergman: Research Support; Self; Fractyl Laboratories, Inc.
116-LB: New Insulin-to-Carb Ratio Formulas for Hybrid Closed-Loop Pump Use
Authors: TABATABAI IDEEN , BUCKINGHAM BRUCE A. 
Published: June 2019

Objective: Formulas to determine Insulin-Carbohydrate Ratio (ICR) use total daily dose (TDD) such as the 450 Rule (450/TDD=ICR) or body weight (BW) (2.8*weight in pounds/TDD). These do not account for age differences or adjust for HCL therapy.
Methods: We analyzed data from Medtronic 670G users meeting the following criteria: Time in Range (TIR, 70-180mg/dl) &gt;65%, Time &lt;70mg/dl &lt;5%, A1c &lt;8%, HCL for &gt;3 months. Subjects were grouped by age: pre-pubertal, pubertal, and adult (18+). Subjects’ current ICR was multiplied by TDD at each meal to determine a formula starting point.
Results: 50 subjects were included (age 6-62, mean A1c 7.2%, TDD 0.8 u/kg/day, TIR 75%, 2.5% &lt;70mg/dl). Compared to baseline, ICRs in HCL were made 10-26% more aggressive. ICRs calculated from the 450 rule were 15-41% less aggressive compared to the ratios used by HCL subjects. BW formula ICRs were too aggressive for pre-pubertal, closely matched the pubertal subjects, and underestimated meal bolus needs in adults on HCL.
Conclusions: Our data offers new initial ICR formulas for HCL users instead of the 450/TDD rule, i.e., a 300/TDD for adults and a 350/TDD for pubertal and prepubertal children at lunch/dinner, and a breakfast 300/TDD rule. Fine-tuning is necessary for each patient, but this offers a better tuned starting point for subjects starting HCL, helping minimize HCL exits due to post-prandial hyperglycemia.

Disclosure
I. Tabatabai: None. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care.
1169-P: The Insulin Dosage Advisor Diassist Can Help Optimize Glucose Control
Authors: SVENSSON HANNA , HANAS RAGNAR 
Published: June 2019

Background: The 500-rule for the insulin to carbohydrate ratio (ICR) and 100-rule for insulin sensitivity factor (ISF) are easy to use but unfortunately do not provide good ratio estimates for many patients. Analysis of downloaded CGM and pump data can give good estimates but require a lot of experience from the user and is time consuming. We have developed an algorithm (Diassist), based on clinical experience and signal processing, which automatically estimates ICR and ISF, and investigated this method in a clinical context.
Methods: Pump and CGM downloads over 2 weeks were used for analysis. The physician interpreted these and compared with the Diassist results. Diassist calculated only valid meals and corrections, i.e., when blood glucose and carbohydrates had been entered by the patient.
8 patients with poor glucose control participated with 3-5 visits over 2-8 months.
Mean (±SD) age was 12.7 ± 1.8 (range 10.4-16.5) years, diabetes duration 8.0±1.1 years. Insulin dose was 0.78±0.17 (0.6-1.1) units/kg/24 hours (% basal 40.8±13.0 (23-58)). The tool estimated ICR and ISF over 2 weeks and proposed to increase or decrease the settings based on actual glucose excursions. To validate the robustness of the method, cross validation with two data sets was used. Data was divided into 2 sets per patient; running Diassist on the two sets and comparing the results.
Results: The physician followed the Diassist recommendations for ICR titration in 73% of the time slots (4-5/day, 58 out of 79), increasing or decreasing by 10-25%. In one occasion the ICR was changed in the opposite direction to the recommendation.
In 98%, the ICR was lowered (more insulin for the meal), in 2% it was increased. HbA1c was not changed (61±4.4 vs. 57±6.3 mmol/mol, 7.7±0.4 vs. 7.4±0.6%).
The quota of carbohydrate and boluses used in analysis were 67% and 58% of the logged data.
Conclusions: Compared to methods used today, Diassist decreased both time and complexity of the estimation task. The proposed method shows promising results for usability, robustness and safety.

Disclosure
H. Svensson: Stock/Shareholder; Self; Diassist Technology AB. R. Hanas: Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; AstraZeneca.
1177-P: Discovery of New Therapeutic Antibodies to Two Metabolically Relevant Targets—GPCR CB1 and Transporter GLUT4—Using Virus-Like Particles
Authors: TUCKER DAVID , CHARPENTIER TOM , MOLINO NICHOLAS , ROSENBERG ERIN , SCRENCI BRAD , STAFFORD LEWIS J. , SULLI CHIDANANDA , CHAMBERS ROSS , DORANZ BENJAMIN J. , RUCKER JOSEPH B. 
Published: June 2019

Integral membrane proteins are important drug targets, and monoclonal antibodies (mAbs) against them are highly sought for therapeutic and diagnostic purposes. However, the complex structure of multipass membrane proteins makes discovery of these mAbs particularly challenging. By employing strategies such as sequential immunization with DNA (prime) and virus-like particles (boost), and using divergent species (chickens) as immunization hosts, we routinely isolate diverse panels of mAbs against structurally complex and highly conserved membrane protein targets. Here, we report the isolation and characterization of mAbs recognizing two distinct metabolically relevant targets: the 12-transmembrane insulin-responsive glucose transporter GLUT4 and the 7-transmembrane GPCR cannabinoid receptor-1 (CB1).
In both cases, we isolated diverse panels of mAbs against native conformational epitopes. Affinities ranged from 2.6 nM (anti-CB1 IM-102) to 1 pM (anti-GLUT4 LM048). Two anti-GLUT4 mAbs discriminated between inward-open and outward-open conformational states, including one mAb (LM048) that inhibited transporter function. Similarly, we isolated several anti-CB1 mAbs that antagonized CB1-mediated calcium flux. Lead mAbs were confirmed to be specific for their target proteins, based on reactivity profiling in the Membrane Proteome Array of &gt;5,600 human membrane proteins. Identified mAbs represent novel and valuable molecular tools for understanding and potentially treating common metabolic diseases, such as type 2 diabetes mellitus and nonalcoholic steatohepatitis/fatty liver disease (NASH/NAFLD). Furthermore, the technologies underpinning their discovery can be rapidly and routinely employed to facilitate discovery of mAbs against other therapeutically relevant membrane protein targets.

Disclosure
D. Tucker: None. T. Charpentier: None. N. Molino: None. E. Rosenberg: None. B. Screnci: None. L.J. Stafford: None. C. Sulli: None. R. Chambers: None. B.J. Doranz: None. J.B. Rucker: None.

Funding
National Institutes of Health
1179-P: Pharmacokinetics, Pharmacodynamics, and Safety of HD-6277, a Selective Agonist of G-Protein-Coupled Receptor 40, in Healthy Subjects as a First-in-Human Study
Authors: KIM KI-HWAN , KIM PAN-KYUNG , YANG HYE-JUNG 
Published: June 2019

HD-6277 is a potent and selective G-protein-coupled receptor 40 agonist for the treatment of type 2 diabetes mellitus. Previous studies with HD-6277 showed enhanced glucose-stimulated insulin secretion and improved glycemic control in type 2 diabetic rodent models. To evaluate the potential benefits of HD-6277 on safety, tolerability, pharmacokinetics and pharmacodynamics, HD-6277 was investigated with six and four sequential cohorts in single and multiple ascending doses in healthy subjects as randomized, double-blind, placebo-controlled study, respectively. HD-6277 was well absorbed over all doses under fasting conditions and systemic exposure was increased in dose-dependent manner both in single and multiple ascending dose study. There was no severe or serious adverse events showing generally mild and transient profile, which suggested no safety concerns with the doses administered. Therefore, this study showed HD-6277 was safe and well tolerated in healthy subjects. Its exploratory efficacy on type 2 diabetes mellitus patients is currently under evaluation.

Disclosure
K. Kim: Employee; Self; Hyundai Pharmaceutical Co., Ltd. P. Kim: Employee; Self; Hyundai Pharmaceutical Co., Ltd. H. Yang: Employee; Self; Hyundai Pharmaceutical Co., Ltd.

Funding
Korean Ministry of Health and Welfare (HI17C2529)
118-LB: Glucose Variability throughout the Menstrual Cycle on Closed-Loop Control in Type 1 DM
Authors: LEVY CAROL J. , OMALLEY GRENYE , BROWN SUE A. , RAGHINARU DAN , KUDVA YOGISH C. , DASSAU EYAL , KOVATCHEV BORIS , ANDERSON STACEY 
Published: June 2019

Many women with type 1 DM report change in glucose (GLU) control and insulin (INS) dosing throughout the menstrual cycle (MC). No trials have reported the effect of closed loop control (CLC) on INS delivery across the MC. Women enrolled in Phase 1 of the IDCL hybrid CLC trial logged MCs to estimate late luteal and early follicular dates. Data from 64 MC across 27 women (13 CLC), 7 using hormonal contraception, aged 28±11 years, weight 67 kg (IQR: 61-80) was analyzed for diurnal GLU control and CLC INS delivery. MC phase did not impact trends toward increased time in range with CLC. There were no differences in GLU and INS variables. While median CLC INS delivery did not change across the MC, there was intrasubject variability across the MC. CLC has the potential to elucidate individual dosing variability and may mitigate reported change in GLU control across the MC.

Disclosure
C.J. Levy: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Allergan. G. OMalley: None. S.A. Brown: Research Support; Self; Ascensia Diabetes Care, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. D. Raghinaru: None. Y.C. Kudva: Advisory Panel; Self; Novo Nordisk Inc. Other Relationship; Self; Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. E. Dassau: Consultant; Self; Eli Lilly and Company, Insulet Corporation. Research Support; Self; Dexcom, Inc., DreaMed Diabetes, Ltd., Insulet Corporation, Roche Diabetes Care, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Roche Diabetes Care. Other Relationship; Self; ModAGC. B. Kovatchev: Advisory Panel; Self; Sanofi. Board Member; Self; TypeZero Technologies, Inc. Consultant; Self; Sanofi, Tandem Diabetes Care. Research Support; Self; Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. Speaker’s Bureau; Self; Dexcom, Inc. Stock/Shareholder; Self; TypeZero Technologies, Inc. Other Relationship; Self; Johnson & Johnson, Sanofi. S. Anderson: Research Support; Self; Medtronic MiniMed, Inc.

Funding
National Institutes of Health
1193-P: Health-Care Costs and Medication Burden in Routine Care Initiators of Empagliflozin: A First Analysis from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study
Authors: PAWAR AJINKYA , PATORNO ELISABETTA , DERUAZ-LUYET ANOUK , BRODOVICZ KIMBERLY , USTYUGOVA ANASTASIA V. , GAUTAM NILEESA , BESSETTE LILY G. , SCHNEEWEISS SEBASTIAN , NAJAFZADEH MEHDI 
Published: June 2019

EMPRISE studies the comparative effectiveness, safety and health care resource utilization of empagliflozin (EMPA) in Medicare and 2 U.S. commercial claims datasets (2014-2019). In this first analysis, we evaluated healthcare costs and medications burden associated with EMPA vs. dipeptidyl peptidase 4 inhibitors (DPP-4i) use in routine care patients with type 2 diabetes (T2D). We identified a 1:1 propensity-score-matched cohort of T2D patients ≥18 years initiating either EMPA or DPP-4i between 08/2014-09/2016. Total (inpatient, outpatient, pharmacy) cost and medication burden were compared for EMPA vs. DPP-4i. We identified 17,549 matched pairs with balanced baseline characteristics (Table 1) with mean follow-up of 5.4 months. Per member per year (PMPY) total cost was similar among EMPA vs. DDP4i initiators ($17,771 vs. $17,814; Diff= -$43, 95% CI: -1,380─1,295). Medical costs tended to be lower and pharmacy costs were higher in EMPA initiators. Distinct medication prescriptions were slightly lower among EMPA initiators [Incidence rate ratio 0.97, 95% CI: 0.96─0.98]. Results stratified by history of CV disease were consistent. Within the first two years of EMPRISE, we observed similar total cost, driven by trend towards lower medical and higher pharmacy costs, and lower medication burden in EMPA vs. DDP4i initiators.

Disclosure
A. Pawar: None. E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Medtronic, Sanofi. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. A.V. Ustyugova: Employee; Self; Boehringer Ingelheim International GmbH. N. Gautam: None. L.G. Bessette: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. M. Najafzadeh: Consultant; Self; Epigenomics.

Funding
Boehringer Ingelheim
1197-P: Two-Year Effects of Ertugliflozin on Renal Function
Authors: CHERNEY DAVID , HEERSPINK HIDDO L. , FREDERICH ROBERT , MALDONADO MARIO , PONG ANNPEY , XU ZHI JIN , LIU JIE , MANCUSO JAMES P. , GANTZ IRA , TERRA STEVEN G. 
Published: June 2019

2 RCT evaluating ertugliflozin 5 mg (E5, n=652), 15 mg (E15, n=640) vs. non-ertugliflozin (NE, glimepiride or placebo, n=644) in T2D patients were pooled to evaluate effects on eGFR (MDRD) and albuminuria (UACR, geometric mean of % change from baseline). eGFR and UACR were analyzed by mixed model repeated measures with treatment, time, trial, baseline measures [A1C, SBP, eGFR/UACR] as covariates in overall population and by presence of UACR &gt;30 mg/g. Baseline characteristics in the treatment groups were balanced. Overall, mean baseline eGFR was 88.2 ml/min/1.73m2 and geometric mean baseline UACR was 11.6 mg/g. At week 6, changes in eGFR were: -2.3, -2.7 and -0.7 ml/min/1.73m2, for the E5, E15 and NE groups, respectively. Mean eGFR with ertugliflozin increased over time, while it decreased in the NE group. The week 104 ΔeGFR [95% CI] compared to NE was 1.81 ([0.13, 3.49]; p=0.04) and 2.10 ml/min/1.73m2 ([0.42, 3.78]; p=0.01) for E5 and E15, respectively. In patients with baseline UACR &gt; 30 mg/g (n=415) the ertugliflozin groups had greater UACR reductions. The week 104 ΔUACR [95% CI] compared to NE was -29.0% ([-47.0, -4.5]; p=0.02) for E5 and -32.7% ([-50.4, -8.6]; p=0.01) for E15. Ertugliflozin acutely reduced eGFR in an expected fashion, possibly based of known hemodynamic effects. Over 104 weeks, eGFR values were higher with ertugliflozin than control, suggestive of renal function preservation. Ertugliflozin reduced UACR in subjects with baseline albuminuria.

Disclosure
D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. R. Frederich: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None. Z. Xu: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. J. Liu: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. S.G. Terra: Employee; Self; Pfizer Inc.

Funding
Pfizer Inc.; Merck & Co., Inc.