bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid Dose Escalation Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension
Authors: HANRAHAN JOHN P. , WAKEFIELD JAMES D. , WILSON PHEBE J. , ZIMMER DANIEL P. , MIHOVA MARINA , CHICKERING JENNIFER , RUFF DENNIS , HALL MICHAEL L. , CURRIE MARK , TODD MILNE G. , PROFY ALBERT T. 
Published: June 2018

Background: Impaired nitric oxide (NO) signaling through soluble guanylate cyclase (sGC) has been associated with microvascular complications of diabetes. Praliciguat (IW-1973), an sGC stimulator that enhances NO signaling, reduced fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In a Phase 1 clinical study in healthy adults, doses of 15-40 mg were tolerated and lowered blood pressure (BP).
Methods: This Phase 2a open-label in-clinic study assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of oral praliciguat in 11 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP therapy. Patients received sequential 3-day dosing cycles escalating through placebo (PBO), 10, 20, 30, 40 and 50 mg praliciguat QD. Assessments included adverse events (AEs), blood chemistry, ambulatory BP and heart rate, platelet function, and reactive hyperemia index (RHI).
Results: The escalating dose regimen was generally well tolerated; there were no serious or severe AEs. Escalation in 2 patients was stopped due to asymptomatic BP lowering. Overall PK showed a median Tmax of 1-3 h, low to moderate variability, and ∼2-fold accumulation supporting QD dosing. Average 12-h daytime mean arterial BP decreased by 2 to 9 mmHg relative to time-matched PBO baseline across praliciguat dose levels, while heart rate increased 4 to 7 bpm. Notable changes from PBO baseline [mean (95% CI)] at the end of treatment were seen for fasting serum glucose [-26.5 mg/dL (-43.4, -9.5], HbA1c [-0.4% (-0.8, -0.04)], cholesterol [-43 mg/dL (-67, -20)], and body weight [-3.5 kg (-4.9, -2.0)]. Praliciguat had no effect on RHI or platelet function.
Conclusion: T2DM patients with hypertension on standard therapy showed improvements in hemodynamics and metabolic parameters in this small in-clinic study. These results support further evaluation of praliciguat in T2DM patients including those with complications.

Disclosure
J.P. Hanrahan: Employee; Self; Ironwood. J.D. Wakefield: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. P.J. Wilson: None. D.P. Zimmer: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. M. Mihova: None. J. Chickering: None. D. Ruff: None. M.L. Hall: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. A.T. Profy: Other Relationship; Self; Ironwood Pharmaceuticals.
IMG-1 Reduces Blood Glucose Levels in Type 1 Diabetic Animal Models
Authors: POLLETT JONATHAN B. , NOH HYE LIM , KIM JASON K. , THAI NGOC 
Published: June 2018

IMG-1 is a novel compound that has been shown to successfully treat type 2 diabetes in ZDF rats and decrease insulin resistance by suppressing HGP and increasing hepatic insulin action in DIO mice. To test the efficacy of IMG-1 to treat type I diabetes Streptozotocin (STZ)-induced diabetic models were employed. In the first study C57BL/6J mice were treated with STZ (50mg/kg) for 5 days to induce diabetes. The animals were either administered IMG-1 or PBS via oral gavage daily for 29 days. Blood glucose (BG) levels were evaluated three times weekly and insulin was measured twice weekly. After 17 days of treatment, IMG-1 treated animals displayed a significant decrease in BG levels (200-300 mg/dl) that persisted for the remainder of the study, while the control animals had continuously high BG levels (400-600 mg/dl). Insulin levels were low in these animals and unaffected by IMG-1. This finding was mimicked in a second experiment where a STZ rat model was used where Sprague-Dawley rats were given a single injection of STZ (60mg/kg) to induce diabetes. In the rat model, the IMG-1 treated animals had significantly lower BG levels by day 9 and remained low for the entire study (200-300 mg/dl). Total bilirubin, ALP, ALT, AST, BUN and creatinine levels were assessed following the 29-day study to determine liver and kidney toxicity. Bilirubin, BUN and creatinine levels were within the normal range, while the ALP, ALT and AST levels were elevated with the STZ treatment (common in this model). IMG-1 did not have any effect on the liver enzymes compared to control. IMG-1 can regulate BG levels in type I diabetic animal models and does not affect kidney or liver function.

Disclosure
J.B. Pollett: Employee; Self; Imagine Pharma. H. Noh: None. J.K. Kim: None. N. Thai: Board Member; Self; Imagine Pharma.
Durable HbA1c Reduction with Initial Combination Therapy with Metformin/Pioglitazone/Exenatide in Subjects with New-Onset Diabetes—Six-Year Follow-Up of the EDICT Study
Authors: ABDUL-GHANI MUHAMMAD , PUCKETT CURTISS L. , TRIPLITT CURTIS L. , MAGGS DAVID , ADAMS JOHN M. , CERSOSIMO EUGENIO , DEFRONZO RALPH A. 
Published: June 2018

Background: We previously have shown that initial combination therapy with metformin/pioglitazone/exenatide (Triple Therapy) produced greater reduction in A1c than sequential add-on therapy in subjects with new onset of type 2 diabetes (T2D).
Research Design and Methods: The EDICT study is a randomized open-label study in which newly diagnosed drug-naïve T2D subjects with new onset diabetes were randomized to receive Triple Therapy (n=132) or escalating dose of metformin followed by sequential addition of glipizide and then glargine insulin (Conventional Therapy) (n=146) to maintain A1c&lt; 6.5. Here, we report the 6-year follow-up results.
Results: Subjects receiving Triple Therapy experienced a significantly greater reduction in A1c after a mean follow-up of 6 years vs. Conventional Therapy (5.8% vs. 6.7%, p&lt;0.001) (Figure 1). Further, more subjects maintained HbA1c &lt;6.5% in the Triple Therapy group (25%) than in the Conventional Therapy (52%). Progression of carotid IMT (read blindly) was reduced by &gt;50% (P&lt;0.001) in Triple Therapy vs. Insulin Therapy.
Conclusion: The results of this study demonstrate that combination therapy with metformin/pioglitazone/ exenatide in newly diagnosed T2DM patients produces greater and more reduction in A1c than sequential add-on therapy with metformin, sulfonylurea, and basal insulin.

Disclosure
M. Abdul-Ghani: None. C.L. Puckett: None. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. D. Maggs: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Spouse/Partner; Gelesis. Employee; Spouse/Partner; Gelesis. J.M. Adams: None. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..
FOXO1 Inhibition Potentiates Endothelial Function and Ischemic Angiogenesis in Diabetes via Suppression of ROCK1/Drp1-Mediated Mitochondrial Fission
Authors: TIE LU , SHI YUNDI , WANG DI 
Published: June 2018

Diabetes-induced endothelial cell (EC) dysfunction and neovascularization impairment constitute vascular complications with limited treatment regimens. Transcription factor FOXO1 is a key angiogenic regulator and plays a pathologic role in progression of diabetes. The present study was designed to determine the involvement of FOXO1 in impaired EC function and post-ischemic neovascularization in diabetes and investigate underlying mechanisms. We found that FOXO1-selective inhibitor AS1842856 improved blood flow recovery and capillary density in ischemic hindlimb, and rescued the delay of wound closure with a concomitant augmentation of mean perfusion rate in diabetic mice. In vitro, treatment with AS1842856 or FOXO1 siRNA abrogated high glucose-induced apoptosis and ameliorated capillary tube formation in human umbilical vein endothelial cells (HUVECs). FOXO1 inhibition relieved alterations in mitochondrial networks and significantly suppressed the overproduction of mitochondrial reactive oxygen species (mtROS) induced by high glucose in ECs. Expression of dynamin-relatedprotein-1 (Drp1) and phosphorylation at Ser616, a protein required for mitochondrial fission, were enhanced by hyperglycemia, which could be neutralized by FOXO1 inhibition. Moreover, the transcription of Rho-associated coiled-coil containing protein kinase 1 (ROCK1), which phosphorylates Drp1 at Ser616, was shown by luciferase assay to be directly regulated by FOXO1. These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in ECs, and FOXO1 may serve as a therapeutic target for microvascular complications of diabetes.

Disclosure
L. Tie: None. Y. Shi: None. D. Wang: None.
Cost-Effectiveness of Interventions to Prevent and Manage Diabetes—A Systematic Review and Update
Authors: SIEGEL KAREN R. , ZHOU XILIN , NG BOON PENG , JAWANDA SHAWN , PROIA KRISTA , ZHANG XUANPING , ZHANG PING 
Published: June 2018

Many interventions are available for preventing type 2 diabetes (DM) and managing DM, but their cost-effectiveness (CE) varies greatly. Previously, we conducted a systematic cost-effectiveness (CE) review of all DM interventions covering studies between 1985 and 2007. Here, we update the study for Jan 20to July 2017. We used the same search strategies (databases, MeSH terms and keywords, exclusion criteria and study quality assessment tool) to select studies. We grouped interventions by CE ratios (CER) in cost per quality-adjusted life years (QALY) or life year gained (LYG)—cost saving (CER ≤ 0); very cost-effective (0 &lt; CER ≤ $25,000); cost-effective ($25,000 &lt; CER ≤ $50,000); marginally cost-effective ($50,000 &lt; ICER ≤ $100,000); or not cost-effective (&gt;$100,000)—and whether evidence was strong, supportive, or uncertain. We used the median CER to represent the CE of an intervention if multiple evaluations exist. Costs and CER were expressed as 2015 U.S. dollars. The initial search yielded 18,195 titles; 46 prevention and 110 management papers were included in the review. Interventions that were cost-saving or very cost-effective with strong evidence included: for preventing type 2 DM, 1) imposing taxes on sweetened beverages and 2) structured lifestyle intervention and metformin in people at high risk; for management of DM and its complications, 1) ACE inhibitor therapy for intensive hypertension (HTN) control, 2) self-monitoring of blood glucose, 3) comprehensive foot care to prevent ulcers, 4) multi-component coordinated care with peer support for managing HTN, hyperglycemia, hyperlipidemia, and chronic kidney disease, and early detection of DM complications. The CERs of other interventions ranged from $30,000 to $4,817,000 per QALY or &lt;$25,000 per QALY with a high degree of uncertainty. Our results provide critical information for making evidence-based clinical and public health policy decisions.

Disclosure
K.R. Siegel: None. X. Zhou: None. B. Ng: None. S. Jawanda: None. K. Proia: None. X. Zhang: None. P. Zhang: None.
Improving Multidisciplinary Care in Pediatric Diabetes Clinic
Authors: DESALVO DANIEL J. , BARTZ SARA K. , YEE CURTIS , SONABEND RONA 
Published: June 2018

Background: A team-based approach facilitates comprehensive assessment and individualized care plan for diabetes patients. The ADA recommends diabetes patients see a Certified Diabetes Educator (CDE), Registered Dietician (RD) and Social Worker (SW) at least once yearly. Prior to this QI project there was no structured process in our pediatric diabetes clinic for these visits, leading to low rates of multidisciplinary patient care.
Objectives: Our goal was to improve the proportion of diabetes patients receiving evidenced-based multidisciplinary care for enhanced education and social support. Specifically, we aimed to improve the percentage of diabetes patients (&lt;21yo) with CDE visits from baseline of 59% in FY2014 to ≥75% in FY2017, RD visits from baseline of 33% in FY2014 to ≥75% in FY2017, and SW visits from baseline of 24% in FY2014 to ≥75% in FY2017.
Methods: Fish bone and key driver diagrams were deployed to identify strategies for improvement. Our intervention established a policy of Annual Visits for multidisciplinary care with a model to ensure optimal communication. PDSA1: Use birthdays as a mechanism to trigger Annual Visit with CDE, RD, SW; PDSA2: Develop and utilize sustainable pre-visit planning document; PDSA3: Staff call patients scheduled for Annual Visit the day prior; PDSA4: Multidisciplinary pre-clinic huddle to discuss daily clinic procedure; PDSA5: Utilization of EMR diabetes patient registry to identify gaps in care; PDSA6: Utilize a Nurse Coordinator to ensure patients receive required services
Results: The rates of patients seen by multidisciplinary staff increased from baseline for all 3 groups in FY2017: CDE-79.4%, RD-64.3% and SW-83.9%. Thus, the goal of ≥75% was achieved for CDE and SW, but not RD visits (primarily due to staffing).
Conclusions: This QI project resulted in improved transparency, organization and accountability within the clinic. Increasing CDE, RD, and SW support for diabetes patients could impact quality of care delivery, value to the patient, and clinical outcomes.

Disclosure
D.J. DeSalvo: Consultant; Self; Dexcom, Inc.. Speaker's Bureau; Self; Insulet Corporation. S.K. Bartz: None. C. Yee: None. R. Sonabend: None.
Drug Copay and Hospitalizations in Elderly Patients with Type 2 Diabetes
Authors: XU LIOU , PAWASKAR MANJIRI , TANG YUEXIN , PUCKREIN GARY , RAJPATHAK SWAPNIL , STUART BRUCE C. 
Published: June 2018

Prior studies have shown that higher drug copay may be associated with a lower medication adherence and higher healthcare resource utilization in type 2 diabetes (T2D) patients but mostly in younger commercially insured population. Hence the current study examined this association in elderly T2D patients. This retrospective database study using Medicare claims database included T2D patients on branded non-insulin anti-hyperglycemic agent (AHA) monotherapy during index period (1/1/2013-2/28/2013). Drug copay was calculated for a 30-day supply of the index AHA. Hospitalization was assessed during 10-month follow-up period. Poisson regression model was used to control for baseline characteristics to evaluate the association between copay and hospitalization. A total of 28,656 T2D elderly patients met the inclusion criteria (mean age 78 years, 53% female, and 90% white). Mean branded drug copay was of $40. Higher drug copay was associated with increase in the risk of hospitalization [(e.g., Compared to patients with &lt;$10 drug copay, those with $60+ drug copay had 17% higher risk of hospitalization (p= 0.02)] (Table). This study suggests that higher drug copays for branded AHAs have significant impact on the risk of hospitalization in elderly patients covered under Medicare. Payers need to take into account drug copays while making formulary decisions.

Disclosure
L. Xu: None. M. Pawaskar: Employee; Self; Merck & Co., Inc. Y. Tang: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc.. G. Puckrein: None. S. Rajpathak: Employee; Self; Merck & Co., Inc. B.C. Stuart: Consultant; Self; Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation.
Factors Associated with Secondary Nonadherence to Oral Antihyperglycemic Agents among Patients with T2DM
Authors: LARSON SHARON , TANG YUEXIN , LESTER KIRCHNER H. 
Published: June 2018

Glycemic control in patients with T2DM remains sub-optimal. A major contributor to poor goal achievement is medication nonadherence. This study aimed to examine secondary nonadherence to oral anti-hyperglycemic agents (AHA) among T2DM patients and to assess its association with community- and individual-level characteristics.
Using claims and electronic medical records in Geisinger Health System during 2003-2015, this retrospective cohort study included adults with newly diagnosed T2DM who filled their 1st order of oral AHA. Secondary nonadherence was determined when patients did not fill the 2nd oral AHA prescription within 30 days after the 1st fill supply ended.
Among 2,413 patients who filled the 1st order, 764 (31.7%) were not adherent to the 2nd prescription. Younger age, non-white (vs. white) and chronic kidney disease was associated with higher odds of nonadherence. Patients with higher baseline HbA1c when ≤ 10% was associated with lower odds of nonadherence, while those with higher baseline HbA1c when &gt;10% were more likely to be non-adherent. Community-level characteristics were not found to be associated with nonadherence.
Nearly one-third of patients did not complete a 2nd fill of their oral AHA. This study identified patient characteristics associated with secondary nonadherence that may provide intervention points for improving medication adherence in diabetes management.

Disclosure
S. Larson: None. Y. Tang: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc.. H. Kirchner: None.
Severe Hypoglycemia (SH) and Diabetic Ketoacidosis (DKA) Hospitalization Rates—Twenty-Five Years in the Epidemiology of Diabetes Complications (EDC) Study
Authors: PAMBIANCO GEORGIA , ORCHARD TREVOR J. 
Published: June 2018

SH and DKA are common serious acute complications of type 1 diabetes (T1D), but whether rates have changed with recent improvements in diabetes management is not clear. We, thus examined data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood onset T1D (mean age 28 and duration 19 years, n=658) to determine if the hospitalized rates of SH and DKA have changed over 25 years of follow-up. Participants reported hospitalizations at each biennial survey for the prior 5 years (1986-1988, 2012-2014) or prior 3 years (1996-1998, 2004-2006). Rates per 100 person years for SH and DKA were then calculated by dividing the total number of self-reported SH or DKA admissions by the total appropriate accumulated person years of reporting at each follow-up. Hospitalization rates for SH declined after 1996-1998 with a fall in HbA1c suggesting better overall management. The DKA hospitalization rate was consistent throughout the follow-up. The factors underlying these encouraging trends require further investigation and survival bias cannot be excluded.

Disclosure
G. Pambianco: None. T.J. Orchard: None.
Cost Effectiveness of DPP-4i and SGLT2i Combination Therapy for the Treatment of Type 2 Diabetes in the U.S.
Authors: PAWASKAR MANJIRI , PINAR BILIR S. , GRABER-NAIDICH ANNA , GONZALEZ CLAUDIO D. , RAJPATHAK SWAPNIL , DAVIES GLENN M. 
Published: June 2018

Management of type 2 diabetes (T2D) needs different treatment strategies to achieve the individualized glycemic goal. This study evaluated the long-term cost effectiveness of strategies involving pathway 1: metformin followed by intensification with dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and insulin vs. pathway 2: metformin followed by intensification with sulfonylurea (SU) and insulin in the U.S. Cost-effectiveness analysis was performed using the validated QuintilesIMS CORE Diabetes Model from a U.S. payer perspective. Clinical and economic outcomes were modeled over a lifetime for a cohort of T2D patients who fail to achieve glycemic goal on metformin monotherapy. Clinical data were obtained from clinical trials. Direct medical costs [e.g., medications (whole sale acquisition costs), diabetes management, adverse events, and complications] were obtained from published sources. Despite higher direct medical costs for pathway 1 compared to pathway 2 ($117,779 vs. $93,196 respectively); pathway 1 improved total quality-adjusted life years (QALY) by 0.28 vs. pathway 2. Pathway 1 also led to cost offsets from fewer diabetes-related complications and delayed initiation of insulin. The incremental cost-effectiveness ratio (ICER) was favorable for pathway 1 at $89,038/QALY. Most of the scenario analysis (changes in treatment effect, hypoglycemia, and cardiovascular protective effects of SGLT2is) resulted in ICERs under $100,000/QALY except for the population with baseline HbA1c of 7%, and older age (65+ years). Negotiated discounts on branded medications resulted in significant improvement in ICERs (ICER of $69,554/QALY for 15% discount and $0/QALY for 75% discount). Among patients failing metformin monotherapy in the U.S, additional intensification with DPP-4i followed by SGLT2i may be considered more cost effective compared to intensification with SU followed by insulin.

Disclosure
M. Pawaskar: Employee; Self; Merck & Co., Inc. S. Bilir: Consultant; Self; Merck & Co., Inc.. A. Graber-Naidich: None. C.D. Gonzalez: Employee; Self; Merck & Co., Inc. S. Rajpathak: Employee; Self; Merck & Co., Inc. G.M. Davies: Employee; Self; Merck & Co., Inc..