bluuebunny/crossref_metadata_2025_split huggingface dataset:
1143-P: Secondary Metformin Monotherapy Failure in Type 2 Diabetes Mellitus Patients
Authors: WEISS TRACEY , IGLAY KRISTY , VERMA PRIYA , RAJPATHAK SWAPNIL , YANG LINGFENG , BLONDE LAWRENCE 
Published: June 2019

Clinical guidelines recommend metformin monotherapy (MM) as an initial glucose-lowering therapy for type 2 diabetes (T2D) patients [pts]. While studies have previously reported the incidence of metformin monotherapy failure, there are limited data specifically assessing the rate of “secondary” MM failure (defined as loss of control following initial achievement of glycemic control). The current study sought to characterize and evaluate factors associated with secondary failure among T2D pts on MM in a diverse U.S. population. Using the GE Centricity Electronic Medical Record database, we conducted a retrospective study of T2D pts ≥18 years initiating MM between 1/2013-5/2016 and achieving an HbA1c &lt;7% (index date) within 6 months of initiation. Secondary MM failure was assessed at 6, 12, 18, and 24 months after index date and was defined based on HbA1c ≥7% or by treatment change (therapy switch or add-on intensification). Multivariable logistic regression was used to evaluate the factors associated with secondary MM failure. Of 4,775 pts included, 53.4% were female, the median age was 63 years and median HbA1c at index date was 6.4%. At 6 months, the proportion of pts who experienced MM failure by HbA1c ≥7% was 9.76% and by treatment change was 6.01%. At 12, 18 and 24 months, these proportions (%) were 16.20/8.00, 22.95/9.36, and 28.82/10.68, respectively. Factors positively associated with secondary MM failure (HbA1c ≥7%) at 24 months were male gender, HbA1c at index date and younger age (&lt;65 years). These data suggest that after initially achieving an A1C &lt;7%, a substantial proportion of pts on MM experience secondary failure within a relatively short period of time, with an increasing number experiencing failure within 2 years. Pts controlled on MM may benefit from regular HbA1c testing to ensure timely treatment modification. Further studies assessing whether initial metformin combination therapy would result in more durable glycemic control would also be of value.

Disclosure
T. Weiss: Employee; Self; Merck & Co., Inc. K. Iglay: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P. Verma: None. S. Rajpathak: None. L. Yang: Employee; Self; Bristol-Myers Squibb Company, Merck & Co., Inc. L. Blonde: Consultant; Self; Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi US. Research Support; Self; Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi US. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US.
1152-P: Erbium-Yttrium Aluminum Garnet (YAG) Laser Accelerates Healing in Indolent Diabetic Foot Ulcers
Authors: JOHNSON MATTHEW J. , LAVERY LAWRENCE A. 
Published: June 2019

Aim: The objective of the study was to evaluate the effect of the Erbium-Yttrium aluminum garnet (YAG) laser on diabetic foot ulcer that had not responded to standard care.
Methods: We retrospectively evaluated 23 patients with c non-healing diabetic foot ulcers that received at least four weeks of standard wound care, demonstrated poor healing response, and were subsequently treated with YAG laser. We measure the percent wound area reduction (PWAR) for the 4 weeks prior to initiating laser therapy and the PWAR for 4 weeks following the initiation of laser therapy. YAG laser treatment consisted of two components: debridement and re-surfacing. The laser settings were the same for all treatments. We used pair t-test to compare pre versus post wound area reduction.
Results: During the 4-week period prior to the initiation of laser therapy, the average PWAR was -32.1%. During this time, the diabetic foot ulcers increased in area. After treatment with YAG laser, after 4 weeks the average PWAR was 63.5% (p&lt;0.01), 66.7%% of patients had &gt; 50% PAR at 4 weeks and 45.8% of patients healed by 12 weeks.
Conclusion: YAG laser therapy accelerated DFU healing in a cohort of patients with ulcers that had been unresponsive to standard of care therapy.

Disclosure
M.J. Johnson: None. L.A. Lavery: Consultant; Self; Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Medline Industries, Inc. Research Support; Self; Cardinal Health, EO2 Concepts, Integra LifeSciences, MedImmune, Osiris Therapeutics, Inc.
1163-P: Comparison of Glycemic Variability between Gemigliptin and Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Randomized, Active-Controlled, Multicenter, 12-Week Clinical Trial (STABLE II Study)
Authors: HWANG YOU CHEOL , KIM JAE HYEON , KWAK SOO HEON , KIM SANGYONG , WON JONG CHUL , BAE JI CHEOL , KIM HYUN JIN , SUH SUNGHWAN , LEE EUN YOUNG , LEE SUBIN 
Published: June 2019

The aim of this study was to evaluate the effect of gemigliptin, a potent and selective dipeptidyl peptidase-4 inhibitor versus dapagliflozin, a sodium glucose co-transporter-2 inhibitor on glycemic variability in patients with type 2 diabetes mellitus (T2DM). This randomized, parallel group, blinded end-point, multicenter, 12-week clinical trial was conducted in 71 patients with T2DM inadequately controlled with metformin alone or drug naïve patients. Subjects were randomized to receive gemigliptin 50mg (N=35) or dapagliflozin 10mg (N=36) daily for 12 weeks. Glycemic variability parameters such as mean amplitude of glycemic excursions (MAGE), standard deviation (SD) and coefficient of variation (CV) were evaluated during 6-day continuous glucose monitoring at baseline and after 12 weeks of treatment. The primary efficacy endpoint was change in MAGE after 12 weeks compared to baseline. Measures of glycemic control, oxidative stress and inflammation, as well as safety profiles were assessed. Adjusted mean change ± standard error in MAGE after 12 weeks were -27.2 ± 4.4 mg/dL (P&lt;0.001) in the gemigliptin group and -7.9 ± 4.9 mg/dL (P=0.160) in the dapagliflozin group. The between-group comparison showed that gemigliptin group had significantly larger reduction in MAGE compared to dapagliflozin group (-19.2 mg/dL, 95% CI -31.3 to -7.2, P=0.002). Other glycemic variability parameters including SD and CV also showed significantly larger reduction in the gemigliptin group. Glycemic control estimated by HbA1c, fasting glucose and safety profiles were comparable between the two groups.
In conclusion, gemigliptin significantly improved glycemic variability than dapagliflozin with similar glycemic efficacy and safety profiles in patients with T2DM inadequately controlled with metformin alone or drug naïve patients. ClinicalTrials.gov Identifier: NCT03202563.

Disclosure
Y. Hwang: None. J. Kim: None. S. Kwak: None. S. Kim: None. J. Won: None. J. Bae: None. H. Kim: None. S. Suh: None. E. Lee: None. S. Lee: Employee; Self; LG Chem.

Funding
LG Chem, Ltd.
1167-P: Safety and Efficacy of 52 Weeks' Therapy with Hydroxychloroquine (HCQ)—First Anti-inflammatory Drug Approved in India for T2D
Authors: PAREEK ANIL , MEHTA RAVI TEJRAJ , DHARMADHIKARI SHRUTI , NAIDU KUMAR BHASKAR 
Published: June 2019

Introduction: This phase 4 study enrolled 600 T2D patients uncontrolled (A1c≥7%) on metformin+SU combination to receive add-on HCQ 400mg for 52 weeks (405 patients have completed 24 weeks and 234 have completed 52 weeks of study till date). Effect on glycemic, lipid and inflammatory parameters was assessed.
Results: Efficacy was assessed in 234 patients completing 52 weeks of study. Patients were divided based on baseline hsCRP (≤3 and &gt;3 mg/L). Enrolled population had more females and they had higher inflammatory load. HCQ significantly reduced glycemic, lipid and inflammatory parameters; with greater reduction in higher inflammatory load group. Similar effect is seen in 405 patients completing 24 weeks of study. Of the 140 AEs, most were GI related (25%), mild in intensity (84%) and unlikely related to HCQ (66%). Ten patients reported hypoglycemia; all were Level 1 as per ADA criteria. Eight NPDR cases were reported, all were mild and 7 were unlikely related to HCQ. Of the 6 SAEs reported, 5 were not related to HCQ. Causality was assessed by study investigators. T2D is characterized by chronic, low-grade inflammation, referred to as metaflammation. HCQ significantly reduced A1c (0.91%) and other glycemic parameters (comparable to other OHAs), with added benefits on lipid and inflammatory markers.
Conclusion: T2D patients have high inflammatory load and HCQ could be effective and well-tolerated option.

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

Funding
Ipca Laboratories Limited
1168-P: The Effects of Long-Term Testosterone Therapy on A1c in Men with Co-occurring T2DM
Authors: JENKINS CRAIG , TATE JOSHUA M. , WARDIAN JANA L. , RITTEL ALEX , FOLARON IRENE 
Published: June 2019

Approximately 25% of men with type 2 diabetes mellitus (T2DM) have hypogonadotropic hypogonadism. Although there is a paucity of trials evaluating testosterone therapy in relation to T2DM, there have been recent studies highlighting possible additional benefits of its use in men with T2DM. Our study aims to evaluate the effects of long-term testosterone therapy on A1c in men with co-occurring T2DM. We identified 12,125 military beneficiaries with dual diagnoses of T2DM and hypogonadism from 2005-2018. Roughly 10.5% (1,125) met inclusion criteria: testosterone treatment ≥5 years and available pre-treatment and post-treatment clinical values (A1c, serum testosterone, and BMI). Patients were categorized as follows based on testosterone adherence rates: Group 1 (≥75%; n=72), Group 2 (50-74%; n=172), Group 3 (25-49%, n=266), Group 4 (&lt;25%; n=762). All groups showed improvement in BMI over time, although it was more substantial in Group 1. Pre- and post-treatment BMI values were 33.7 kg/m2 vs. 32.8 kg/m2 for Group 1 (-0.93 kg/m2), 33.7 kg/m2 vs. 33.5 kg/m2 for Group 2 (-0.2 kg/m2), 34.1 kg/m2 vs. 33.8 kg/m2 for Group 3 (-0.3 kg/m2), 33.8 kg/m2 vs. 33.4 kg/m2 for Group 4 (-0.4 kg/m2). Pre- and post-treatment A1c values were 6.8% vs. 6.6% for Group 1 (-0.18%), 7% vs. 7.1% for Group 2 (+0.11%), 7% vs. 7.3% in Group 3 (+0.3%), and 7.4% vs. 7.6% in Group 4 (+0.25%). Thus, the A1c improvement in Group 1 was statistically significant when compared to Group 3 (p=0.045) and Group 4 (p=0.047). Despite improvement in BMI for all groups, only Group 1 showed improvement in A1c. This speaks to the potential effect of testosterone on A1c specifically, irrespective of BMI, as evidenced by the glycemic benefit only seen in those with the highest adherence rates.

Disclosure
C. Jenkins: None. J.M. Tate: None. J.L. Wardian: None. A. Rittel: None. I. Folaron: None.
118-OR: Activation of Dopamine Signaling in the Brain Causes HAAF
Authors: DE ABREU ADRIANA VIEIRA , AGRAWAL RAHUL , MEIER ETHAN R. , CHAN OWEN , FISHER SIMON 
Published: June 2019

Hypoglycemia-associated autonomic failure (HAAF) is comprised of both a blunted counterregulatory response to hypoglycemia and hypoglycemia unawareness. We previously demonstrated that both these aspects of HAAF can be reversed by treatment with the dopamine receptor antagonist, metoclopramide. These findings suggest that repetitive activation of the dopaminergic system may contribute to HAAF. We now evaluate whether both the blunted counterregulatory response to hypoglycemia and hypoglycemia unawareness are mediated by repeated activation of brain dopaminergic receptors. To test this hypothesis, male Sprague-Dawley rats were randomized to receive either the dopamine receptor agonist, bromocriptine, (Bromo; 20 µg/d) intracerebroventricularly (ICV) for 3 consecutive days or recurrent ICV saline (controls). On the fourth day, all rats underwent either, 1) a hyperinsulinemic (50 mU/kg/min) hypoglycemic (∼50 mg/dl) clamp to assess counterregulation, or 2) had food consumption measured in response to insulin-induced (15 U/kg; SQ) hypoglycemia (∼40 mg/dl) to assess hypoglycemia awareness. In response to hypoglycemia, antecedent Bromo blunted, 1) the epinephrine response by 86%* (see Fig), 2) the glucagon response by 56%§, and 3) hypoglycemia awareness by 37%§, as compared to controls (*p&lt;0.01, §p&lt;0.05). These findings demonstrate that dopaminergic signaling in the central nervous system contributes to the development of HAAF.

Disclosure
A. Vieira de Abreu: None. R. Agrawal: None. E.R. Meier: None. O. Chan: Research Support; Self; Zucara Therapeutics Inc. S. Fisher: None.
1186-P: Lean Women with Polycystic Ovary Syndrome and Insulin Resistance Have Normal Incretin Effect, which Is Unaffected by Metformin Therapy
Authors: VEDTOFTE LOUISE , FOGHSGAARD SIGNE , ZIERAU LOUISE , VILSBØLL TINA , KNOP FILIP K. 
Published: June 2019

Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and a high risk of type 2 diabetes. We investigated the incretin effect (IE) and gastrointestinal-mediated glucose disposal (GIGD) in lean women with PCOS and IR, but normal fasting plasma glucose, and whether metformin affects the IE and GIGD in these women.
Ten normoglucose-tolerant, lean women with PCOS and IR (homeostatic model assessment (HOMA-IR) &gt; 1.5) were randomly allocated to receive metformin (500 mg bid) or placebo for 12 weeks interposed by a 6-week wash-out period in a double-blind, cross-over design. The women underwent an OGTT and an isoglycemic intravenous glucose infusion (IIGI) at baseline and at the end of each treatment period. Ten healthy, lean women without PCOS served as controls and underwent one OGTT and one IIGI.
At baseline, the control group and the PCOS group had similar age (25±3 vs. 25±4 years (mean±SD), P=0.91), BMI (22±2 vs. 23±2 kg/m2, P=0.42), fasting plasma glucose (4.8±0.3 vs. 5.0±0.2 mmol/l, P=0.11), GIGD (58±15 vs. 59±12%, P=0.84) and IE (56±15 vs. 51±13%, P=0.45); the PCOS group had higher HOMA-IR (1.8±0.4 vs. 1.0±0.3, P&lt;0.0001) and lower Matsuda index (6±3 vs. 9±2, P=0.03). Compared to placebo, 12 weeks’ metformin treatment had no effect on BMI (P=0.42), fasting plasma glucose (P=0.71), HOMA-IR (P=0.95) and Matsuda index (P=0.52). Compared to baseline, metformin treatment lowered the IE in the PCOS group (-9.2% [-17.8;-0.6] (mean [95% CI])), but the change was not different from the change observed after placebo treatment (0.9% [-8.2;10.1], P=0.11) and metformin treatment tended to lower the GIGD (-9.7 [-21.3; 1.9] vs. 1.9% [-10.6; 14.5], P=0.05).
We conclude that the studied lean women with PCOS and IR have similar IE and GIGD as matched, insulin-sensitive controls and, surprisingly, we observed no effect of metformin on IR, IE or GIGD in these women.

Disclosure
L. Vedtofte: None. S. Foghsgaard: None. L. Zierau: None. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.

Funding
Augustinus Foundation; A.P. Møller Foundation
1190-P: IFN-Alpha Kinoid: A Promising Vaccine against Type 1 Diabetes Targeting IFN-alpha in NOD Mice
Authors: CAILLOT NOÉMIE , COLAONE FABIEN , BERTRAND ROMAIN , SILVA JENNIFER DA , HAMDI SAMIR , BONNEFOY JONATHAN , LEHUEN AGNES , BOITARD BOITARD F. , GROUARD-VOGEL GÉRALDINE 
Published: June 2019

Major elements highlight IFNα implication in type 1 diabetes (T1D) pathogenesis. While there is still no cure for this autoimmune disease, we aimed to evaluate the benefit of IFNα kinoid (IFN-K). This conjugated vaccine consisting of IFNα coupled to Keyhole limpet hemocyanin as a carrier protein elicits the production of polyclonal anti-IFNα neutralizing antibodies and has shown beneficial effects in a recent phase IIb trial in lupus (NCT02665364). Three independent experiments in NOD mice were performed to evaluate the activity of anti-IFNα neutralizing antibodies, conveyed either by maternal transfer or by passive or active immunization. Glycemia was monitored by a glucometer, neutralizing antibodies by the virus-induced cytopathic effect assay and H&E pancreas sections were evaluated in blind. In the first study, we compared T1D incidence in offsprings from IFN-K or KLH immunized mothers with sentinels. In the second study, mice were passively immunized with purified total IgG from sera collected in NOD mice immunized with IFN-K or KLH. Finally, active immunization was performed with IFN-K, KLH or PBS in combination with a squalene oil-in-water adjuvant. Mice were immunized at 5, 10 or 15 weeks of age. Anti-IFNα neutralizing antibodies were effectively conveyed from mothers to offspring, and levels decreased over time to completely disappear by month 3. In progeny from IFN-K immunized mice, despite transient and low amount of neutralizing antibodies, insulitis was decreased compared to control groups and T1D onset was delayed. In the second study, long-lasting administrations of total IgG comprising anti-IFNα neutralizing antibodies conferred protection towards T1D development, while total IgG from KLH-immunized mice did not. Finally, diabetes incidence was reduced when IFN K immunization started at week 10 of age. These different elements point out the need to neutralize IFNα during NOD lifetime to prevent T1D, and encourage us to evaluate IFN-K in newly diagnosed T1D patients.

Disclosure
N. Caillot: None. F. Colaone: None. R. Bertrand: None. J. Da Silva: None. S. Hamdi: None. J. Bonnefoy: None. A. Lehuen: Board Member; Spouse/Partner; Inatheris. Consultant; Self; Neovacs. B.F. Boitard: None. G. Grouard-Vogel: None.
1194-P: NT-proBNP, Subclinical Diastolic Dysfunction in Patients with DM Type 1 Treated with iSGLT2
Authors: CHERVIAKOVA SVITLANA , SOKOLOVA LIUBOV K. , BELCHINA IILIA , KORZUN IILIA , TRONKO MYKOLA D. 
Published: June 2019

Aim: Subclinical diastolic dysfuntion in patients with preclinical heart failure with preserved ejection fraction (HFpEF) has been demonstrated in patients with DM type 1. We investigated the relationship between diastolic dysfunction and NT-proBNP levels in patients with diabetes treated with iSGLT2 (dapagliflozin).
Methods: NT-proBNP and diastolic function were assessed in 35 patients with DM 1 (31 ± 1,6 y, duration of DM 12,0± 1,2 y) and 15 control subjects (mean age - 29,9± 1,8years) without clinical evidence of heart disease. Data presented as M±m. The results were compared using Student’s paired test.
Results: All patients had a normal ejection fraction (53,9±2,3 vs. 56,1± 4,3, (p &gt; 0,05) in those with and without DM, respectively. 34,2% of the diabetic patients had evidence of diastolic dysfunction as assessed by the presence of at least two abnormal variables of mitral inflow velocity. The ratio of peak early to peak late (atrial) filling velocity was significantly decreased in diabetic compared with control subjects (E/A ratio 0,9±0,05 vs. 1,2± 0,06, p&lt; 0,05), the DT was 257,1±28,2 ms vs. 186±14,6 ms p&lt;0,05, in those with and without DM, respectively. Also, the IRT was increased in diabetic patients compared with control subjects (130±14,0 ms vs. 79,3±6,1 ms, p&lt; 0,05). Median NT-proBNP plasma levels were elevated [189.54 pg/mL (86.16-308.27) and increased with greater severity of the diastolic dysfunction. Median NT-proBNP plasma levels have been decreased - 51.89 pg/mL (29.94-69.71); P&lt;0.001] after 1 month treatment period with dapagliflozin.
Conclusions: DM type 1 patients presenting with normal ejection fraction show disturbed diastolic function and higher NT-proBNP levels. 2. iSGLT2 (dapagliflozin) decreased NT-proBNP levels in DM1 patients with subclinical diastolic dysfunction.

Disclosure
S. Cherviakova: None. L.K. Sokolova: None. I. Belchina: None. I. Korzun: None. M.D. Tronko: None.
12-OR: Trends in Total and Out-of-Pocket Payment on a Yearly Insulin Supply among Private Health Insured U.S. Adults with Diabetes from 2003 to 2016
Authors: SHAO HUI , LAXY MICHAEL , BENOIT STEPHEN R. , CHENG YILING J. , GREGG EDWARD , ZHANG PING 
Published: June 2019

High spending, especially out-of-pocket (OOP) payment on insulin, could lead individuals with diabetes to skip or ration doses and worsen future health outcomes. We examined the trends in total and OPP payment on a yearly supply of insulin by type from 2003 to 2016. Using the 2003-2016 MarketScan claims database, we analyzed 1,703,343 adults with diabetes who were continuously enrolled in fee-for-service health plans. Insulin was grouped into 6 types (human insulin, Glargine, Lispro, Aspart, Detemir and Glulisine) using National Drug Code. Total and OOP payment for each drug type were modelled at a 30-day supply level, and later multiplied by 12 to obtain yearly estimates. A joinpoint regression was used to identify inflection points and to estimate trends in each defined segment. Payments were standardized to 2016 USD. The total payment for insulin increased at annual rate of $162 per year from 2003 ($1982) to 2012 ($3686), followed by more than a 3-fold increase in the annual rate of increase to $708 per year between 2013 ($4392) and 2016 ($6250). By type, the annual rate of increases ranged from $64 (2%) for Glulisine to $133 (6%) for Glargine before the inflection point and raised to a range from $631 (16%) for Glargine to $1246 (26%) for Glulisine after the inflection point. OPP payment on a yearly supply of insulin decreased by $6 per year (-1.5%) between 2003 ($390) and 2009 ($384) followed by a 3% ($12) per year increase between 2010 ($405) and 2016 ($451). The annual rate of changes ranged from -$72 (14.8%) for Detemir to -$31 (-6%) for Glulisine before the inflection point and varied from $8 (2%) for Aspart to $41 (7.6%) for Glulisine after the inflection point. Total payment on a yearly supply of insulin had been increasing since 2003 but accelerated after 2011. The OPP payment reversed its trends from a decrease to an increase. But the much smaller increase in OPP payment than the total payment after 2011 suggests that payers bore most of the insulin spending increase.

Disclosure
H. Shao: None. M. Laxy: None. S.R. Benoit: None. Y.J. Cheng: None. E. Gregg: None. P. Zhang: None.