bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of SGLT2 Inhibition on Body Water Distribution and Its Relevance to Body Composition Measures
Authors: NAKAYAMA HITOMI , IWATA SHIMPEI , OHKI TSUYOSHI , NAGAYAMA AYAKO , YAMADA KENTARO , TAJIRI YUJI , NOMURA MASATOSHI
Published: June 2018

Many studies have reported the effect of SGLT2 inhibition on body composition. However, its effect on water distribution and the resultant influence on body composition measures are still unclear. The subjects of this study consisted of 29 tofogliflozin (TOFO) -treated type 2 diabetic inpatients aged 48±14 years with BMI of 29.4±6.3 kg/m2, and 29 age- and BMI-matched type 2 diabetic inpatients treated with other therapies. TOFO was administered for 7 days at a dose of 20 mg/day without changing the dose of other drugs. Average glucose levels assessed by CGM decreased from 188±43 to 142±32 mg/dL. Body composition and fluid status were estimated using a multifrequency BIA. The TOFO and the control groups lost 1.64±0.95 and 0.80±0.74 kg body weight, together with 1.31±1.02 and 0.38±0.87 kg body fat, respectively. The reduction of skeletal muscle was not statistically significant due to large variation in either group (0.21±0.84 and 0.39±1.03 kg, respectively). Thus we further analyzed factors associated with the skeletal muscle reduction. Although the change in skeletal muscle mass was correlated with changes in both body fat and body water, a multiple regression analysis showed that the change in intracellular water was the independent factor. Intracellular water was decreased in the TOFO group by 0.29±0.61 kg, but not in the control group. Extracellular water was not changed in either group. Serum sodium concentration was increased in the TOFO group (140.0±1.9 to 141.0±2.7 mEq/L) but not in the control group. The reduction in intracellular water was strongly correlated with that in skeletal muscle in the TOFO group (r=0.863), although there was an inverse correlation in the control group (r=-0.469). These observations indicate that SGLT2 inhibition results in the decrease of intracellular water likely due to increased osmotic diuresis despite plasma glucose reduction. The altered water distribution may affect the assessment of skeletal muscle by BIA.

Disclosure

H. Nakayama: Speaker's Bureau; Self; Medtronic, MSD K.K.. S. Iwata: None. T. Ohki: None. A. Nagayama: None. K. Yamada: Speaker's Bureau; Self; MSD K.K., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc.. Y. Tajiri: None. M. Nomura: None.
Changing Glucose Tolerance during Pregnancy—Implications for Diagnosis of Gestational Diabetes Mellitus (GDM)
Authors: KNOWLER WILLIAM C. , DREWS KIMBERLY , REDMAN LEANNE , JOSHIPURA KAUMUDI J. , ARTEAGA S. SONIA , PI-SUNYER XAVIER , HORN LINDA VAN , WING RENA R. , KLEIN SAMUEL ,   LIFE-MOMS RESEARCH GROUP
Published: June 2018

Background: ADA recommends testing for GDM at 24-28 weeks gestation. This recommendation is based on the assumption that glucose tolerance worsens during pregnancy and, therefore, testing earlier in pregnancy will miss many cases that develop only later. We tested this assumption in the LIFE-Moms consortium.

Methods: LIFE-Moms was a consortium of randomized clinical trials of lifestyle interventions aimed at limiting gestational weight gain compared with standard care in 1,150 pregnant women with BMI ≥25 kg/m2 recruited from different racial/ethnic groups in the U.S. Women with known or probable diabetes preceding this pregnancy were excluded. As previously reported, the lifestyle interventions modestly reduced excessive gestational weight gain (the primary outcome) but had no significant effect on the prevalence of GDM at 24-31 weeks. We report here results of 75 g 2-hour OGTTs performed sequentially during pregnancy in a subset of 296 women tested at <16 weeks (mean 12.6 weeks) gestation and again at 24-31 weeks. Tests were interpreted by the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria.

Results: Plasma or serum glucose declined from the early to later tests by a mean of 2.5 mg/dl (fasting), 10.9 mg/dl (1-hr), and 9.3 mg/dl (2-hr), each p<0.0001. The prevalence of GDM by IADPSG criteria declined from 20% at <16 weeks gestation to 15% at 24-31 weeks (p=0.04). Only 9% of women without GDM at <16 weeks gestation developed it by 24-31 weeks, whereas 65% of those meeting GDM criteria at <16 weeks gestation did not meet GDM criteria at follow-up. None of the changes in glucose or GDM prevalence differed significantly by treatment group.

Conclusions: In pregnant women with BMI ≥25 kg/m2 who are otherwise healthy, glucose tolerance improves on average rather than deteriorates during gestation. Testing for GDM early in pregnancy is needed to understand pregnancy effects on glycemia and the clinical implications of earlier detection of GDM.

Disclosure

W.C. Knowler: None. K. Drews: None. L. Redman: None. K.J. Joshipura: None. S. Arteaga: None. X. Pi-Sunyer: None. L. Van Horn: None. R.R. Wing: None. S. Klein: Stock/Shareholder; Self; Aspire Bariatrics. Consultant; Self; Pfizer Inc.. Research Support; Self; Merck & Co., Inc., Johnson & Johnson Services, Inc., REMD Biotherapeutics.
What Is the Role of A1C in Comorbidities?
Authors: PERLMAN JORDAN E. , ROSENBAUM JENNIFER L. , MCNULTY BRIDGET K. , HIRSCH IRL B.
Published: June 2018

The ADAG Study Group defined the relationship between average blood glucose (AG) and A1C. They derived an equation valid across diabetes types but excluded comorbidities known to impact A1C. The goal of this study is to examine the relationship between AG and A1C in patients omitted from prior analyses. A retrospective chart review was performed of downloaded glucose data from patients prescribed insulin at the UW Diabetes Center between 1/2011-10/2017. Patients were identified who had either 1) documentation and/or laboratory confirmation of anemia; 2) CKD; or 3) NAFLD. Eligible charts required: 1) 2 weeks of fingerstick glucose (SMBG) data with ≥14 checks or 1 month of CGM with ≥14 complete days and, 2) an A1C measured within 1 month of the encounter. The SMBG and CGM means were obtained from downloads. An AG was extrapolated from the A1c using the ADAG equation. The downloaded data and A1C-derived AGs were compared. There was a linear correlation between AG and A1C (R2=0.48) in anemic patients regardless of etiology. Non-anemic patients (N=220) had better ADAG agreement (70% of AGs inside 15% of predicted) than anemic patients (55% of AGs, N=123, p=0.006). Normal GFR yielded 71% of AGs inside 15% of ADAG estimation (N=440). This decreased to 59% if limited to anemic patients (N=83, p<0.001). ADAG agreement decreased as a function of renal impairment. The impact of anemia was only significant in CKD stage 3A (N=49, p=0.02). In CKD stage 4/ESRD there was no correlation between AG and A1C (N=14, R2=0.0004). Abnormal LFTs did not affect ADAG agreement. In NAFLD there was no correlation between AG and A1C (N=14, R2=0.03) but 64% of AGs were inside 15% of ADAG projection. For many, SMBG and CGM data provide an important confirmatory assessment of A1C. However, in certain conditions there is significant discordance between AG and A1C. There is a complete lack of correlation between AG and A1C in advanced renal dysfunction and NAFLD as measured by our lab. These findings suggest glucose downloads are a better assessment of diabetes control in several common comorbidities.

Disclosure

J.E. Perlman: None. J.L. Rosenbaum: None. B.K. McNulty: None. I.B. Hirsch: Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Abbott, Bigfoot Biomedical, Roche Diabetes Care Health and Digital Solutions, ADOCIA.
Antidiabetes Drug Prescription in Indian Scenario—A Cross-Sectional Analysis from a Large, Pan India Database of the Apollo Sugar Clinics
Authors: SESHADRI KRISHNA G. , VENKATARAMAN S. , RM MANIKANDAN , CS DWARAKANATH , TS BOOCHANDRAN , NK NARAYANAN , GOPAL JAYASREE , DUVURU SHANTHARAM , AYYAGARI USHA , BEHL ANISH ,   APOLLO SUGAR RESEARCH GROUP
Published: June 2018

Aim: Our objective was to determine nature of antidiabetes prescriptions across the Apollo Sugar Ecosystem, India, a healthcare organization with more than 30 centres (as standalones, secondary and tertiary institutions) that provide care to patients with diabetes

Methods: An eligible 206prescriptions with a diagnosis of T2DM from Jan 2016 to June 2017 were included in this analysis to determine the choice of therapy, frequency of usage of different class of anti-iabetes medications, types of insulin, combination and of number of OHAs with insulin. Descriptive analysis was used to report the results.

Results: The mean age of the patients was 53.2 years, 63% males and 37% females. The majority of the patients were on OHAs (68.2%) with 22.8% of patients on OHAs+insulin and 9.0% on insulin alone. Biguanides (55.7%) were most commonly prescribed in combination with other OHAs followed by DPP-4 inhibitors (DPP-4i) (35%). 63% of patients requiring insulin were using at least one oral drug. The most common drugs used along with insulin included biguanides (50.5%) followed by DPP-4i (46.7%). Among Insulins short acting insulin was most commonly prescribed followed by Insulin glargine (22.5%) and premixed insulin and analogues (13.55).

Conclusions: Several observations stand out from this large cross sectional analysis. 1 A significant number of patients are on monotherapies other than MF. 2. Use of DPP-4i as the most common drug after MF when two drugs are used reflects a significant shift from a SU dominated practice system in India. 3. SGLT2i and insulin find progressive inclusion when three or more drugs are required. 4. A greater adoption of basal and short acting insulin as opposed to premix insulin in a country that was traditionally considered a premix market. The data provided here give a snap shot of the changing trends in adoption of therapeutic practices with availability of newer medications, physician education and patient ability to afford care.

Disclosure

K.G. Seshadri: None. V. S.: None. M. Rm: None. D. Cs: None. B. Ts: None. N. Nk: None. J. Gopal: None. S. Duvuru: None. U. Ayyagari: None. A. Behl: None.
Recombinant Protease Inhibitor Enhances Oral Insulin Pharmacodynamics in Pigs
Authors: NAGARAJU RAMACHANDRA , MADAN SONIA , ARORA KAJAL , ARORA NUPUR M. , KUNDU PRABUDDHA K. , GREENBERG-SHUSHLAV YAEL , KIDRON MIRIAM , HERSHKO AVRAM
Published: June 2018

Oral insulin delivery is projected to provide both physiologic and technical benefits, and has been the focus of rigorous research efforts in recent years. The ORMD-0801 oral insulin formulation relies on the activities of both protease inhibitors and an absorption enhancer to ensure insulin integrity and bioavailability. In efforts to further improve its efficacy, a recombinant protease inhibitor (rPI), identical in sequence to its naturally sourced (nsPI) counterpart, was cloned and expressed in Pichia pastoris. The enzymatic activity of the isolated and purified protein was then tested in vitro. In addition, the glucose-lowering effect of ORMD-0801 formulated with various doses of rPI was assessed in 8 healthy, fasting pigs administered the preparation directly to the duodenum. rPI effectively inhibited its standard substrate in a dose-dependent manner and demonstrated >2.5-fold higher activity as compared to nsPI. When integrated in the ORMD-0801 formulation, pigs treated with the formulation containing 25 mg rPI experienced a 20% greater change from baseline serum glucose concentrations as compared to those treated with the PI-free formulation (AUC: -6369 mg/dL vs. -2201 mg/dL, respectively). In parallel, the duration of its effect (140±33 minutes) was 75% longer than the duration of the effect of the PI-free formulation (80±37 minutes). Further calibrations of the rPI-supplemented ORMD-0801 formulation promise to enhance oral insulin bioavailability and its salutary effects, subsequently improving its clinical potential and value.

Disclosure

R. Nagaraju: None. S. Madan: None. K. Arora: None. N.M. Arora: None. P.K. Kundu: None. Y. Greenberg-Shushlav: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc. A. Hershko: Advisory Panel; Self; Oramed Pharmaceuticals, Inc..
IMG-1 Lowers Insulin Resistance by Decreasing Hepatic Glucose Production in a DIO Mouse Clamp Test
Authors: POLLETT JONATHAN B. , NOH HYE LIM , KIM JASON K. , THAI NGOC
Published: June 2018

IMG-1 is a novel therapeutic compound for the treatment of diabetes. IMG-1 has been shown to successfully treat both type 1 mice and rats (STZ models) and type 2 ZDF rats. To test how IMG-1 is able to treat type II diabetes, diet-Induced Obese (DIO) C57BL/6J mice were used in a hyperinsulinemic-euglycemic clamp assay. The hyperinsulinemic-euglycemic clamp is the gold-standard method to assess insulin sensitivity. The euglycemic clamp is widely used in clinics and laboratories to measure insulin action on glucose utilization in humans and animals for clinical and basic science research. Sixteen DIO C57BL/6J mice underwent a 2-hour hyperinsulinemic-euglycemic clamping to assess insulin action and glucose metabolism in IMG-1 treated (2µg IMG-1 administered IV via tail vein 48 and 24hours prior to the clamp test, n=8) or PBS treated animals (n=8). IMG-1 treated animals had significantly higher steady-state glucose infusion rates during clamping than PBS treated animals, indicating that IMG-1 is able to decrease insulin resistance in DIO mice. IMG-1 did not affect whole-body glucose turnover, glycolysis or glycogen synthesis in any of the treated animals. Glucose metabolism in skeletal muscle and adipose tissue was not significantly different in either IMG-1 or PBS treated animals during the clamp assay. However, Hepatic Glucose Production (HGP) was dramatically suppressed in all animals treated with IMG-1 (a decrease from 3.mg/kg/m to -6.16 mg/kg/m). Furthermore, hepatic insulin action (the percent suppression of HGP) was increased in all IMG-1 treated animals during the hyperinsulinemic-euglycemic clamp (from 70.9 control to 99.7 IMG-1). IMG-1 is a novel compound for the treatment of diabetes. These results show that IMG-1 decreases insulin resistance in a type 2 diabetic mouse model by suppressing HGP and increasing hepatic insulin action.

Disclosure

J.B. Pollett: Employee; Self; Imagine Pharma. H. Noh: None. J.K. Kim: None. N. Thai: Board Member; Self; Imagine Pharma.
Role of Vitamin E for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Patients with T2DM—A Randomized, Controlled Trial
Authors: BRIL FERNANDO , BIERNACKI DIANE M. , LOMONACO ROMINA , KALAVALAPALLI SRILAXMI , SUBBARAYAN SREEVIDYA K. , LAI JINPING , TIO FERMIN O. , SUMAN AMITABH , ORSAK BEVERLY K. , HECHT JOAN , CUSI KENNETH
Published: June 2018

While the use of vitamin E (Vit E) in nondiabetic patients with NASH has proven to be effective in the PIVENS study (NEJM 2010), there is no information about its effect in patients with NASH and T2DM. To examine this, we performed a randomized, double blind, controlled trial assessing the efficacy of Vit E, alone or combined with pioglitazone (PIO) in this population. Patients (n=105) were randomized 1:1:1 to Vit E 400 U BID, Vit E 400 U BID + PIO 45mg QD, or placebo for 18 months. The primary endpoint was histological improvement, defined as a 2-point reduction in the NAFLD activity score from 2 different parameters, without worsening of fibrosis. Secondary outcomes: resolution of NASH, individual histological scores, and metabolic parameters. Based on 2 planned primary comparisons, a p<0.025 was considered to indicate statistical significance. Groups were well matched at baseline. A total of 87 patients completed 18 months of follow-up. More patients on Vit E and PIO combination achieved the primary outcome compared to placebo (65% vs. 22%, p<0.001), but not in the Vit E alone group (36% vs. 22%, p=0.18). The same trend was observed for resolution of NASH, with a significant improvement only in the combination group (57% vs. 18%, p<0.001), but not with Vit E alone (42% vs. 18%, p=0.036). While steatosis grade improved with either combination (p<0.001) or Vit E alone (p=0.018), inflammation (p=0.018) and ballooning (p=0.022) grades only improved with Vit E + PIO. No improvement in fibrosis was observed in any group. Four patients died of cardiovascular causes during the study (2 on Vit E alone and 2 on combination). Weight gain, peripheral edema and hypoglycemia were more frequent in the combination group.

Conclusion: Vit E alone was ineffective to treat NASH in patients with T2DM. While the combination of Vit E and PIO was significantly better than placebo, response rate was similar to that reported for PIO alone in patients with T2DM, suggesting no role of Vit E in this population.

Disclosure

F. Bril: None. D.M. Biernacki: None. R. Lomonaco: None. S. Kalavalapalli: None. S.K. Subbarayan: None. J. Lai: None. F.O. Tio: None. A. Suman: None. B.K. Orsak: None. J. Hecht: None. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..
Long-Term Safety and Tolerability of Dasiglucagon, a Stable-in-Solution Glucagon Analog
Authors: CASTLE JESSICA R. , ELANDER MIKAEL , O'HALLORAN SEAN A.
Published: June 2018

Several groups are developing fully integrated dual-hormone artificial pancreas systems, which deliver insulin or glucagon in response to changes in glucose to maintain euglycemia. These systems hold the potential to transform management of type 1 diabetes, but in order to be realized these systems require a stable-in-solution glucagon analog suitable for chronic use. Dasiglucagon is a novel glucagon analog stable in liquid formulation. The present studies evaluated safety and tolerability of chronically administered dasiglucagon in rats and dogs.

Rats and dogs were dosed s.c. daily for 26 and 39 weeks, respectively, in 4 groups of 20 rats with 0 (vehicle), 0.5, 2, or 8 mg/kg/day; 4 groups of 4 beagle dogs with 0, 0.02, 0.1, or 0.3 mg/kg/day.

Glucose and insulin levels increased in a dose-dependent manner in all treated animals. In dogs, heart rate increased at the 0.1 and 0.3 mg/kg/day dose level. Liver and kidney weights increased at all dose levels for in both species, and microscopic pathology demonstrated increase in hepatocyte glycogen vacuolation and increase in chronic progressive nephropathy (a normal finding in aging rats). Heart weights increased with no histopathological correlate. All findings showed full/partial recovery after 4-week treatment free periods. Some animals developed anti-drug-antibodies but with no apparent effect on pharmacodynamics. The NOAEL (no observed adverse effect level) dose of 2 mg/kg/day in rats and 0.1 mg/kg/day in dogs represents exposure multiples (AUC) of 22 and 2 compared to anticipated human doses of up to 1 mg/day.

Chronic administration of dasiglucagon multiple times above relevant human doses was well tolerated. All findings were consistent with the known pharmacological effects of glucagon. The risk of glycogen accumulation is not considered relevant for humans treated with dasiglucagon to maintain euglycemia. These findings support long-term human testing of dasiglucagon in dual-hormonal artificial pancreas systems.

Disclosure

J.R. Castle: Consultant; Self; Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk Inc. M. Elander: Employee; Self; Zealand Pharma A/S. S.A. O'Halloran: None.
Effectiveness and Safety of Oral Hypoglycemic Agents as Initial Treatment in Comparison to Insulin Injection in Newly Diagnosed Type 2 Diabetes Mellitus
Authors: CHEN XI , WANG YUFAN , ZHANG AIFANG , WANG NIAN , LI NA
Published: June 2018

Objective: To explore the effectiveness and safety of oral hypoglycemic agents (OHA) and insulin (INS) therapy as initial treatment in patients with newly diagnosed type 2 diabetes mellitus (T2DM).

Subjects and Methods: An retrospective cohort study was conducted between December 2015 and June 2017 in diabetic clinic in Shanghai General Hospital.195 newly diagnosed T2DM were enrolled. 107 subjects received OHA while 88 subjects received insulin therapy of which 39 switched to OHA in 6 months. The general characteristics, HOMA-B and HOMA-IR, the glycemic control, glucose control rate and hypoglycemia were compared between OHA group and INS group. All of those data were compared between continued insulin group and switch to OHA group.

Results: 1.The baseline A1C levels were higher and HOMA-B was lower in INS group. While the A1C levels was significantly higher and the rates of glycemic control were significantly lower in INS group than in OHA group after 6 months’ treatment. The incidences of hypoglycemia, changes of BMI were similar in both groups. However, Multiple linear regression analysis indicated that baseline A1C was independently associated with glycemic control (P =0.005). 2. 44.32% patients switched to OHA in INS group in 6 months. This subgroup was younger, had better glycemic control and more male subjects compared with patients who still used insulin. There were no significant differences in terms of A1C, BMI and HOMA-B at baseline, the changes of BMI and rates of hypoglycemia.Binary logistic regression showed that age was significantly associated with continuous usage of insulin. (P=0.005).

Conclusion: Our results demonstrate that baseline A1C was negatively associated with glycemic control and the younger the more possibility to switch from insulin to oral hypoglycemic agents in real word setting. Incidences of hypoglycemia were similar in OHA and INS groups.

Disclosure

X. Chen: None. Y. Wang: None. A. Zhang: None. N. Wang: None. N. Li: None.
L-Carnitine and Resveratrol Action on Oxidative Response and Differentiation in H9c2 Rat Cardiomyocytes
Authors: TERRUZZI ILEANA , SENESI PAMELA , MONTESANO ANNA , VACANTE FERNANDA , LUZI LIVIO
Published: June 2018

Diabetic heart disease (DHD) results in structural and functional deterioration due to progressive loss of cardiomyocytes and cardiac stem cells, leading to a premature aging of the diabetic heart. The causes of DHD development are not completely clarified, but it is evident that higher oxidative stress of diabetes induces cardiac structural alterations. Recently, the use of stem cells or cardiac progenitors have inspired the most promising therapeutic strategies but these approaches are limited in diabetic patients. Herein we investigate L-Carnitine (LC) and Resveratrol (RSV) actions on oxidative stress and differentiation process in H9c2 rat cardiomyocytes. H9c2, during proliferation or differentiation condition, were treated with LC (0.5 or 5mM) or RSV (0.1 or 25μM). LC significantly enhanced anti-oxidative response by increasing (48 and 72h) mitochondrial SOD2 protein expression and STAT3 activation. LC did not induce p21 translocation at the nuclear level, demonstrating not to have an inhibitory effect on the cell cycle. LC decreased protein synthesis of CaMKII, whose activation is associated with hypertrophic process. In addition, the protective LC effect on H9c2 cardiomyocytes in stress condition was evaluated treating cells with LC 48h before exposure to H2O2: LC significantly reduced intracellular ROS concentration in a dose-dependent manner. RSV 0.1μM while increasing CaMKII content, did not show any effect on the proliferative potential of H9c2. RSV 25μM induced a significant proliferation decrease in favor of H9c2 differentiation, as shown by ERKs pathway activation and α-actinin protein synthesis promotion. RSV 25μM significantly reduced ROS generation induced by rotenone in neo cardiomyotubes (72h). The ability to improve the microenvironment damaged by oxidative stress and to stimulate cardiac progenitor differentiation could recognize LC/RSV as valid adjuvant therapies to preserve cardiomyocytes survival and ameliorate heart regeneration.

Disclosure

I. Terruzzi: None. P. Senesi: None. A. Montesano: None. F. Vacante: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew.
Telmisartan Combination with Amlodipine Inhibits RAGE
Authors: SRIRAMOJU SWETHA , GOETZ KERRY
Published: June 2018

Diabetic Retinopathy (DR) is the leading cause of blindness in the United States corresponding to 20,000 new diagnoses annually (cite this). Hyperglycemia is a major risk factor of type 2 diabetes and leads to the formation of plasma proteins known as Advanced Glycation End Products (AGEs). In the eye, AGES’s bind to the receptor of the Advanced Glycation End Products (RAGEs) eventually leading to DR. The following study analyzed drug targets (single drugs and combination of drugs) that are currently marketed for heart disease, diabetes, and hypertension to understand how they interact with RAGE with the goal of identifying compounds that are predicted to inhibit the ligand-receptor interaction. Docking programs, AutoDock Tools and AutoDock Vina, were used to determine the binding affinity and visual orientation of the drug receptor binding. Cholesterol lowering drugs such as Atorvastatin and Fenofibrate were able to bind to RAGE with a high hydrophobicity and great negative affinity (-7.5 and -7.7). In combination, the hypertensive drugs such as Telmisartan (Angiotensin II receptor blocker) and Amlodipine (calcium channel blocker) bind with the RAGE receptor with a high hydrophobicity and high negative affinity (-9.7). Metformin administered alone or in combination was not shown to bind to RAGE. Overall this analysis shows that a combination of hypertensive drugs and cholesterol lowering drugs may decrease the progression of DR in type II diabetes.

Disclosure

S. Sriramoju: None. K. Goetz: None.
Cost-Effectiveness of Telephone-Delivered Behavioral Skills Intervention for African-American Adults with Diabetes
Authors: EGEDE LEONARD E. , DISMUKE CLARA , EILER CHRISTIAN , WALKER REBEKAH J.
Published: June 2018

Background: To investigate cost differences between intervention arms of a telephone-delivered self-management training for African Americans with diabetes.

Methods: This RCT used a 2x2 factorial design, randomizing African American adults with poorly controlled diabetes to: 1) knowledge only, 2) skills training only, 3) combined knowledge and skills training, or 4) control group receiving general health education. The primary outcome for cost effectiveness was glycemic control (HbA1c) at 12-months post-randomization. Costs for healthcare utilization were measured using Medical Expenditure Panel Survey (MEPS) estimates and costs for lost wages were estimated using interval regression. All costs were adjusted to 2012 dollars. Cost utility was quality-adjusted life years (QALYs) estimated via the area under the curve technique using utilities obtained from respondents’ answers to SF-12 questions and mortality estimates based on CDC lifetables. Empirical joint distribution of incremental costs, QALYs, and cost effectiveness acceptability curves were generated using non-parametric bootstrapping.

Results: There was no significant difference in cost (p=0.44) or change of QALYs between arms (p=0.36). With no statistically significant difference in cost, the incremental cost effectiveness ratios (ICER) were not significant compared to control, however, the knowledge only arm was $660 less expensive, the behavioral skills arm was $813 more expensive, and the combined arm was $3,630 less expensive than the control arm to achieve a 0.6% decrease in HbA1c.

Conclusions: Combined with the clinical findings, these results suggest telephone-delivered education and behavioral skills training is a cost-effective way to improve glycemic control. In particular, the combined knowledge and skills training intervention arm resulted in costs $3,600 lower than the control, and dropped HbA1c by 0.6%, achieving a clinically significant change for lower cost.

Disclosure

L.E. Egede: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Advisory Panel; Self; Novo Nordisk Inc.. C. Dismuke: None. C. Eiler: None. R.J. Walker: None.
Cost-Effectiveness Analysis of the EndoBarrier Device in Patients with Type 2 Diabetes
Authors: GUPTA PIYA SEN , ARMSTRONG STEPHANIE , AMIEL STEPHANIE A. , RYDER ROBERT E. , PENNINGTON MARK W.
Published: June 2018

Objective: There are multiple pharmacotherapy options for type 2 diabetes mellitus (T2DM) including injectable glucacon-like peptide-1 receptor agonists (GLP-1RA) e.g., liraglutide. EndoBarrier is an innovative impermeable liner implanted endoscopically into the proximal intestine for up to one year, before removal. We compared the cost effectiveness of three strategies in patients with suboptimally controlled diabetes despite at least 6 months’ liraglutide: EndoBarrier combined with 1.2mg liraglutide (E+L); EndoBarrier without liraglutide (E), and 1.8mg liraglutide without Endobarrier (L) for the treatment of obese patients with T2DM from a National Healthcare perspective.

Methods: Seventy patients were randomised to one of three treatment arms (REVISE-Diabesity ISRCTN00151053) and followed for two years. Quality of life was measured with EQ-5D-5L and Quality Adjusted Life-Years (QALYs) calculated. Treatment costs were estimated including the costs of adverse events related to treatment. The incremental cost-effectiveness ratio (ICER) was calculated over a two-year horizon. The Core Diabetes Model (QuintilesIMS) was used to estimate outcomes and costs beyond two years based on patient physiological data at two years, allowing calculation of the lifetime ICER.

Results: At two years, QALYs were highest in the E group, followed by E+L, after adjustment for baseline differences. Costs were lowest in the L group and highest in the E group. The ICER of E compared with L was £25,130. However, E+L generated the largest reductions in both HbA1c level (-0.6% compared with L) and weight (-2.1 Kg compared with L) at two years. Consequently, over the lifetime of a patient E+L generated the most QALYs and the lowest cost.

Conclusion: Our analysis suggests a role for EndoBarrier along with GLP-1RA therapy for the control of HbA1c and weight in patients with T2DM. Further research to confirm the sustainability of gains in HbA1c and weight following removal of EndoBarrier is recommended.

Disclosure

P. Sen Gupta: None. S. Armstrong: None. S.A. Amiel: Advisory Panel; Self; Medtronic MiniMed, Inc., Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. R.E. Ryder: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; Bioquest, Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. M.W. Pennington: Consultant; Self; Merck Sharp & Dohme Corp..
Health Care Access, Utilization, and Glycemic Control in Youth and Young Adults with Diabetes in South Carolina
Authors: LIESE ANGELA D. , MA XIAONAN , REID LAUREN , EBERTH JAN M. , BELL BETHANY A. , PROBST JANICE , TURLEY CHRISTINE B. , MAYER-DAVIS ELIZABETH J.
Published: June 2018

Affordability and spatial accessibility are key dimensions of access to health care and important determinants of health. In populations with diabetes, evidence is largely limited to those with type 2 diabetes and older adults. We evaluated the association of insurance coverage and diabetes care provider characteristics with glycemic control in youth and young adults (YYA) with diabetes aged 6 to 30 years (median 16 years), participating in the SEARCH for Diabetes in Youth study in South Carolina between January 2012 and July 2015. A total of 540 YYAs with diabetes (437 type 1, 103 type 2) provided information on health insurance type, diabetes care provider (type and address); HbA1c was measured in-person. Geographic information systems were used to calculate distance to the reported provider. Multivariate linear regression analyses were utilized to evaluate the association. More than half of YYAs with diabetes utilized state/federal insurance (46%) or were uninsured (18%). Only 79% indicated a diabetes care provider. The majority (62%) were seeing an endocrinologist, traveling 27 miles on average (median 16 miles). Average HbA1c was 9.2%. Compared to those with private insurance, YYAs with state/federal health insurance had 0.78 higher HbA1c levels (p<.001) and those with no insurance had 1.1 higher HbA1c (p<.0001), independent of age, sex, race/ethnicity, urbanicity, diabetes type, duration, and medication regimen. Compared to receiving care by an endocrinologist, reporting care by a primary care provider was associated with a 0.6 higher HbA1c (p=.028) and a 0.8 higher level (p=.007) with no routine diabetes care provider reported. Distance to provider was not associated with glycemic control (p=.18).

In summary, health insurance status and type, and provider type were significantly associated with glycemic control. This study underscores the importance of social determinants of health on diabetes management outcomes in youth and young adults.

Disclosure

A.D. Liese: None. X. Ma: None. L. Reid: None. J.M. Eberth: None. B.A. Bell: None. J. Probst: None. C.B. Turley: Stock/Shareholder; Self; AbbVie Inc., Johnson & Johnson Services, Inc., Pfizer Inc., CVS/Caremark, Amgen Inc., Walgreen Co., UnitedHealth Group, Novartis AG, Abbott. E.J. Mayer-Davis: None.
Delays in Antihyperglycemic Treatment Intensification and Risk of Diabetes Complications
Authors: NICHOLS GREGORY , ROMO-LETOURNEAU VICTORIA J. , VUPPUTURI SUMA , THOMAS SHEILA
Published: June 2018

Longer delays in anti-hyperglycemic treatment intensification (TI) are associated with poorer glycemic control, but whether these delays increase the risk of poor outcomes is unclear. We combined 2005-2016 data from the Northwest and Mid-Atlantic regions of Kaiser Permanente to identify 3 cohorts of patients who intensified therapy by: 1) initiating metformin (MET) as their 1st diabetes drug (n=18,762); 2) adding a sulfonylurea (SU) to existing MET (n=10,076); 3) initiating insulin after MET and/or SU therapy (n=9,778). We used the TI date to calculate time between A1C ≥7% and TI, pre-TI A1C, and achievement of A1C >7% within 1 year. From the ∼1-year post-TI A1C, we followed patients through December 2016 until they experienced an MI, stroke, or other cardiovascular (CV) event, a heart failure (HF) hospitalization or all-cause mortality, censoring follow-up when the cohort therapy changed. Multivariable cox regression controlled for CV risk factors including age, sex, race/ethnicity, smoking, blood pressure, statin and ACE/ARB use, and prior history of CV or HF. After adjustment for CV risk factors, Pre-TI A1C and time from A1C ≥7% to TI date was significantly associated with the outcomes (Table). Delays in treatment intensification increase CV, HF and mortality risk at all stages of diabetes therapy; intensifying therapy at the first sign of deteriorating glycemic control may be critically important.

Disclosure

G. Nichols: Research Support; Self; Boehringer Ingelheim GmbH, Amarin Corporation, Janssen Pharmaceuticals, Inc., Sanofi. V.J. Romo-LeTourneau: Employee; Self; Sanofi. S. Vupputuri: Research Support; Self; Sanofi US. S. Thomas: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi.
Efficacy and Safety of an Expanded Dulaglutide Dose Range—A Phase 2, Placebo-Controlled Trial in T2D Patients on Metformin
Authors: FRIAS JUAN P. , WYNNE ALAN G. , MATYJASZEK-MATUSZEK BEATA , BARTASKOVA DAGMAR , COX DAVID , WOODWARD BRAD , LI GRACE , MILICEVIC ZVONKO
Published: June 2018

Dulaglutide is approved at two doses (0.75 and 1.5 mg) for treatment of T2D. There has been limited assessment of higher doses. We hypothesized that higher doses of dulaglutide may provide further improvement in glucose and body weight control. In this study, 3 and 4.5 mg doses were evaluated for safety/efficacy after 18 weeks (weeks) of treatment, including a 6 week dose escalation. Patients (N=318) on ≥1500 mg metformin, were randomized (1:1:1:1) to placebo (n=82), dulaglutide 1.5 mg (n=81), dulaglutide 3 mg (n=79), dulaglutide 4.5 mg (n=76). The primary objective was superiority of dulaglutide doses over placebo in HbA1c reduction at 18 weeks. Table 1 presents the primary and selected secondary efficacy data. Reductions in HbA1c and body weight were significant for each dose vs. placebo. Incidence of gastrointestinal events (mostly mild to moderate) were dose-dependent for nausea (placebo, 4.9%; dulaglutide 1.5 mg, 22.2%; dulaglutide 3 mg, 24.1%; dulaglutide 4.5 mg, 30.3%) but not for vomiting (placebo 4.9%; dulaglutide 1.5 mg, 11.1%; dulaglutide 3 mg, 10.1%; dulaglutide 4.5 mg, 13.2%). No patients experienced severe hypoglycemia. The results of this trial show that 3 mg and 4.5 mg doses, compared to the 1.5 mg dose, may provide additional glycemic benefit and weight reduction with an acceptable safety profile in treatment of T2D patients, providing support for further phase 3 development.

Disclosure

J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc.. A.G. Wynne: None. B. Matyjaszek-Matuszek: None. D. Bartaskova: None. D. Cox: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company. G. Li: Employee; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company.
A Model of Good Inpatient Diabetes Care with Consistently Low Level of Medication Errors
Authors: PARSAD MEENAKSHI , LAMBERT KIMBERLEY D. , ARDERN DIANE , MEZZULLO ABIGAIL C.
Published: June 2018

The National Diabetes Inpatient Audit is a yearly audit aimed at providing a snapshot view on various aspects of diabetes care across hospitals in England. Results are provided for each hospital and are shown in comparison to other hospitals. Since 2011, our 450-bedded hospital has been in the first quartile with regards to medication errors, prescription errors, medicine management errors and insulin errors. In the 2016 audit, we had 11.6% medication errors whereas across England, there were 44.6% medication errors. Our service is exemplary on many fronts. Foundation year doctors get formal training in diabetes care. Information Technology is key in providing the fail-proof electronic prescribing software, access to General Practitioner’s Health records, safe insulin prescribing e-module, and up-to-date online clinical guidelines. We have Pharmacists and Pharmacist Technicians who check electronic prescriptions on a daily basis. We also benefit from the service of a Diabetes Specialist Pharmacist. We provide a twice-weekly specialist diabetes ward round across the whole hospital and patients are usually identified from the Electronic Patients Record software. The Diabetes Specialist Nurses are additionally available for one-to-one education Monday to Friday 0900 to 1700. Finally, we run a comprehensive diabetes education day for nurses and other allied health care professionals twice a year.

Disclosure

M. Parsad: None. K.D. Lambert: None. D. Ardern: None. A.C. Mezzullo: None.
Effects of Ileo-Colonic Delivery of Conjugated Bile Acids on Glucose Metabolism, GLP-1, and Body Weight in Patients with Obesity and Type 2 Diabetes Mellitus—A Randomized Controlled Trial
Authors: MANRIQUE GERARDO CALDERON , DAVIS JUDITH , BONIS ALISON N. , KHEMANI DISHA , GEDULIN BRONISLAVA , VELLA ADRIAN , CAMILLERI MICHAEL , ACOSTA ANDRES
Published: June 2018

Bile acid secretion increases significantly after Roux-in-Y gastric bypass and may play a role in weight loss after bariatric surgery. The acute intrajejunal-delivery or intra-rectal delivery of bile acids improves glucose metabolism. We aimed to study the effect of conjugated bile acids released on the ileo-colonic region (IC-CBAS) on glucose metabolism and body weight. In a placebo-controlled, double-blinded, randomized, 28-days trial, we studied the effect of IC-CBAS 500 mg BID on glucose metabolism, incretin hormones (GLP-1 and FGF-19), gastric emptying (scintigraphy) and weight loss in obese type 2 diabetic subjects (n=24 white patients, age=57±2 years, BMI=38.6±1.3 kg/m2, HbA1c=8.5±0.2%, fasting glucose 9.9±0.4 mmol/L). Participants were taking stable doses of DPP-4 inhibitors and metformin and were instructed to continue their current diet and exercise routine. Subjects underwent a meal challenge at baseline and at the end of the treatment period. The primary analyses compared treatment groups at the end of 28 days’ treatment using analysis of covariance models incorporating the corresponding baseline study value as a covariate. IC-CBAS significantly increases postprandial GLP-1 (mean p=0.04, AAB p=0.04), postprandial insulin (AAB p=0.04) and postprandial c-peptide (AAB p=0.01); and decreases fasting insulin (p=0.04) when compared to placebo. IC-CBAS also induced a numerically (but not statistically significantly) improvement in fasting glucose (delta -16 mg/dl), postprandial glucose (delta mean -14 mg/dl) and weight (delta -0.45±.4 kg) compared to placebo. There were no reported side effects, or dropouts; and no difference in FGF-19, gastric emptying or number of bowel movements. IC-CBAS 28-day treatment results in significant increase in GLP-1 and postprandial insulin, suggesting a beneficial role in incretins, insulin and glucose homeostasis.

Disclosure

G. Calderon Manrique: None. J. Davis: None. A.N. Bonis: None. D. Khemani: None. B. Gedulin: None. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG. M. Camilleri: None. A. Acosta: None.
Comparing Diabetes Screening Strategies in China—An Agent-Based Modeling Approach
Authors: XIE XIAOLEI , PANG BOWEN , LI YAN
Published: June 2018

Purpose: There are 114 million people with diabetes in China and more than 60% of them are undiagnosed. People with undiagnosed diabetes have a high risk of developing complications or death. Early detection of diabetes through screening is thus critical in preventing costly complications. This study aims to compare long-term impact of several diabetes screening strategies on Chinese adults.

Methods: We developed an agent-based model to simulate the development of diabetes and its complications (i.e., neuropathy, nephropathy and cardiovascular diseases). Based on data from the China Health and Nutrition Survey and the published literature, we estimated model parameters and validated the model. We compared a set of screening strategies, including screening for 10%, 20%, and 50%, and screening people who smoke, have unhealthy diet or have limited physical activity. We simulated 10,000 people for 10 years and reported the number of diabetes, myocardial infarction (MI), stroke, neuropathy and nephropathy.

Results:Random screening for 50% of the population performs well in reducing all complications. Screening people with unhealthy diet is more effective in reducing cases of MI and neuropathy, and screening people who smoke is more effective in reducing cases of stroke.

Conclusions:Agent-based modeling is a promising tool to evaluate diabetes screening strategies, which can provide decision support to policymakers.

Disclosure

X. Xie: None. B. Pang: None. Y. Li: None.
Individualized Diabetes Risk Prediction in Women with a History of Gestational Diabetes
Authors: MAN BERNICE , SCHWARTZ ALAN , XIA YINGLIN , GERBER BEN S.
Published: June 2018

Without treatment, prediabetic women with a history of gestational diabetes (GDM) are 71% more likely to progress to type 2 diabetes (DM) compared to parous women without prior GDM. In women with prior GDM, both intensive lifestyle intervention (ILI) and metformin are effective in reducing the progression to DM in the Diabetes Prevention Program (DPP). Evidence suggests heterogeneity in treatment response.

We performed a secondary analysis of DPP data, including 1555 parous women with prediabetes; 19% had prior GDM, 31% were < 45 years old, 44% were of non-Caucasian race/ethnicity and 71% were obese. At three years, 323 women developed diabetes. We examined 16 baseline clinical variables using Cox proportional hazards regression with backward elimination (excluding variables with p>0.05) to predict DM risk. Our final multivariable model includes treatment arm (ILI vs. metformin vs. placebo), BMI category, height, waist-hip ratio, fasting glucose and triglycerides, and hemoglobin A1c (Table). Interactions with treatment arms were explored.

This model differs from others recently developed for the general population at risk for DM. There remains a need for external validation to determine predictive performance. In the future, use of a clinical prediction model to calculate individual 3-year DM risk specifically for women with prior GDM may improve decision making for prediabetes treatment in this high-risk group.

Disclosure

B. Man: None. A. Schwartz: None. Y. Xia: None. B.S. Gerber: None.
Outcomes of Telehealth in the Management of Type 2 Diabetes—A Systematic Review and Meta-analysis of Randomised Controlled Trials
Authors: NANGRANI NISHA , MALABU USMAN , VANGAVETI VENKAT
Published: June 2018

Background: The outcomes of telehealth in the management of type 2 diabetes (T2DM) have not been evaluated since the publication of recent clinical trials.

Objective: To conduct a systematic review and meta-analysis of recently published randomized controlled trials (RCTs) to assess the biochemical, clinical and psychosocial outcomes of telehealth in subjects with T2DM.

Methods: Electronic databases, MEDLINE, CINAHL, INFORMIT, SCOPUS and the Cochrane Central Register of Controlled Trials and reference lists of existing systematic reviews were searched until August 2017 to identify relevant studies. Study search and selection were performed by two independent reviewers. 4791 articles were retrieved of which 11 RCTs (n=3772) were included. A meta-analysis with random effects model was applied to estimate the pooled results.

Results: Telehealth was associated with a statistically significant and clinically relevant absolute decline in glycosylated haemoglobin (HbA1c) compared to usual care (mean difference -0.17%; 95% CI -0.25 to -0.09%; p<0.0001), especially if participants had a mean baseline HbA1c≥8.0%; were less than sixty years of age or received telehealth for less than one year. There was no clinically significant reduction in LDL-cholesterol (LDL-c), body mass index (BMI), systolic (SBP) or diastolic blood pressure (DBP).

Conclusion: Telehealth interventions were associated with improved glycaemic control (HbA1c) in T2DM diabetic patients. However, no clinically relevant impact was observed on lipid profile, blood pressure, body mass index and psychosocial well-being. Future studies should seek to evaluate the effect of intervention duration on HbA1c, psychosocial outcomes and the effectiveness of telehealth in rural and underserved populations.

Disclosure

N. Nangrani: None. U. Malabu: None. V. Vangaveti: None.