bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapy Optimization with Once Daily Glargine Gla-300–Based Therapy in Patients Insufficiently Controlled on Premixed Insulins or Twice Daily Basal Regimens—Real-Life Data
Authors: KOMEL JANA , FABCIC DEJAN , VUKELIC KATARINA
Published: June 2018

Introduction: In Slovenia, as in many Central Europe countries, there is a high share of patients with T2D treated with human basal and premixed insulins. Many of them are often sub optimally controlled. One barrier to the achievement of optimal glycaemic control is the risk of hypoglycaemia, a common side effect of insulin therapy. Gla-300 is a new formulation of insulin glargine delivering the same amount of insulin as insulin glargine 100 units/mL (Gla-100) in a 1/3 volume. Pharmacokinetic and pharmacodynamic action profiles of Gla-300 are more constant and prolonged compared with Gla-100, due to a more gradual and extended release of glargine from the subcutaneous depot which allows continued blood glucose control beyond 24 hours.

Study Design: We performed a retrospective, observational study. We have obtained data from medical charts of T2D and T1D patients, who initiated Gla-300 in the period from May 1st, 2016 to June 1st, 2017. The primary objective was to evaluate a real-life efficacy of once daily Gla-300 basal insulin therapy in patients insufficiently controlled on premixed insulins or twice- daily basal regimens, defined as the mean change in HbA1c value 3 or 6 months after the switch. The secondary objective was relationship between the occurrence of hypoglycaemia before and after the switch.

Results: Data from 107 patients on Gla-300 have been analysed. Switching to insulin Gla-300 significantly reduced HbA1c (∆ -1.0%, p=0.000), FPG (∆ - 1.7mmol/l, p=0.000) and PPG (∆ -2.8mmol/l, p=0.000). More patients achieved target HbA1c concentrations (≤ 7%) after the switch to Gla-300 (8.4% before vs. 32% after the switch). 90.2% of subjects reported reduced number of hypoglycaemic events after switching to Gla-300.

Conclusion: Switching to insulin Gla-300 proved to be safe and effective for patients with both, T1D and T2D.

Disclosure

J. Komel: Research Support; Self; Novo Nordisk Inc.. Other Relationship; Self; Sanofi, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. D. Fabcic: None. K. Vukelic: None.
Survivin from Flk1+ Endothelial Progenitor Cells in the Developing Embryo Ameliorates Maternal Diabetes–Induced Neural Tube Defects through Exosome
Authors: CAO SONGYING , SHEN WEI-BIN , YANG PEIXIN
Published: June 2018

Neural tube defects (NTDs) are among the most common and severe structural birth defects and maternal diabetes induces NTDs. During mouse embryonic development, blood vessel formation initially occurs in the yolk sac, preceding neurulation which takes place from embryonic day 8 (E8) to E10.5. Our previous studies have demonstrated that maternal diabetes induces embryonic vasculopathy at early embryonic developmental stage. We hypothesize that early vasculopathy accounts for late failed neural tube closure in diabetic pregnancy. To test this hypothesis, we created the Flk1 promoter driven survivin (the cell cycle-regulated apoptosis inhibitor) transgenic mice. Maternal diabetes induced the loss of Flk1+ progenitors, impaired blood island formation and reduced blood vessel densities. Expression of survivin in the Flk1+ progenitors ameliorated diabetes-induced NTDs. Under nondiabetic conditions, survivin overexpression did not affect embryonic development. Overexpression of survivin significantly reduced diabetes-induced NTDs. Flk1+ progenitors produced survivin-containing exosomes. Immunocytochemistry staining indicated that survivin-containing exosomes were transported and incorporated into cells of the developing neuroepithelium, leading to blockage of neuroepithelial cell apoptosis induced by maternal diabetes. Furthermore, we isolated exosomes from Flk1+ progenitors derived from E7.5 embryos. In utero delivery of the survivin-containing exosomes by microinjection into the amniotic cavity of diabetic mice at E9 significantly inhibited maternal diabetes-induced neuroepithelial cell apoptosis and reduced NTDs. Taken together, these data revealed that the cross-talk between the extra-embryonic structures and the developing neuroepithelium through the survivin-containing exosome plays a critical role for the proper neural tube closure.

Disclosure

S. Cao: None. W. Shen: None. P. Yang: None.
Assessing the Real-World Use of Combination Insulin Glargine-Lixisenatide in Patients with Type 2 Diabetes Mellitus—A Retrospective Review from an Ambulatory Care Endocrinology Practice
Authors: STRYKER MATTHEW D. , BLOW CURTIS A. , FRIEDMAN ERICA B. , BUSCH ROBERT S. , KANE MICHAEL P.
Published: June 2018

Purpose: This is a pre-post observational study from an endocrinology ambulatory care practice assessing the effectiveness and safety of a single injectable combination antidiabetic agent, the basal insulin, insulin glargine, and the glucagon-like peptide-1 (GLP-1) receptor agonist, lixisenatide, to background therapy for patients with type 2 diabetes mellitus (T2DM).

Methods: The study population will consist of subjects with T2DM who have failed to achieve adequate glycemic control and require the addition of once-daily insulin glargine-lixisenatide (iGlarLixi). Five groups will be assessed: patients initiating iGlarLixi, patients on a basal insulin at baseline, patients on a GLP-1 receptor agonist at baseline, patients on basal insulin and GLP-1 receptor agonist (single-entity products) at baseline and patients only on oral antidiabetic agents at baseline. Potential subjects will be identified via a computerized text search of medication lists from patients’ electronic medical records, which will be reviewed to ascertain if study criteria are met.

Outcome: The primary study outcome is change in HbA1c. Secondary outcomes include percentage of patients achieving an HbA1c of < 7% or ≤ 6.5%, change in weight, change in systolic and diastolic blood pressures and change in lipid parameters. Safety will be assessed via collection of reported adverse effects.

Results: Thirty subjects initiated therapy with iGlarLixi and 23 had follow-up data. The mean duration of T2DM was 11.3 years and baseline HbA1c was 8.27%. The median starting dose of iGlarLixi was 30 units and the mean dose at follow-up was 41 units. After an average of about 4 months on therapy, HbA1c decreased by 0.94% in the entire cohort (p = 0.02). Fifty-seven percent of subjects achieved an HbA1c < 7% and 26% achieved an HbA1c ≤ 6.5%. iGlarLixi was well tolerated and discontinuation was low (3 subjects) and mainly due to medication cost.

Disclosure

M.D. Stryker: Other Relationship; Self; Amgen Inc.. Research Support; Self; AstraZeneca. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Regeneron Pharmaceuticals, Inc.. C.A. Blow: None. E.B. Friedman: None. R.S. Busch: Speaker's Bureau; Self; AbbVie Inc., AstraZeneca. Research Support; Self; Bayer AG, Intarcia Therapeutics, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Amgen Inc.. Research Support; Self; Sanofi US. Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Amarin Corporation. M.P. Kane: None.
Novel Risk Panel for CAD and All-Cause Mortality in Type 1 Diabetes
Authors: KESHAWARZ AMENA , SIPPL RACHEL M. , REBUCK HEATHER , DONALD SARAH , HUANG SHARON Y. , CHRISTENSON ROBERT H. , SNELL-BERGEON JANET K.
Published: June 2018

Coronary artery disease (CAD) prevalence is increased and life expectancy is reduced by more than a decade in people with type 1 diabetes (T1D) compared to nondiabetics (non-DM), but traditional risk factors do not explain all of the increased risk. We examined whether three novel risk markers, high-sensitive cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15), are elevated in T1D and predict CAD and mortality.

1,416 adults age 19-56 (652 T1D, 754 non-DM) were enrolled in the Coronary Artery Calcification in type 1 diabetes (CACTI) study from 2000-2002. We assessed CAD events (fatal or non-fatal myocardial infarction, coronary artery bypass graft, or angioplasty) with annual follow-up questionnaires. In-person visits occurred at 3, 6, and 12 years after baseline. Serum samples from the visit prior to a CAD event or death or from the last in-person visit were available for 1,389 participants and were assayed for hs-cTnT, NT-proBNP, and GDF-15 at the University of Maryland. Elevated marker levels were defined as those above the 95th percentile among non-DM participants. Biomarker levels were compared by T1D status in linear regression, and logistic regression was used to examine associations with CAD and all-cause mortality.

Age- and sex-adjusted LSmeans ± SE for log hs-cTnT (2.0±0.02 vs. 1.6±0.02, p<0.0001), log NT-proBNP (3.8±0.04 vs. 3.5±0.03, p#x003C;0.0001), and log GDF-15 (6.5±0.02 vs. 6.2±0.02, p#x003C;0.0001) were significantly higher in T1D than non-DM participants. Over the follow-up period, there were 72 CAD events (53 T1D, 19 non-DM) and 76 deaths (58 T1D, 18 non-DM). Having elevated levels of all 3 vs. none of the markers was a significant predictor of both CAD (OR [95% CI] 6.4 [2.0-20.7]) and all-cause mortality (OR [95% CI] 10.7 [3.3-35.4]), independent of age, sex, renal function and T1D status.

A panel of novel markers, hs-cTnT, NT-proBNP, and GDF-15, are elevated in T1D and may help identify those at risk for CAD events and mortality.

Disclosure

A. Keshawarz: None. R.M. Sippl: None. H. Rebuck: None. S. Donald: None. S.Y. Huang: None. R.H. Christenson: Consultant; Self; Roche Diagnostics Corporation, Siemens, Becton, Dickinson and Company. J.K. Snell-Bergeon: Stock/Shareholder; Self; Abbott. Research Support; Self; Roche Diagnostics Corporation.
Altered Gonadal Fat Stromal Cell Populations in Adipocyte-Specific Oncostatin M Receptor Knockout Mice—A Possible Role for Local SDF1
Authors: ELKS CARRIE M.
Published: June 2018

The IL-6 family cytokine, oncostatin M (OSM), has several physiological roles, but its exact role in adipose tissue homeostasis is still unclear. We recently reported that high-fat diet-fed male mice with an adipocyte-specific deletion of the OSM-specific receptor (OSMR FKO mice) were insulin-resistant and had increased markers of inflammation in epididymal adipose tissue (eWAT). In the current study, we more closely examined eWAT stromal cell populations in high-fat fed OSMR FKO mice using flow cytometry. Results from flow cytometry studies revealed that, despite no differences in eWAT weights between genotypes, OSMR FKO mice had significantly fewer stromal cells per gram eWAT. Although there were fewer stromal cells overall, a significantly higher percentage of these cells were CD45+ leukocytes. Significant decreases in the numbers of adipose tissue macrophages (CD64+; CD11c+/-) and preadipocytes (CD45-; CD31-; Sca1+) were also observed in OSMR FKO eWAT. A cytokine array was performed on eWAT to assess differences in tissue cytokine profiles that may contribute to the alterations observed in stromal cell populations. Array results indicated a significant decrease in stromal cell-derived factor 1 (SDF1) protein expression in eWAT of OSMR FKO mice. Future studies will focus on the role of adipocyte OSM signaling as a regulator of adipose tissue SDF1 production and stromal cell homeostasis. Overall, our results suggest a homeostatic role for adipocyte OSM signaling in the maintenance of stromal cell populations in gonadal fat.

Disclosure

C.M. Elks: None.
Meta-analysis of HbA1c-Lowering Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Combination with Insulin in T2DM Patients
Authors: YANG JIN , TIAN QING , TANG YUEXIN , SHAH ARVIND K. , ZHANG RUYA , CHEN GUOJUAN , ZHANG YE , RAJPATHAK SWAPNIL , HONG TIANPEI
Published: June 2018

Randomized controlled trials (RCTs) have evaluated the efficacy of dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to insulin compared to insulin alone in T2DM patients, while there have been differences in the magnitude of the outcome effect across studies. This updated systematic review and meta-analysis aimed to evaluate the effect of DPP-4i in combination with insulin on HbA1c in T2DM patients.

MEDLINE, EMBASE, and Cochrane databases were searched for RCTs that compared DPP-4i plus insulin to insulin alone for T2DM patients, with or without background therapy with other oral agents. The primary endpoint was the absolute change of HbA1c from baseline. Weighted mean difference (WMD) with 95% confidence intervals (CI) was calculated using a random effect model. The methodological quality of included RCTs was evaluated using the Cochrane risk of bias tool.

Eighteen RCTs involving 6,493 patients with average follow-up of 32 weeks were identified and analyzed. DPP-4i plus insulin showed greater reduction in HbA1c than insulin alone (WMD -0.52%, 95% CI -0.61 to -0.43; P<0.0001) (Figure 1).

In conclusion, compared with use of insulin alone, DPP-4i in combination with insulin can significantly lower HbA1c levels in T2DM patients. Further analysis is needed to better understand effects of this combination therapy on other outcomes, such as hypoglycemia and insulin.

Disclosure

J. Yang: None. Q. Tian: 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. A.K. Shah: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. R. Zhang: Employee; Self; Merck Sharp & Dohme Corp. G. Chen: Employee; Self; Merck Sharp & Dohme Corp.. Y. Zhang: None. S. Rajpathak: Employee; Self; Merck & Co., Inc. T. Hong: Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca.
Effectiveness and Tolerability of Vildagliptin plus Metformin Compared with Other Oral Dual Antidiabetes Agents in Different Baseline BMI Patients with Type 2 Diabetes—A Real-World Study (China PDS)
Authors: JIN HUI , HAN YING , CHEN LIXIAN , HU DAQING , YANG NAILONG , SHI XIAOYUN , LI QUANMIN , LIANG LINLANG , ZANG LI , LIU MINGMING , HE JAMES , MU YIMING
Published: June 2018

Background and Aim: The real-world study of China PDS with 2083 type 2 diabetes mellitus (T2DM) patients showed that vildagliptin plus metformin (VM) therapy could effectively control the HbA1c with good tolerability. Here, we present the results of baseline BMI subgroups.

Materials and Methods: In China PDS, T2DM patients with poor glycemic control on monotherapy were assigned to either VM dual therapy or other oral dual agents(OD) therapy according to local physician’s decision. For this analysis, patients were divided into three subgroups according to baseline BMI(<24kg/m2, 24-28kg/m2, >28kg/m2). The primary outcome was the proportion of patients with HbA1c<7% and without tolerability events(hypoglycemia, weight gain, or discontinuation due to gastrointestinal event) at 12th month. Secondary outcomes included mean changes in HbA1c from baseline to study endpoint and tolerability.

Results: In total, 389(149 in VM vs. 240 in OD) patients in BMI<24kg/m2 group, 625(304 in VM vs. 321 in OD) patients in BMI 24-28kg/m2 group, and 260(151 in VM vs. 109 in OD) patients in BMI>28kg/m2 group were enrolled. Compared with OD, significantly higher proportion patients reached primary outcome in VM in BMI<24kg/m2 group (47.0% vs. 35.0%; P=0.019), in BMI 24-28kg/m2 group (52.6% vs. 33.3%; P<0.001), and in BMI>28kg/m2 group (51.0% vs. 33.9%; P=0.006). Mean HbA1c changes were significantly greater in VM than in OD(BMI<24kg/m2: -1.23% vs. -0.76%; BMI 24-28kg/m2: -1.32% vs. -0.79%; BMI>28kg/m2: -1.29% vs. -0.84%; P<0.for all). VM resulted in less tolerability findings than OD in BMI<24kg/m2 (11.4% vs. 19.2) and BMI 24-28kg/m2 (3.6% vs. 14.6%) groups (P<0.for both), but not in BMI >28kg/m2 group (4.6% vs. 5.5%, P>0.05).

Conclusion: In different baseline BMI groups, vildagliptin plus metformin dual therapy was associated with better glycemic control and was well tolerated compared with OD.

Disclosure

H. Jin: None. Y. Han: None. L. Chen: None. D. Hu: None. N. Yang: None. X. Shi: None. Q. Li: None. L. Liang: None. L. Zang: None. M. Liu: None. J. He: None. Y. Mu: None.
Effect of an Add-On SGLT2 Inhibitor on the Efficacy of DPP-4 Inhibitor Therapy in Improving Postprandial Hyperglycemia
Authors: ONISHI TETSUROU , TANIGUCHI YUKIKO , MORI YUTAKA
Published: June 2018

Objective: This study was conducted to investigate the effect of an add-on SGLT2 inhibitor on the efficacy of DPP-4 inhibitor therapy improving postprandial hyperglycemia in terms of its effect on diurnal glycemic variability (GV) to provide insight into the effect of the SGLT2 inhibitor on incretin-responsive insulin secretion.

Patients and Methods: This study enrolled 12 type 2 diabetic patients with inadequate glycemic control despite treatment with the DPP-4 inhibitor teneligliptin (T) (20 mg/day) (Age, 69.5±7.4 years; BMI, 27.2±3.7 kg/m2; HbA1c, 7.7±0.7%). All patients were treated with add-on canagliflozin (Cana) 100 mg/day for 8 weeks and compared for diurnal GV before and after treatment with add-on Cana using CGM.

Results: With the initiation of add-on Cana, a significant decrease was noted in body weight and BMI (P < 0.05). The HbA1c and GA values were significantly decreased (P < 0.05) and the adiponectin values significantly increased (P < 0.05). The diurnal GV indices, such as the SD of glucose values, total area between the 24-h mean glucose levels and glucose curve, and mean amplitude of glucose excursions (MAGE) significantly decreased (P < 0.05), as the pre-breakfast glucose values and the 24-hour mean glucose values significantly decreased with add-on Cana. Additionally, treatment with add-on Cana led to a significant decrease in the % of time in hyperglycemia but no significant change in the % of time in hypoglycemia.

Conclusions: The mechanisms through which add-on Cana reduced diurnal GV in type 2 diabetic patients receiving T may be accounted for as follows: add-on Cana improved incretin-responsive insulin secretion through resolution of glucotoxicity resulting in enhancement of the efficacy of T in improving postprandial hyperglycemia, as well as weight loss through calorie loss via glycosuria, which, coupled with attendant improvements in insulin resistance, led to improvements in postprandial hyperglycemia and reductions in diurnal GV.

Disclosure

T. Onishi: None. Y. Taniguchi: None. Y. Mori: None.
AAV-Mediated Overexpression of BMP7 in White Adipose Tissue Induces Adipogenesis and Ameliorates Insulin Resistance
Authors: LORENTE ESTEFANIA CASANA , JIMENEZ VERONICA , FRAILE VICTOR SACRISTÁN , MUÑOZ SERGIO A. , PALLARÉS CLAUDIA JAMBRINA , RODÓ JORDI , DARRIBA SARA , MALLOL CRISTINA , GARCIA MIQUEL , LEON XAVIER , GRASS IGNASI , FRANCKHAUSER SYLVIE , BOSCH FATIMA
Published: June 2018

Obesity and type 2 diabetes are strongly associated and a major health problem because of their alarmingly growing prevalence worldwide. The hypertrophic expansion of white adipose tissue (WAT) promotes ectopic fat accumulation and development of insulin resistance whereas WAT hyperplasia is associated with preservation of insulin sensitivity. Several members of the Bone Morphogenetic Protein (BMP) family have been shown to play a role in white and/or brown adipogenesis and energy homeostasis. Although BMP7 has extensively been reported to induce brown adipogenesis in vitro, its role on WAT expandability and its potential contribution to insulin sensitivity remains to be elucidated. Here, we showed that local administration of adeno-associated viral vectors (AAV) encoding BMP7 in WAT resulted in hyperplasic expansion of WAT together with reduced liver steatosis and amelioration of insulin sensitivity in both HFD-fed and ob/ob obese mice. In contrast, the AAV-mediated overexpression of BMP7 specifically in the liver did not promote WAT hyperplasia although the circulating levels of BMP7 achieved were similar to those obtained after intra-WAT administration of AAV vectors. Nevertheless, when liver-derived BMP7 circulating levels were further increased, body weight and insulin sensitivity were normalised in HFD-fed as well as in ob/ob mice. Altogether, these results unravel a new role of BMP7 on white adipogenesis. In addition, this study suggests the potential of BMP7 gene therapy to ameliorate obesity and insulin resistance.

Disclosure

E. Casana Lorente: None. V. Jimenez: None. V. Sacristán Fraile: None. S.A. Muñoz: None. C. Jambrina Pallarés: None. J. Rodó: None. S. Darriba: None. C. Mallol: None. M. Garcia: None. X. Leon: None. I. Grass: None. S. Franckhauser: None. F. Bosch: None.
The Impact of Endocrinology Consultation in the United States on Global Diabetes Care
Authors: ALI KHAWLA F. , MIKHAEL ALEXANDRA , ZAYOUNA CHRISTINE , CECILIA LANSANG M.
Published: June 2018

Introduction: Medical travel, a form of patient mobility across borders, has gained significant momentum in the last years. Nevertheless, limited evidence exists regarding the clinical outcomes for these patient-sought treatments at U.S. institutions. We aimed to examine the characteristics of global patients referred to our institution for short-term diabetes management and the impact of our consultation on the cohort’s glycemic control.

Methods: We identified adult patients with established diabetes mellitus, who sought medical care at the Cleveland Clinic Foundation between the years 2010 and 2016 from the following countries: Bahrain, Qatar, UAE, Kuwait, Saudi Arabia and Oman, and were seen at least once by an endocrinology provider. Our control group included an internationally identical cohort with diabetes mellitus, but without an office visit to endocrinology. Continuous, normally distributed data were described using means and standard deviations (SD), while non-normally distributed data were described using medians and quartiles. To assess the impact of our endocrine consultations, changes in HbA1C were assessed after single and multiple endocrine visits using paired t-tests.

Results: Our study included 1,1subjects (771 in study group, 337 in control group), with a mean age (±SD) of 61.3±12.7 years, 62% male, and a median follow-up duration of 136 days [IQR: 57, 660]. Compared to controls, study subjects had higher baseline mean HbA1C level (8.0±1.8% vs. 7.1±1.4%, p<0.001) and higher prevalence of cardiovascular disease (64.6% vs. 56.0%, p=0.006). After only one visit with endocrinology, there was a significant decrease in mean HbA1C of -1.00% (95% CI:-1.23, -0.78) (p<0.001). The greatest degrees of change in mean HbA1C were -1.47% (95% CI: -2.21, -0.74) and -1.27% (95% CI: -1.89, -0.66) after 3 and 4 visits, respectively (p<0.001).

Conclusion: Global patients seen for diabetes management had a significant drop of nearly 1 point in HbA1c even after one endocrinology consultation.

Disclosure

K.F. Ali: None. A. Mikhael: None. C. Zayouna: None. M. Lansang: None.
Persistence to Treatment with DPP-4 Inhibitors, SGLT2 Inhibitors, and GLP-1-RAs Compared with Insulin after Failure with First Antidiabetic Drug in T2DM Patients
Authors: JERMENDY GYORGY , ROKSZIN GYÖRGY , ABONYI-TÓTH ZSOLT , WITTMANN ISTVAN , KEMPLER PETER
Published: June 2018

Adequate persistence to antidiabetic treatment is highly important to achieve proper glycemic control. Data on persistence with new antidiabetic drugs are limited. The aim of the study was to evaluate the persistence to treatment with DPP-4-inhibitors, SGLT2-inhibitors and GLP-1-RAs in comparison to insulin (INS) in a nationwide cohort of T2DM patients. Using the database of the Hungarian National Health Insurance Fund, the persistence to the treatment with DPP-4-inhibitors (n=59,900), SGLT2-inhibitors (n=26,052), GLP-1-RAs (n=17,332) and INS (n=51,781) was analyzed between 2014 and 2016. We captured the antihyperglycemic agents either in monotherapy or in add-on combinations after failure with first antidiabetic drug. Persistence was defined as the duration of time from initiation to discontinuation of the particular therapy. A permissible gap of 180 days (grace period) was allowed. The results are reported as the rate of persistent patients at year 1 and year 2. The persistence of DPP-4-inhibitors and SGLT2-inhibitors was similar at year 1 (68%, 67%), both of which decreased by year 2 (55% and 56%, respectively). The persistence of GLP-1-RAs was 66% at year 1, which decreased remarkably to year 2 (51%). DPP-4-inhibitors + metformin in fix combination had higher persistence (64% and 50%) than that of free add-on combinations (43% and 29%, at year 1 and year 2, respectively). Similar trend was observed regarding SGLT2-inhibitors + metformin fix vs. free add-on combinations at year 1 (75% vs. 55%). Treatment with INS had a relatively high persistence (71% and 61% at year 1 and year 2, respectively). Persistence to treatment with innovative drugs was the highest in patients with age of 40-60 years. Persistence data of different antihyperglycemic agents provide useful information and should be considered as one of components that help to guide the proper decision at initiation of antidiabetic treatment.

Disclosure

G. Jermendy: None. G. Rokszin: None. Z. Abonyi-Tóth: None. I. Wittmann: None. P. Kempler: None.
Physician Visits and Antidiabetic Medication Use among Adolescents with Type 2 Diabetes with Commercial Insurance or Medicaid
Authors: CURTIS SARAH , JOHNSTON JOSEPH A. , ANDERSON PAMELA W. , SCHROEDER KRISTA M. , WU JIANMIN , ZEITLER PHIL
Published: June 2018

Background: Type 2 diabetes (T2D) is becoming more prevalent in adolescents. Multi-disciplinary care with periodic follow-up is required to ensure optimal management with lifestyle modification and medications. The purpose of this study was to estimate physician visitation rates and antidiabetic medication use (including off-label use) among adolescents with T2D and examine the impact of insurance type (Commercial vs. Medicaid).

Methods: We used data from the Truven MarketScan Commercial and Medicaid administrative claims databases to identify a cohort of adolescents aged 10-17 years with T2D (≥2 T2D diagnoses or ≥1 T2D diagnosis and ≥1 antidiabetic medication) with continuous medical and prescription enrollment in 2015. Patients with gestational diabetes, diabetes complicating pregnancy, and secondary diabetes were excluded. Visits to specified providers (pediatric endocrinologist, pediatrician, and family practitioner) and use of medications overall and by class were assessed.

Results: Substantially more commercially insured than Medicaid patients had ≥1 visit to any specified provider (88% vs. 45%) and to pediatric endocrinologists (33% vs. 14%). The use of any antidiabetic medication was similar in both insurance types (92% vs. 90%); however, off-label use was higher in commercially insured patients (9% vs. 6%), specifically those visiting only family practitioners (12%). The most commonly used off-label drug class was sulfonylureas.

Conclusions: A higher proportion of commercially insured adolescents received multi-disciplinary care. While use of any antidiabetic medication was similar, off-label use was greater among commercially insured. Concerted efforts are needed to enhance patient access, generate evidence regarding non-approved medications, and educate providers about optimal care of youth with T2D, particularly on the use of sulfonylureas, which are not recommended by current guidelines.

Disclosure

S. Curtis: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. J.A. Johnston: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. P.W. Anderson: Other Relationship; Self; Eli Lilly and Company. K.M. Schroeder: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Wu: None. P. Zeitler: Consultant; Self; Daiichi Sankyo Company, Limited, Merck & Co., Inc., Eli Lilly and Company, Takeda Development Center Americas, Inc., Boehringer Ingelheim GmbH.
Understanding and Addressing Enrollment Challenges in Pediatric T2D Clinical Trials Compared with T1D
Authors: TERRY AMANDA M. , BOLLEPALLI SUREKA , SMITH LAURA , WALKER ASHBY F. , GAL ROBIN L. , BEAULIEU LINDSEY C. , EDELEN RACHEL C. , LESS JOANE E.
Published: June 2018

Background: While behavior and diet modifications are the first line of defense in treating T2D, pediatric patients requiring additional intervention have few options compared with adults with T2D. The disparity in available treatments can be attributed, in part, to enrollment challenges in pediatric T2D clinical trials that delay FDA approval of new therapies.

Methods: Established in 2008, the Pediatric Diabetes Consortium has connected 49 diabetes research institutes and Industry partners to address enrollment challenges at a structural level. Yet, we must also address the social, economic and cultural barriers to participation specific to T2D pediatric patients.

Barriers: The overall prevalence in 2009 of T1D vs. T2D in youth was 1.93/1,000 compared to 0.24/1,000, with T1D affecting a wider age span. T2D is rarely diagnosed in children <10 years. While there are racial and ethnic disparities in diabetes prevalence overall, they are more pronounced in T2D. Thus, compared to T1D, potential T2D pediatric study participants are fewer, older and more likely to face barriers to participation that include financial concerns, transportation issues, familial disruptions, distrust of research, health illiteracy, language barriers and parents’ inability to miss work.

Conclusion: Addressing barriers is critical to ensure clinical trial success and improved quality of life for these patients. Industry sponsors should make translated materials, such as e-diaries available for non-English speakers, particularly for Spanish speakers and consider quality of life assessments as a secondary outcome. Researchers should partner with community leaders in areas with high T2D prevalence, to establish trust between the patient community and research institution. Additionally, incentives that address families’ social and economic needs should be offered, including direct compensation to offset costs associated with trial participation such as travel and lost income.

Disclosure

A.M. Terry: None. S. Bollepalli: None. L. Smith: None. A.F. Walker: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc.. R.C. Edelen: None. J.E. Less: None.
Exploring the Role of Insulin and IGF-I Receptor Signaling in the Pluripotency, Differentiation, and Maintenance of Stem Cells
Authors: OKAWA ERIN , GUPTA MANOJ K. , HU JIANG , SLIPP BRITTANY A. , KULKARNI ROHIT
Published: June 2018

Pluripotent stem cells (PSCs) express insulin receptors (IR) and insulin-like growth factor-1 receptors (IGF-1R). In human embryonic stem cells (hESCs), IGF-1R is necessary for cell survival, self-renewal and differentiation into endoderm. Data on the role of IR in hESCs is limited; it’s been linked to self-renewal and pluripotency of murine neural stem cells. What’s still unclear is the significance of IR and IGF-1R in modulating stem cell function, pluripotency and differentiation. We created murine induced PSCs (iPSCs) with double knockout (DKO) of IGF-1R and IR. Analysis of 4 individual iPSC clones from 4 control and DKO mice showed similar cell proliferation and morphology. QPCR of pluripotency markers showed significant decreases in Lin28a (p<0.005) and Tbx3 (p<0.0005) expression in DKOs; Lin28a protein levels were also decreased. IPSCs from both groups developed into embryoid bodies in vitro and formed teratomas in vivo, indicating equal abilities to differentiate. With directed differentiation towards a neural lineage, DKOs showed upregulation of neural markers Brn2, Pax6, Sox1, Ngn2 and NeuN. We next examined downstream signaling of IR and IGF-1R. Although both groups showed mTor, Akt and Erk phosphorylation in the basal state, mTor phosphorylation in DKOs was significantly lower (28% of controls; p<0.05). Total mTor and Akt protein levels in DKOs were also lower (31% and 59% of controls, respectively; p<0.05). Prior to stimulation, basal phosphorylation of Stat3 was evident only in DKOs. It was increased 3-fold (p<0.05) upon treatment with IGF-1 or insulin (100 nM) compared to controls. Stimulation with LIF (100 unit/mL) led to Stat3 phosphorylation in both groups; this was 1.5-fold greater in DKOs compared to controls (p<0.005). These data suggest activation of a receptor independent of IR and IGF-1R and/or alterations in downstream proteins in the canonical IR/IGF-1R pathway that allow DKO iPSCs to maintain pluripotency and undergo differentiation.

Disclosure

E. Okawa: None. M.K. Gupta: None. J. Hu: None. B.A. Slipp: None. R. Kulkarni: None.
Flash on Gut Microbiome in GDM and Non-GDM Pregnancies
Authors: FESTA CAMILLA , CORLETO VITO D. , TOSCANO MARCO , BITTERMAN OLIMPIA , DRAGO LORENZO , NAPOLI ANGELA
Published: June 2018

Aims: A specific composition of gut microbiota can increase insulin resistance. The aim of this pilot study was to find differences between pregnant women with GDM and controls in terms of gut microbiota composition during the 3rd trimester.

Methods: This study was carried out in 20 women, 10 with GDM (IADPSG criteria) (Age 36.2±4.4 years; BMI 24.6 (21.4-26.8)Kg/m2) and 10 controls (Age 32.0±2,7 years; BMI 22.1 (19-24.1)Kg/m2) at the 34-36th week of gestation, when fecal samples were collected. Exclusion criteria: antibiotics/probiotics/symbiotics/metformin use during gestation, GADAb+, twin pregnancy, IBD. Genera and species were detected by using a Next Generation Sequencing technology (Ion Torrent Personal Genome Machine). Statistics: SPSS.

Results: the two groups were well matched a part from age (p=0.04). No difference in weight gain (GDM 12.2±4.9; Controls 12.4±5.1 Kg). With regard to the primary aim we found an higher Relative Abundance of Bacteroides caccae, massiliensis, thetaiotaomicron (respectively 87%, 89,4%, 91%; p<0.05) together with a reduction of Bacteroides vulgatus, Eubacterium eligens, Lactobacillus rogosae, Prevotella copri (respectively 27,4%, 41,5%, 6%, 25%; p<0,05) in women with GDM. No difference in biodiversity indexes.

Conclusion: the recognition of a “GDM-related” gut microbiome could lead to symbiotics/probiotics formula for GDM prevention and/or treatment.

Disclosure

C. Festa: Consultant; Self; Menarini Group. Other Relationship; Self; Merck Sharp & Dohme Corp.. V.D. Corleto: None. M. Toscano: None. O. Bitterman: None. L. Drago: None. A. Napoli: Other Relationship; Self; Merck Sharp & Dohme Corp..
Diabetes Can Accelerate Sarcopenia in the Diaphragm
Authors: YAMAMOTO MASASHI , TAKEMOTO MINORU , MASUYAMA HIDENORI , KOSHIZAKA MASAYA , MAEZAWA YOSHIRO , YOKOTE KOUTARO
Published: June 2018

The diaphragm is a skeletal muscle that is involved not only in respiration but also in swallowing and lymphatic functions and maintaining posture. Only a few studies have described diaphragm thickness in patients with diabetes. Diaphragm thickness is usually evaluated using ultrasonography (U.S.). However, because evaluation of diaphragm thickness using U.S. is not routinely performed, it is difficult to assess it in a retrospective manner. Therefore, in this study, we developed a new method to evaluate diaphragm thickness in patients with diabetes using computed tomography (CT) and evaluated the correlation between U.S. and CT findings. Then, we evaluated the relationship among diaphragm thickness, age, and blood glucose metabolism. We prospectively evaluated the diaphragm thickness of 50 patients with diabetes using both U.S. and CT. The diaphragm thickness using CT was evaluated in the zone of apposition on contact with the thoracic cavity between the most frontal and dorsal positions, and the results were expressed as a sum of left and right measurements. The mean diaphragm thickness was 3.35 ± 0.64 mm and 3.73 ± 1.00 mm using U.S. and CT, respectively. The diaphragm thicknesses evaluated using both U.S. and CT were significantly correlated with each other (r = 0.3809, P = 0.0063). Then, we studied the data of 1patients with tuberculosis who had undergone CT and had a high morbidity of diabetes. The diaphragm thickness was positively correlated with body weight (r = 0.2911, P = 0.0088) and negatively with age and HbA1c (r = −0.4493, P < 0.0001; r = −0.5507, P < 0.0001, respectively). Moreover, the diaphragm thickness was significantly less in patients with diabetes than in those without diabetes. A thin diaphragm has been found to be related to poor prognosis among patients with acute pneumonia in intensive care units. Our results indicate that diabetes can accelerate sarcopenia of the diaphragm. Because the diaphragm has multiple functions, sarcopenia of the diaphragm in patients with diabetes might affect prognosis.

Disclosure

M. Yamamoto: None. M. Takemoto: None. H. Masuyama: None. M. Koshizaka: None. Y. Maezawa: None. K. Yokote: Research Support; Self; Astellas Pharm Ltd, MSD K.K..
The Changes of Leukocyte Telomere Length after Different Treatments in Patients with Type 2 Diabetes Mellitus (T2DM)
Authors: LIU JUANHONG , MA DELIN , YANG YAN
Published: June 2018

Objective: The telomere length is closely related with cell growth, proliferation, senescence and carcinogenesis. Increasing evidences demonstrated that there may be a potential importance of telomere biology in type 2 diabetes. In this study, we intend to investigate the effects of different treatments on leukocyte telomere length in T2DM patients.

Methods: 436 T2DM patients randomly selected from the outpatient of Tongji Hospital were divided into 5 groups according to the their treatments: insulin group, acarbose group, metformin group, sulfonylurea group, and control group without any treatment. Clinical characteristics were collected and leukocyte telomere length was measured.

Results: Multiple linear regression analysis revealed that leukocyte telomere length of all T2DM patients was inversely associated with age(r=-0.3401,P<0.01).The leukocyte telomere length had no significant difference among patients with different duration of T2DM (F=0.8913,P=0.4111).We grouped patients based on their treatments and compared the difference of their telomere length. One-way ANOVA analysis showed patients with different treatments had different leukocyte telomere attrition rates (F=61.7, P<0.001). Insulin group had the slowest leukocyte telomere attrition rate (-13.36 ± 4.611) and sulfonylurea group (-14.91 ± 6.428) was slightly faster than insulin group. Leukocyte telomere attrition rates in metformin group (-17.33 ± 7.954) and control group (-17.7 ± 4.384) were almost the same. Acarbose group had the fastest leukocyte telomere attrition rate(-29.69 ± 6.696).

Conclusions: Leukocyte telomere length was decreased with age in T2DM patients, and different therapys had different effects on leukocyte telomere lengths. Insulin had an effect of slowing down the telomere attrition as well as acarbose seemed accelerating it. These results suggest that insulin might slow down aging during the period of T2DM while acarbose accelerate it.

Disclosure

J. Liu: None. D. Ma: None. Y. Yang: None.
Association between Allopurinol and Cardiovascular Events and All-Cause Mortality in Diabetes—A Population-Based Cohort Study
Authors: WEISMAN ALANNA , TOMLINSON GEORGE A. , LIPSCOMBE LORRAINE , PERKINS BRUCE A. , HAWKER GILLIAN A.
Published: June 2018

Higher uric acid (UA) is associated with cardiovascular events and mortality. Allopurinol, a UA-lowering therapy, may reduce risk of these outcomes. Despite the high prevalence of elevated UA in diabetes, the association between allopurinol and cardiovascular events and mortality in diabetes is unclear.

A population-based cohort was constructed using administrative data in Ontario, Canada. Subjects with diabetes entered on receipt of a new prescription for allopurinol after age 66 (April 1/2002-March 31/2012) and were followed until a composite of all-cause mortality, stroke, myocardial infarction or revascularization. A Cox proportional hazards model was used for each sex, with time-varying allopurinol exposure modeled as yes/no, dose categories and cumulative dose.

Over a median [IQR] follow-up time of 4.7[1.8-7.8] years, the composite outcome occurred in 16,262/23,103 males and 10,566/15,313 females. Allopurinol exposure was associated with a reduction in the composite outcome in a dose-response manner but there was no cumulative dose effect (Table 1).

Any allopurinol exposure and higher allopurinol doses were associated with reduced cardiovascular events and mortality in a large diabetes cohort. Potential mechanisms include an acute reduction of oxidative stress and endothelial dysfunction.

Table 1: Hazard Ratios by Sex.Males (n=23,103)Females (n=15,313)Allopurinol ExposureUnadjusted HRAdjusted HRUnadjusted HRAdjusted HRExposed time v. unexposed time0.82 (0.79, 0.84)0.77 (0.75, 0.80)0.88 (0.85, 0.92)0.81 (0.78, 0.84)Dose categories0mg---->0 and ≤100mg1.03 (0.99, 1.08)0.84 (0.80, 0.88)1.(1.01, 1.12)0.86 (0.81, 0.90)>100 and ≤200mg0.82 (0.78, 0.85)0.75 (0.72, 0.78)0.83 (0.79, 0.87)0.76 (0.72, 0.80)>200mg0.71 (0.68, 0.74)0.75 (0.72, 0.78)0.78 (0.73, 0.82)0.81 (0.77, 0.86)Cumulative Dose (per 100g increase)0.99 (0.98, 1.00)1.00 (0.99, 1.01)0.99 (0.98, 1.01)0.99 (0.98, 1.00)

Disclosure

A. Weisman: None. G.A. Tomlinson: None. L. Lipscombe: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc.. G.A. Hawker: None.
Effect of Insulin Deprivation on Brain Mitochondrial ATP Production and Mitochondrial Proteome in Diabetic Mice
Authors: RUEGSEGGER GREGORY , SHANKARAPPA MANJUNATHA , SUMMER PRISKA , GOPALA SRINIVAS , ZABIELSKI PIOTR , KLAUS KATHERINE , DASARI SURENDRA , LANZA IAN R. , SREEKUMARAN NAIR K.
Published: June 2018

Accumulating evidence indicates a strong association between diabetic status and degenerative brain disease, including cognitive impairment. Here we hypothesized that although insulin is not necessary for glucose metabolism in brain, like in skeletal muscle insulin is critical for mitochondrial function in brain. We measured oxygen consumption rate (OCR), maximal ATP production rate (MAPR), and reactive oxygen species (ROS) production in isolated brain mitochondria of streptozotocin (STZ) diabetic mice. STZ mice deprived of insulin treatment for 96 hours (D-I), in comparison to nondiabetic mice (ND) showed a significant reduction in State 3 MAPR [1.77±0.14 vs. 2.35±0.27 (pmol/s/ug)], phosphorylation efficiency [0.42±0.04 vs. 0.54±0.07 (mol ATP produced/mol of oxygen consumed)] and respiratory control ratio [2.95±0.16 vs. 3.12±0.18] indicating reduced mitochondrial coupling efficiency during insulin deprivation. Citrate synthase and cytochrome c oxidase activities were significantly decreased in the hypothalamus of D-I compared ND. Surprisingly, no significant differences in ROS emission were detected between ND and D-I suggesting additional factors, potentially elevated ketone bodies, may protect against increased oxidative stress in the D-I brain. Proteomics analysis of the cerebrum found post-translational modification involving oxidative damage of several mitochondrial proteins that potentially cause tau phosphorylation and neurofibrillary degeneration in D-I vs. ND. In STZ mice with continued insulin treatment (D+I), state 3 OCR, MAPR, and phosphorylation efficiency were comparable to ND, demonstrating the restorative effects of insulin and euglycemia on brain mitochondrial function. We conclude that insulin deprivation and hyperglycemia significantly alter brain mitochondrial function. Insulin treatment and control of glycemia could have salutary effects on these parameters.

Disclosure

G. Ruegsegger: None. M. Shankarappa: None. P. Summer: None. S. Gopala: None. P. Zabielski: None. K. Klaus: None. S. Dasari: None. I.R. Lanza: None. K. Nair: None.
Uncontrolled Glycaemia Is the Strongest Predictive Factor of Liver-Related and Cardiovascular Death in Diabetic Patients with Cirrhosis
Authors: HIGUERA-DE LA TIJERA FATIMA , SERVIN-CAAMANO ALFREDO I. , NAVARRO-ESTRADA ALICIA , RÁBAGO-ESCOTO RUTH , CRUZ-ESTRADA ANTONIO , ALEXANDERSON-ROSAS ELVIRA G.
Published: June 2018

Diabetes is a common comorbidity in cirrhotic patients; there are insufficient studies in this context.

Aim: to investigate risk factors for liver-related death (LRD) and cardiovascular death (CVD) in a cohort of diabetic patients with cirrhosis. Follow-up 10 years. We included 380 diabetics with cirrhosis, according to Child-Pugh: 141(37.1%) A, 170(44.7%) B, 69(18.2%) C. Thirty three (8.7%) died for LRD, 29(7.6%) died for CVD. Those died for LRD, compared with those alive, had higher glucose 211±80 vs. 143±62 mg/dL p<0.0001; HbA1c 8.0±1.4 vs. 6.8±1.1% p<0.0001. Univariate analysis (UA): hepatic encephalopathy (HE) p=0.02; ascites, spontaneous bacterial peritonitis (SBP), HbA1c >7.0%, and decompensated cirrhosis (Child B/C) were factors associated with LRD p<0.0001. Variceal bleeding (VB) was not significant (NS). Multivariate analysis (MA): only HbA1c >7.0% was associated with liver-related death HR=3.0; 95% CI=1.4-6.6 p<0.006. Those died for CVD had higher glucose 230±92 vs. 143±62 mg/dL p<0.0001; HbA1c 8.8±1.6 vs. 6.8±1.1% p<0.0001. UA: ascites p=0.001; HE, SBP, HbA1c ≥7.0% were associated with CVD p<0.0001. Child B/C and VB were NS. MA: HbA1c ≥7.0% was the strongest factor related to CVD HR=8.4; 95% CI=3.1-22.6 p<0.0001. Uncontrolled glycaemia is the most important risk factor predicting LRD and CVD. A tight glycemic control is need in cirrhotic patients.

Disclosure

F. Higuera-de la Tijera: Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Takeda Development Center Americas, Inc., Sanofi-Aventis, Silanes. A.I. Servin-Caamano: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Takeda Development Center Americas, Inc., Eli Lilly and Company, Sanofi-Aventis, silanes. A. Navarro-Estrada: None. R. Rábago-Escoto: None. A. Cruz-Estrada: None. E.G. Alexanderson-Rosas: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Takeda Development Center Americas, Inc., Sanofi, Silanes, Novo Nordisk Inc., Novartis Pharmaceuticals Corporation, Janssen Pharmaceuticals, Inc..