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Journal Cover Diabetes, Obesity and Metabolism
  [SJR: 2.729]   [H-I: 87]   [280 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1462-8902 - ISSN (Online) 1463-1326
   Published by John Wiley and Sons Homepage  [1577 journals]
  • Efficacy and safety of the addition of ertugliflozin in patients with type
           2 diabetes mellitus inadequately controlled with metformin and
           sitagliptin: the VERTIS SITA2 placebo-controlled randomized study
    • Authors: Samuel Dagogo-Jack; Jie Liu, Roy Eldor, Guillermo Amorin, Jeremy Johnson, Darcy Hille, Yuqin Liao, Susan Huyck, Gregory Golm, Steven G. Terra, James P. Mancuso, Samuel S. Engel, Brett Lauring
      Abstract: AimsTo assess ertugliflozin in patients with type 2 diabetes inadequately controlled on metformin and sitagliptin.Materials and MethodsIn this double-blind randomized study (NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0–10.5% [53–91 mmol/mol] on metformin ≥1500 mg/day and sitagliptin 100 mg/day; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2) were randomized to ertugliflozin 5 mg once-daily, 15 mg once-daily, or placebo. Primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52.Results464 patients were randomized (mean baseline HbA1c 8.0% [64.3 mmol/mol]; eGFR 87.9 mL/min/1.73 m2). After 26 weeks, placebo-adjusted least squares (LS) mean changes in HbA1c from baseline were –0.7% (–7.5 mmol/mol) and –0.8% (–8.3 mmol/mol) for ertugliflozin 5 mg and 15 mg, respectively (both p
      PubDate: 2017-09-17T23:50:21.546296-05:
      DOI: 10.1111/dom.13116
  • Efficacy and safety of alirocumab in insulin-treated individuals with type
           1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN
           randomized trial
    • Authors: Lawrence A. Leiter; Bertrand Cariou, Dirk Müller-Wieland, Helen M. Colhoun, Stefano Del Prato, Francisco J. Tinahones, Kausik K. Ray, Maja Bujas-Bobanovic, Catherine Domenger, Jonas Mandel, Rita Samuel, Robert R. Henry
      Abstract: AimsTo investigate efficacy and safety of alirocumab in participants with type 2 or type 1 diabetes treated with insulin and with elevated low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin therapy.Materials and MethodsParticipants at high cardiovascular risk with type 2 (n = 441) or type 1 diabetes (n = 76) and LDL-C ≥70 mg/dL (≥1.8 mmol/L) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks (Q2W), for 24 weeks’ double-blind treatment. Alirocumab-treated participants received a 75 mg Q2W dose, with blinded dose increase to 150 mg Q2W at week 12 if week 8 LDL-C ≥70 mg/dL. Primary endpoints were percentage change in calculated LDL-C from baseline to week 24, and safety assessments.ResultsAlirocumab reduced LDL-C from baseline to week 24 by (mean ± standard error) 49.0 ± 2.7% and 47.8 ± 6.5% vs placebo (both P
      PubDate: 2017-09-14T02:26:57.889281-05:
      DOI: 10.1111/dom.13114
  • Risk of Lower Extremity Amputations in Patients With Type 2 Diabetes
           Mellitus Treated With SGLT2 Inhibitors in the United States: A
           Retrospective Cohort Study
    • Authors: Zhong Yuan; Frank J. DeFalco, Patrick B. Ryan, Martijn J. Schuemie, Paul E. Stang, Jesse A. Berlin, Mehul Desai, Norm Rosenthal
      Abstract: AimsTo examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co-transporter 2 inhibitors (SGLT2i) overall, and canagliflozin specifically, compared with non-SGLT2i antihyperglycemic agents (AHAs).Materials and MethodsPatients with T2DM newly exposed to SGLT2i or non-SGLT2i AHAs were identified using the Truven MarketScan database. The incidence of below-knee lower extremity (BKLE) amputation was calculated for patients treated with SGLT2i, canagliflozin, or non-SGLT2i AHAs. Patients newly exposed to canagliflozin and non-SGLT2i AHAs were matched 1:1 on propensity scores, and a Cox proportional hazards model was used for comparative analysis. Negative controls (outcomes not believed to be associated with any AHA) were used to calibrate P values.ResultsBetween April 1, 2013-October 31, 2016, 118,018 new users of SGLT2i, including 73,024 of canagliflozin, and 226,623 new users of non-SGLT2i AHAs were identified. The crude incidence rate of BKLE amputation was 1.22, 1.26, and 1.87 events per 1,000 person-years with SGLT2i, canagliflozin, and non-SGLT2i AHAs, respectively. For the comparative analysis, 63,845 new users of canagliflozin were matched with 63,845 new users of non-SGLT2i AHAs, resulting in well-balanced baseline covariates. The incidence rate of BKLE amputation was 1.18 and 1.12 events per 1,000 person-years with canagliflozin and non-SGLT2i AHAs, respectively; the hazard ratio (95% confidence interval) was 0.98 (0.68-1.41; P=0.92, calibrated P=0.95).ConclusionsThis real-world study observed no evidence of increased risk of BKLE amputation for new users of canagliflozin compared with non-SGLT2i AHAs in a broad population of patients with T2DM.
      PubDate: 2017-09-12T10:25:31.065919-05:
      DOI: 10.1111/dom.13115
  • Insulin Resistance and Cardiovascular Outcomes in the ORIGIN Trial
    • Authors: Hertzel C. Gerstein; Ele Ferrannini, Matthew C. Riddle, Salim Yusuf,
      Abstract: AimsIn the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, titrated doses of basal insulin glargine targeting fasting normoglycemia had a neutral effect on cardiovascular outcomes. The dose of insulin required to achieve normoglycemia provides a unique measurement of each individual's resistance to insulin's action, and was therefore used to examine the link between insulin resistance and cardiovascular outcomes.Materials and MethodsSelf-titration of insulin doses targeting a fasting plasma glucose < 5.3 mmol/l (95 mg/dl) was promoted at every visit and cardiovascular and other serious health outcomes were ascertained. All analyses were restricted to participants allocated to insulin glargine, who added it to lifestyle or 1 glucose lowering oral agent at randomization. Normoglycemia was defined as a fasting plasma glucose
      PubDate: 2017-09-12T04:16:09.03186-05:0
      DOI: 10.1111/dom.13112
  • Sitagliptin and Roux-en-Y gastric bypass modulate insulin secretion via
           regulation of intra-islet PYY
    • Authors: Claudia Guida; Laura J McCulloch, Mahdieh Godazgar, Sam D Stephen, Charlotte Baker, Davide Basco, Jiawen Dong, Duan Chen, Anne Clark, Reshma D Ramracheya
      Abstract: AimsThe gut hormone peptide tyrosine tyrosine (PYY) is critical for maintaining islet integrity and restoring islet function following Roux-en-Y gastric bypass (RYGB). The expression of PYY and its receptors (NPYRs) in islets has been documented but not fully characterized. Modulation of islet PYY by the proteolytic enzyme DPP-IV has not been investigated and the impact of DPP-IV inhibition on islet PYY function remains unexplored. Here we have addressed these gaps and their effects on glucose-stimulated insulin secretion (GSIS). We have also investigated changes in pancreatic PYY in diabetes and following RYGB.MethodsImmunohistochemistry and gene expression analysis were used to assess PYY, NPYRs and DPP-IV expression in rodent and human islets. DPP-IV activity inhibition was achieved by sitagliptin. Secretion studies were used to test PYY and sitagliptin effects on insulin release, and the involvement of GLP-1. Radioimmunoassays were used to measure hormone content in islets.ResultsPYY and DPP-IV localized in different cell types in islets while NPYRs expression was confined to the beta-cells. Chronic PYY application enhanced GSIS in rodent and diabetic human islets. DPP-IV inhibition by sitagliptin potentiated GSIS; this was mediated by locally-produced PYY, and not GLP-1. Pancreatic PYY was markedly reduced in diabetes. RYGB strongly increased islet PYY content, but did not lead to full restoration of pancreatic GLP-1 levels.ConclusionLocal regulation of pancreatic PYY, rather than GLP-1, by DPP-IV inhibition or RYGB can directly modulate the insulin secretory response to glucose, indicating a novel role of pancreatic PYY in diabetes and weight-loss surgery.
      PubDate: 2017-09-11T09:59:46.477867-05:
      DOI: 10.1111/dom.13113
  • Estimated glucose disposal rate predicts mortality in adults with type 1
    • Authors: Thomas Nyström; Martin J. Holzmann, Björn Eliasson, Ann-Marie Svensson, Ulrik Sartipy
      Abstract: AimsThis study aimed to investigate the association between insulin resistance as determined by the estimated glucose disposal rate (eGDR), and survival in adults with type 1 diabetes (T1D) in Sweden.Material and MethodsUsing the Swedish National Diabetes Register, people with T1D were included from January 1, 2005 to December 31, 2012. Outcomes were retrieved from National healthcare registers. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the associations between eGDR (mg/kg/min) categorized into
      PubDate: 2017-09-08T04:35:48.325172-05:
      DOI: 10.1111/dom.13110
  • Initiating therapy in patients newly diagnosed with type 2 diabetes:
           combination therapy versus a stepwise approach
    • Authors: Eugenio Cersosimo; Eric L. Johnson, Christina Chovanes, Neil Skolnik
      Abstract: There is clear evidence that achieving glycaemic targets reduces the risk of developing complications as a result of type 2 diabetes (T2D). Many patients, however, continue to have suboptimal glycaemic control due to issues that include unclear advice on how to achieve these targets as well as clinical inertia. The two management approaches recommended for patients newly diagnosed with T2D are stepwise and combination therapy, each of which has advantages and disadvantages.Stepwise therapy may result in good patient adherence and allow greater individualization of therapy, minimization of side effects, and cost, and so may be appropriate for patients who are closer to goal. However, stepwise therapy may also lead to frequent delays in achieving glycaemic goals and longer exposure to hyperglycaemia. Combination therapy, which is now emerging as an important therapy option, has a number of potential advantages over stepwise therapy, including reduction in clinical inertia and earlier and more frequent achievement of glycated haemoglobin goals by targeting multiple pathogenic mechanisms simultaneously, which may more effectively delay disease progression. Compared with stepwise therapy, the disadvantages of combination therapy include reduced patient adherence due to complex, multi-drug regimens, difficulty determining the cause of poor efficacy and/or side effects, patient refusal to accept disease, and higher cost. Fixed-dose and fixed-ratio combinations are novel therapeutic approaches which may help address several issues of treatment complexity and patient burden associated with combination therapy comprising individual drugs. However, the choice of which drugs to administer and the decision to use stepwise versus combination therapy should always be made on an individualized basis.
      PubDate: 2017-09-01T09:21:23.295465-05:
      DOI: 10.1111/dom.13108
  • Comparative Effectiveness of Once-Weekly GLP-1 Receptor Agonists on
           6-Month Glycemic Control and Weight Outcomes in Patients with Type 2
    • Authors: Sudhir Unni; Eric Wittbrodt, Junjie Ma, Marisa Schauerhamer, Jeff Hurd, Natalia Ruiz-Negrón, Carrie McAdam-Marx
      Abstract: A retrospective cohort study was conducted in patients with type 2 diabetes (T2D) in an electronic medical record database to compare real-world, 6-month A1C and weight outcomes for exenatide QW (EQW) vs. dulaglutide and vs. albiglutide. The study included 2,133 EQW, 201 dulaglutide, and 131 albiglutide patients. Overall mean (SD) age was 60 (11) years and 54% were men; neither differed between comparison groups. Mean baseline A1C was similar for EQW [8.3 (1.7)%] and dulaglutide [8.5 (1.5)% (p=0.165)], but higher for albiglutide [8.7 (1.7)% (p
      PubDate: 2017-09-01T08:55:24.637409-05:
      DOI: 10.1111/dom.13107
  • Performance of individually-measured vs population-based C-peptide
           kinetics to assess β-cell function in presence and absence of acute
           insulin resistance
    • Authors: Ron T. Varghese; Chiara Dalla Man, Marcello C. Laurenti, Francesca Piccinini, Anu Sharma, Meera Shah, Kent R. Bailey, Robert A. Rizza, Claudio Cobelli, Adrian Vella
      Abstract: AimsStandardized, population-based kinetics of C-peptide distribution and clearance are used to estimate insulin secretion from plasma C-peptide concentrations without direct measurement of C-peptide kinetics. We then compared the performance of population-based kinetics to directly measured C-peptide kinetics when used to calculate β-cell responsivity indices. To ensure that population-based kinetics apply to all conditions where β-cell function is measured, subjects were studied in the presence and absence of acute insulin resistance.Materials and MethodsSomatostatin was used to inhibit endogenous insulin secretion in 56 nondiabetic subjects. Subsequently, a C-peptide bolus was administered and the changing concentrations used to calculate individual kinetic parameters of C-peptide clearance. In addition, they were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid (FFA) elevation to cause insulin resistance, was achieved by infusion of intralipid + heparin. Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics.ResultsThere were marked differences in the exchange parameters (k12 and k21) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance, i.e. the irreversible loss from the accessible compartment (k01), obtained from population-based estimates compared to experimental measurement. Since it is predominantly influenced by k01, DI estimated using individual kinetics correlated well with those estimated using population-based kinetics.ConclusionsThese data support the use of population-based measures of C-peptide kinetics to estimate β-cell function during OGTT.
      PubDate: 2017-09-01T08:35:21.354146-05:
      DOI: 10.1111/dom.13106
  • Better glycaemic control and less hypoglycaemia with insulin glargine 300
           U/mL versus glargine 100 U/mL: one-year patient-level meta-analysis of the
           EDITION clinical studies in people with type 2 diabetes
    • Authors: Robert Ritzel; Ronan Roussel, Andrea Giaccari, Jiten Vora, Claire Brulle-Wohlhueter, Hannele Yki-Järvinen
      Abstract: AimsTo investigate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) versus insulin glargine 100 U/mL (Gla-100) over 12 months in a patient-level meta-analysis using data from EDITION studies in people with type 2 diabetes (T2DM).MethodsEDITION 1, 2 and 3 were multicentre, randomised, open-label, two-arm, parallel-group, treat-to-target phase 3a studies. Similar study designs and endpoints enabled a meta-analysis to be conducted.ResultsReductions in HbA1c were better sustained over 12 months with Gla-300 than Gla-100 (least squares [LS] mean difference in change from baseline: −0.10 [95% confidence interval (CI): −0.18 to −0.02] % [−1.09 (−2.01 to −0.20) mmol/mol] [p = 0.0174]). Risk of confirmed (≤3.9 mmol/L) or severe hypoglycaemia was 15% lower with Gla-300 versus Gla-100 at night (relative risk 0.85 [95% CI: 0.77 to 0.92]) and 6% lower at any time of day (0.94 [0.90 to 0.98]). Rates of hypoglycaemia were 18% lower with Gla-300 versus Gla-100 at night (rate ratio 0.82 [0.67 to 0.99]), but comparable at any time of day. HbA1c
      PubDate: 2017-09-01T08:20:39.590495-05:
      DOI: 10.1111/dom.13105
  • Effect of ertugliflozin on glucose control, body weight, blood pressure
           and bone density in type 2 diabetes mellitus inadequately controlled on
           metformin monotherapy (VERTIS MET)
    • Authors: Julio Rosenstock; Juan Frias, Dénes Páll, Bernard Charbonnel, Raluca Pascu, Didier Saur, Amanda Darekar, Susan Huyck, Harry Shi, Brett Lauring, Steven G. Terra
      Abstract: IntroductionWe evaluated efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0–10.5%) on metformin monotherapy (≥1500 mg/day for ≥8 weeks).MethodsDouble-blind, 26-week, multicentre study with ongoing 78-week extension; 621 participants randomized 1:1:1 to placebo, ertugliflozin 5 or 15 mg/day. Primary endpoint: change from baseline in HbA1c at week 26. Secondary efficacy endpoints: change from baseline at week 26 in fasting plasma glucose (FPG), body weight, systolic/diastolic blood pressure (SBP/DBP); participants with HbA1c
      PubDate: 2017-08-31T06:01:41.198937-05:
      DOI: 10.1111/dom.13103
  • Metformin extended-release versus immediate-release: an international,
           randomized, double-blind, head-to-head trial in pharmacotherapy-naïve
           patients with type 2 diabetes
    • Authors: Naresh Aggarwal; Anuj Singla, Chantal Mathieu, Eduard Montanya, Andreas F. H. Pfeiffer, Eva Johnsson, June Zhao, Nayyar Iqbal, Clifford Bailey
      Abstract: This international, randomized, double-blind trial (NCT01864174) compared the efficacy and safety of metformin extended-release (XR) and immediate-release (IR) in patients with type 2 diabetes. After a 4-week placebo lead-in, pharmacotherapy-naïve adults with glycated haemoglobin (HbA1c) 7.0%–9.2% were randomized (1:1) to receive once-daily metformin XR 2000 mg or twice-daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG), and patients (%) with HbA1c
      PubDate: 2017-08-31T04:22:10.387442-05:
      DOI: 10.1111/dom.13104
  • Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum
           uric acid level: A meta-analysis of randomized controlled trials
    • Authors: Yumo Zhao; Lubin Xu, Dongli Tian, Peng Xia, Hua Zheng, Li Wang, Limeng Chen
      Abstract: To describe the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM), PubMed, CENTRAL, EMBASE, and were searched for randomized controlled trials of SGLT2 inhibitors in patients with T2DM up to 20 May 2017. Sixty-two studies totaling 34,941 patients were included. Either SGLT2 inhibitor (empagliflozin, canagliflozin, dapagliflozin, tofogliflozin, luseogliflozin or ipragliflozin) significantly decreased SUA levels compared with control (total WMD −37.73 µmol/L, 95% CI [−40.51, −34.95]). Treatment with empagliflozin resulted in a superior reduction in SUA (WMD −45.83 µmol/L, 95% CI [−53.03, −38.63]). The effect persisted for long-term treatment duration. Dapagliflozin decreased SUA in a dose-dependent manner (from 5 mg to 50 mg, p = 0.014). In subgroup analyses, greater reductions could be observed in early diabetes course and the SUA-lowering effect was abolished in patients with chronic kidney disease (estimated glomerular filtration rate less than 60 mL per min per 1.73 m2). The drug class effect of SUA reduction suggesting SGLT2 inhibitors might be beneficial for diabetic patients with hyperuricemia.
      PubDate: 2017-08-28T08:55:23.427088-05:
      DOI: 10.1111/dom.13101
  • The Glucagon Receptor as a Drug Target – a Witches’ Brew of Eye of
           Newt (Peptides) and Toe of Frog (Receptors)
    • Authors: Derek J. Nunez; David D'Alessio
      Abstract: Glucagon has a noble history in the annals of metabolic disease (1), even though to a layperson insulin is its more famous counter-regulatory partner. For decades medical students have been taught that glucagon raises blood glucose by increasing hepatic glucose output and that alleviation of hypoglycemia is its primary function (2). Thus, inhibition of glucagon secretion (3) or action (4) are logical approaches to the development of therapeutics that improve glycemic control in both type 2 and type 1 diabetes mellitus; indeed, this strategy has been pursued for nearly 4 decades.
      PubDate: 2017-08-26T00:20:42.577458-05:
      DOI: 10.1111/dom.13102
  • Cover Image, Volume 19, Issue 9
    • Authors: John Blundell; Graham Finlayson, Mads Axelsen, Anne Flint, Catherine Gibbons, Trine Kvist, Julie B. Hjerpsted
      Abstract: The cover image, by John Blundell et al., is based on the Original Article Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity,
      DOI : 10.1111/dom.12932The cover image, by John Blundell et al., is based on the Original Article Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity,
      DOI : 10.1111/dom.12932
      PubDate: 2017-08-23T04:22:48.563792-05:
  • Therapeutic inertia in the treatment of hyperglycaemia in patients with
           type 2 diabetes: a systematic review
    • Authors: Kamlesh Khunti; Marilia B. Gomes, Stuart Pocock, Marina V. Shestakova, Stéphane Pintat, Peter Fenici, Niklas Hammar, Jesús Medina
      Abstract: AimsTherapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner according to evidence-based clinical guidelines, is a key reason for uncontrolled hyperglycaemia in patients with type 2 diabetes. The aims of this systematic review were to identify how therapeutic inertia in the management of hyperglycaemia was measured and to assess its extent over the past decade.Materials and methodsSystematic searches for articles published from 1 January 2004 to 1 August 2016 were conducted in MEDLINE and Embase. Two researchers independently screened all of the titles and abstracts, and the full texts of publications deemed relevant. Data were extracted by a single researcher using a standardized data extraction form.ResultsThe final selection for the review included 53 articles. Measurements used to assess therapeutic inertia varied across studies, making comparisons difficult. Data from low- to middle-income countries were scarce. In most studies, the median time to treatment intensification after a glycated haemoglobin (HbA1c) measurement above target was more than 1 year (range 0.3 to>7.2 years). Therapeutic inertia increased as the number of antidiabetic drugs rose and decreased with increasing HbA1c levels. Data were mainly available from Western countries. Diversity of inertia measures precluded meta-analysis.ConclusionsTherapeutic inertia in the management of hyperglycaemia in patients with type 2 diabetes is a major concern. This is well documented in Western countries, but corresponding data are urgently needed in low- and middle-income countries, in view of their high prevalence of type 2 diabetes.
      PubDate: 2017-08-22T07:45:19.858121-05:
      DOI: 10.1111/dom.13088
  • Attenuated Suppression of Lipolysis Explains Increases in Triglyceride
           Secretion and Concentration with Basal Insulin Peglispro (BIL) Relative to
           Insulin Glargine Treatment in Patients with Type 1 Diabetes
    • Authors: Rakel Fuglsang Johansen; Esben Søndergaard, Helle Linnebjerg, Parag Garhyan, Eric Chen Quin Lam, Niels Porksen, Scott J Jacober, Søren Nielsen
      Abstract: AimsIn patients with type 1 diabetes, basal insulin peglispro (BIL) lowers weight and increases plasma triglycerides (TG) and hepatic fat relative to insulin glargine (GL). To explain this, we hypothesised that BIL's attenuated peripheral effects may include increased free fatty acid flux to the liver, causing increased VLDL-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition.Materials and MethodsIn this open-label, randomised, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualised, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10-3H]palmitate infusion. VLDL-TG secretion, clearance and oxidation rate were assessed using primed-constant infusion of ex-vivo labelled [1-14C]VLDL-TG, while VLDL-TG storage rate was assessed using [9,10-3H]VLDL-TG bolus injection.ResultsVLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means (95% confidence interval [CI]) for VLDL-TG clearance and oxidation were 0.92 (0.72, 1.17) and 1.31 (0.91, 1.90), respectively. The difference in LS means (95% CI) for VLDL-TG storage rate was -0.36 (-0.83, 0.12).ConclusionsBIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration versus GL, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato-preferential glucodynamic effects.
      PubDate: 2017-08-17T10:10:22.881324-05:
      DOI: 10.1111/dom.13087
  • Effect of Once-weekly Dulaglutide on HbA1c and Fasting Blood Glucose in
           Patient Subpopulations by Gender, Duration of Diabetes, and Baseline HbA1c
    • Authors: Baptist Gallwitz; Samuel Dagogo-Jack, Vivian Thieu, Luis-Emilio Garcia-Perez, Imre Pavo, Maria Yu, Kenneth E. Robertson, Nan Zhang, Francesco Giorgino
      Abstract: To evaluate the efficacy and safety of dulaglutide 1.5 mg and 0.75 mg in type 2 diabetes patients by subgroups of gender, duration of diabetes, and baseline HbA1c in the dulaglutide clinical development program (AWARD-1 to -6 and -8 clinical trials).Materials and methodsChange in HbA1c was analysed by gender, duration of diabetes (
      PubDate: 2017-08-17T10:00:22.519247-05:
      DOI: 10.1111/dom.13086
  • Primary sulfonylurea therapy in a newborn with transient neonatal diabetes
           due to a paternal uniparental disomy 6q24 (UPD6)
    • Authors: Uta Neumann; Christoph Bührer, Oliver Blankenstein, Peter Kühnen, Klemens Raile
      Abstract: Neonatal diabetes may be of transient or permanent nature. While certain mutations in ABCC8 and KCNJ11 genes coding the ATP-dependent potassium channel (KATP) cause both transient (TNDM) and permanent neonatal diabetes (PNDM), chromosomal abnormalities in 6q24 are the most frequent cause for TNDM.
      PubDate: 2017-08-17T09:50:31.657773-05:
      DOI: 10.1111/dom.13085
  • Single Dose Euglycemic Clamp Studies Demonstrating Pharmacokinetic and
           Pharmacodynamic Similarity Between MK-1293 Insulin Glargine and Originator
           Insulin Glargine (Lantus) in Type 1 Diabetes and Healthy Subjects
    • Authors: Michael Crutchlow; John S. Palcza, Kate M. Mostoller, Chantal D. Mahon, April M. Barbour, Michael C. Marcos, Yang Xu, Elaine Watkins, Linda Morrow, Marcus Hompesch
      Abstract: AimsMK-1293 is an insulin glargine that has an identical amino acid sequence to that of Lantus, the originator insulin glargine. Two euglycemic clamp studies, one in subjects with Type 1 diabetes (T1D) and one in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293 and Lantus commercially procured in both the European Union (EU-Lantus) and United States (US-Lantus).Materials and MethodsBoth studies were single-dose, randomized, double-blind, single-center, crossover studies with ≥7 days between dosing periods. A 2-treatment, 4-period replicate crossover study in T1D subjects (N=76) compared the PK and PD of MK-1293 to EU-Lantus for 30 hours after dosing. A 3-period crossover study in healthy subjects (N=109) compared the PK and PD of MK-1293, EU-Lantus, and US-Lantus for 24 hours after dosing. In both studies, all subjects received single 0.4 units/kg subcutaneous doses of MK-1293 or Lantus in all dosing periods. Pharmacokinetic assessment was based on LC-MS/MS-based measurement of the major insulin glargine metabolite (M1) and PD was characterized using the euglycemic clamp platform.ResultsIn both studies, pre-specified similarity criteria were met between MK-1293 and Lantus for comparison of PK (AUC0-24hr and Cmax of M1) and PD (GIR-AUC0-24hr, GIR-AUC0-12hr, GIR-AUC12-24hr, and GIRmax) primary endpoints. All treatments were well tolerated.ConclusionBased on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK-1293 are highly similar to those of Lantus. ( NCT02059174)
      PubDate: 2017-08-17T09:35:27.055103-05:
      DOI: 10.1111/dom.13084
  • Patterns of glycaemic control in patients with type 2 diabetes mellitus
           initiating second-line therapy after metformin monotherapy: Retrospective
           data for 10 256 individuals from the United Kingdom and Germany
    • Authors: Kamlesh Khunti; Thomas R. Godec, Jesús Medina, Laura Garcia-Alvarez, Josh Hiller, Marilia B. Gomes, Javier Cid-Ruzafa, Bernard Charbonnel, Peter Fenici, Niklas Hammar, Kiyoshi Hashigami, Mikhail Kosiborod, Antonio Nicolucci, Marina V. Shestakova, Linong Ji, Stuart Pocock
      Abstract: AimTo investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second-line glucose-lowering therapies.Materials and methodsThis cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second-line glucose-lowering therapy (switch from or add-on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre-specified patient characteristics on 6-month HbA1c changes were assessed using analysis of covariance.ResultsPatients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy; the remainder initiated add-on therapy. Mean (SE) unadjusted 6-month HbA1c change was −1.27% (0.02). When adjusted for baseline HbA1c, 6-month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c
      PubDate: 2017-08-17T09:05:23.037022-05:
      DOI: 10.1111/dom.13083
  • Safety and efficacy of semaglutide once weekly versus sitagliptin once
           daily, both as monotherapy in Japanese subjects with type 2 diabetes
    • Authors: Yutaka Seino; Yasuo Terauchi, Takeshi Osonoi, Daisuke Yabe, Nobuyuki Abe, Tomoyuki Nishida, Jeppe Zacho, Shizuka Kaneko
      Abstract: AimsSemaglutide is a glucagon-like peptide-1 (GLP-1) analogue in development for type 2 diabetes (T2D). This trial assessed the safety and efficacy of monotherapy with once-weekly subcutaneous (s.c.) semaglutide versus sitagliptin in Japanese subjects with T2D.Materials and methodsIn this phase 3a randomized, open-label, parallel-group, active-controlled, multicentre trial, adult Japanese subjects with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed-out in run-in period) received once-weekly s.c. semaglutide (0.5 or 1.0 mg) or once-daily oral sitagliptin 100 mg. The primary endpoint was number of treatment-emergent adverse events (TEAEs) after 30 weeks.ResultsOverall, 308 subjects were randomized and exposed to treatment, with similar baseline characteristics across groups. In total, 2.9% of subjects in both the semaglutide 0.5 mg and the sitagliptin group prematurely discontinued treatment, compared with 14.7% in the semaglutide 1.0 mg group. The majority of discontinuations in the semaglutide 0.5 and 1.0 mg groups were due to adverse events. More TEAEs were reported in semaglutide- versus sitagliptin-treated subjects (74.8%, 71.6% and 66.0% in the semaglutide 0.5, 1.0 mg and sitagliptin groups, respectively). Adverse events were mainly mild to moderate. Gastrointestinal adverse events, most frequently reported with semaglutide, diminished in frequency over time. Mean HbA1c (baseline 8.1%) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, versus 0.7% with sitagliptin (estimated treatment difference versus sitagliptin [ETD] –1.13% [95% confidence interval –1.32; –0.94] and –1.44% [–1.63; –1.24], both p
      PubDate: 2017-08-08T06:20:21.978677-05:
      DOI: 10.1111/dom.13082
  • Sodium-Glucose Cotransporter-2 Inhibition Improves Incretin Sensitivity of
           Pancreatic β-cells in Patients with Type 2 Diabetes
    • Authors: Chang Ho Ahn; Tae Jung Oh, Soo Heon Kwak, Young Min Cho
      Abstract: AimsThe β-cell response to glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), at their physiologic concentrations, is reduced in patients with type 2 diabetes mellitus (T2DM). We hypothesized that dapagliflozin improves β-cell responses to incretin hormones (or β-cell incretin sensitivity) by alleviating glucose toxicity.Materials and MethodsNineteen patients with T2DM underwent a 3-hour hyperglycemic clamp study with incretin infusion before and after 8-week treatment with dapagliflozin added to the background treatment. Ten subjects with normal glucose tolerance (NGT) underwent a single hyperglycemic clamp study. The hyperglycemic clamp was targeted at 15.5 mmol/L for 3 hours with synthetic GLP-1 and GIP infusion over a 60-180 minute and a 120-180 minute period, respectively.ResultsCompared to baseline, the C-peptide response to GLP-1 [incremental area under the curve (iAUC) of C-peptide60-120min] significantly increased (83.6 ± 42.1 to 106.6 ± 45.7 nmol/L×min, P = 0.011), and that to GIP/GLP-1 (iAUC of C-peptide120-180min) tended to increase after dapagliflozin treatment (82.5 ± 58.4 to 101.9 ± 50.3 nmol/L×min, P = 0.087), whereas both the insulin responses to GLP-1 and GIP/GLP-1 increased significantly. First-phase C-peptide response, which reflects β-cell function, significantly increased after dapagliflozin treatment. However, all these improved values in the T2DM subjects were far lower than those of the NGT subjects. In addition, the improvement of insulin responses to hyperglycemia was correlated with the improvement of insulin responses on incretin infusion.ConclusionsDapagliflozin improved β-cell responses to incretin hormones as well as glucose during the hyperglycemic clamp in patients with inadequately controlled T2DM.
      PubDate: 2017-08-08T05:35:22.138562-05:
      DOI: 10.1111/dom.13081
  • The bile acid-sequestering resin sevelamer eliminates the acute GLP-1
           stimulatory effect of endogenously released bile acids in patients with
           type 2 diabetes
    • Authors: Andreas Brønden; Anders Albér, Ulrich Rohde, Lærke S. Gasbjerg, Jens F. Rehfeld, Jens J. Holst, Tina Vilsbøll, Filip K. Knop
      Abstract: AimsThe discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes.Materials and methodsWe performed a randomized, placebo-controlled, and double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. Four experimental study days in randomized order with administration of either sevelamer 3,200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min). The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, fibroblast growth factor-19 and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed.ResultsCCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions.ConclusionsSingle-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.
      PubDate: 2017-08-08T05:15:18.683149-05:
      DOI: 10.1111/dom.13080
  • Efficacy and safety of teneligliptin added onto canagliflozin monotherapy
           in Japanese patients with type 2 diabetes mellitus: a multicentre,
           randomised, double-blind, placebo-controlled, parallel-group comparative
    • Authors: Takashi Kadowaki; Nobuya Inagaki, Kazuoki Kondo, Kenichi Nishimura, Genki Kaneko, Nobuko Maruyama, Nobuhiro Nakanishi, Maki Gouda, Hiroaki Iijima, Yumi Watanabe
      Abstract: Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose co-transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP-4 inhibitor) added onto canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed-dose combination of teneligliptin and canagliflozin.Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomised to receive add-on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between-group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (−0.94%; p
      PubDate: 2017-08-08T04:56:34.400954-05:
      DOI: 10.1111/dom.13079
  • Efficacy and pharmacokinetics of subcutaneous exendin (9–39) in patients
           with post-bariatric hypoglycemia
    • Authors: Colleen M Craig; Li-fen Liu, Thi Nguyen, Candice Price, Justus Bingham, Tracey L McLaughlin
      Abstract: AimPost-bariatric hypoglycemia (PBH) is a rare but growing complication of bariatric surgery with severe, debilitating, potentially life-threatening consequences and no safe and effective treatment. Previous studies involving continuous intravenous (IV) infusion of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin (9–39) (Ex-9) in patients with PBH have demonstrated efficacy in preventing symptomatic postprandial hypoglycemia. Subcutaneous (SC) injection of Ex-9 would represent a more practical therapeutic approach. The present first-in-human SC administration study was aimed at evaluating the efficacy, pharmacokinetics and tolerability of SC Ex-9 in patients with PBH.MethodsIn this 2-part, single-blinded, single ascending dose study, 9 female post-Roux-en-Y gastric bypass participants with recurrent symptomatic hypoglycaemia were enrolled. In Part 1, a single participant underwent equimolar low-dose IV vs SC Ex-9 administration; in Part 2, 8 participants were administered single ascending doses of SC Ex-9 during oral glucose tolerance testing (OGTT). Glycemic, hormonal, pharmacokinetic, and symptomatic responses were compared to those obtained during baseline OGTT.ResultsWhile an exposure-response relationship was observed, all doses effectively prevented hyperinsulinemic hypoglycemia and improved associated symptoms. On average, the postprandial glucose nadir was increased by 66%, peak insulin was reduced by 57%, and neuroglycopenic symptoms were reduced by 80%. All doses were well tolerated with no treatment emergent adverse events observed.ConclusionsSC Ex-9 appears to represent a safe, effective, and targeted therapeutic approach for treatment of PBH. Further investigation involving multiple doses with chronic dosing is warranted.
      PubDate: 2017-08-04T04:25:20.666342-05:
      DOI: 10.1111/dom.13078
  • Dapagliflozin Compared to DPP-4 inhibitors is Associated with Lower Risk
           of Cardiovascular Events and All-cause Mortality in Type 2 Diabetes
           Patients (CVD-REAL Nordic): a multinational observational study
    • Authors: F Persson; T Nyström, M E Jørgensen, B Carstensen, H L Gulseth, M Thuresson, P Fenici, D Nathanson, J W Eriksson, A Norhammar, J Bodegard, K I Birkeland
      Abstract: AimsTo compare the sodium glucose-cotransporter-2-inhibitor (SGLT-2i) dapagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) regarding risk associations of MACE (nonfatal myocardial infarction, nonfatal stroke or cardiovascular [CV] mortality), hospital events for heart failure (HHF), atrial fibrillation, and severe hypoglycemia for type 2 diabetes (T2D) patients in a real-world setting.MethodsAll T2D patients dispensed with glucose lowering drugs (GLDs) during 2012—2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided in two groups; new users of dapagliflozin and new users of DPP-4i, matched 1:3 by propensity score, calculated by patient characteristics, co-morbidities and drug treatment. Cox survival models estimated hazard ratio per country separately; a weighted average was calculated.ResultsAfter matching, a total of 40,908 T2D patients were identified as new users of dapagliflozin (n=10,227) or DPP-4i (n=30,681). The groups were well balanced at baseline; mean-age was 61 years and 23% had CV disease. Mean follow-up time was 0.95 years, with a total of 38,760 patient-years. Dapagliflozin was associated with lower risk of MACE, HHF and all-cause mortality compared to DPP-4i; hazard ratios (HRs): 0.79 (95% CI 0.67-0.94), 0.62 (0.50-0.77), and 0.44 (0.33-0.60), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [0.72-1.16]), stroke (0.79 [0.61-1.03]) and CV mortality (0.76 [0.53-1.08]) Atrial fibrillation and severe hypoglycemia showed neutral associations.ConclusionsDapagliflozin was associated with lower risks of cardiovascular events and all-cause mortality compared to DPP-4i in a in a real-world clinical setting and broad T2D population.
      PubDate: 2017-08-03T08:20:20.394411-05:
      DOI: 10.1111/dom.13077
  • A First-in-Human Pharmacodynamic and Pharmacokinetic Study of a
           Fully-Human Anti-Glucagon Receptor Monoclonal Antibody in Normal Healthy
    • Authors: Ana Kostic; Alexander T. King, Feng Yang, Kuo-Chen Chan, George D. Yancopoulos, Jesper Gromada, Joyce B. Harp
      Abstract: AimsGlucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and 2 diabetes. Here we report the safety, tolerability, pharmacokinetics [PK], and pharmacodynamics [PD] of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double blind trial.Materials and MethodsHealthy men and women received single ascending doses of REGN1193 ranging from 0.05 mg/kg to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability, and PK were assessed over 106 days. The glucose lowering effect of REGN1193 was assessed after induction of hyperglycemia by serial glucagon challenges.ResultsREGN1193 was generally well-tolerated. There were small (50 mg/dL, and did not required treatment or medical assistance. Concentration-time profiles suggest a two-compartment disposition and marked non-linearity, consistent with target-mediated clearance. REGN1193 inhibited glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose AUC 0–90 minutes by 80-90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2, and glucagon with plasma levels returning to baseline by day 29 in all dose groups.ConclusionsREGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggest an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown.
      PubDate: 2017-07-28T22:50:48.768205-05:
      DOI: 10.1111/dom.13075
  • The efficacy and safety of lixisenatide in a predominantly Asian
           population with type 2 diabetes insufficiently controlled with basal
           insulin: the GetGoal-L-C randomized trial
    • Authors: W. Yang; K. Min, Z. Zhou, L. Li, X. Xu, D. Zhu, A. Venkateshwar Rao, L. S. Murthy, N. Zhang, I. Li, E. Niemoeller, S. Shang
      Abstract: AimsTo assess the effects on glycaemic control of lixisenatide versus placebo as add-on treatment to basal insulin (BI) ± metformin on glycated haemoglobin (HbA1c) reduction in patients with insufficiently controlled type 2 diabetes (T2D).MethodsPatients (n = 448) with inadequately controlled T2D were randomized (1:1) to lixisenatide or placebo as add-on to BI ± metformin for 24 weeks after an 8-week run-in phase, during which BI was titrated to a target self-monitored plasma glucose (SMPG; 4.4–5.6 mmol/l). The primary endpoint was absolute change in HbA1c from baseline to week 24. Secondary efficacy endpoints included: percentage of responders, changes in 2-hour postprandial plasma glucose (PPG), 7-point SMPG (daily average), body weight, total daily BI dose, fasting plasma glucose and safety assessments.ResultsBaseline demographics were similar across treatment groups. Following insulin optimization during run-in, lixisenatide was superior to placebo in mean change from baseline (7.9% [standard deviation; 0.66] and 7.9% [0.70], respectively) to week 24 in HbA1c (least squares mean [standard error] change −0.62% [0.09] vs −0.11 [0.09]; p < 0.0001, respectively) and higher proportions of patients achieved HbA1c targets. 2-hour PPG, daily mean SMPG and body weight were reduced further and daily BI dose was lower with lixisenatide than placebo (–1.12 kg vs 0.04 kg [p < 0.0001]; –3.0 U vs –1.9 U [p = 0.0033], respectively). Treatment-emergent adverse events were greater with lixisenatide than placebo (63.8% vs 40.8%, respectively). The incidence of symptomatic hypoglycaemia was comparable (lixisenatide 15.6% vs placebo 13.5%).ConclusionsIn Asian patients insufficiently controlled on BI ± metformin, lixisenatide was superior versus placebo in glycaemic control, with a tolerability profile in line with other glucagon-like peptide-1 receptor agonists.Clinical trial number: NCT01632163 (
      PubDate: 2017-07-25T10:20:22.694091-05:
      DOI: 10.1111/dom.13072
  • Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel
           dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1
           agonist RG7697 after single subcutaneous administration in healthy
    • Authors: Agnès Portron; Shirin Jadidi, Neena Sarkar, Richard DiMarchi, Christophe Schmitt
      Abstract: AimsTo evaluate the pharmacodynamics, pharmacokinetics and safety of single subcutaneous (s.c.) injection of ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in healthy subjects.MethodsA total of 51 healthy volunteers were enrolled in this double-blind, placebo-controlled study investigating RG7697 doses ranging from 0.03 to 5 mg. Adverse events (AEs) were monitored and drug concentrations, fasting glycaemic variables, vital signs, ECG, antibody formation and routine laboratory variables were assessed. A meal tolerance test (MTT) was performed at the same time on day −1 (baseline) and day 1.ResultsRG7697 was generally well tolerated in healthy participants after s.c. injections up to 3.6 mg. Tolerability was limited by gastrointestinal AEs (nausea and vomiting) at the highest dose. There was a small dose-dependent increase in heart rate. No episodes of hypoglycaemia occurred. RG7697 concentrations peaked at 2 to 4 hours post-dose with a half-life of 19 to 25 hours. During MTT, RG7697 at doses ≥1.8 mg, reduced glucose maximum plasma concentration (Cmax; −46%) without affecting overall glucose area under the curve (AUC). Its effect on insulin was more pronounced, with reductions in both Cmax (−64%) and AUC (−51%). Pharmacodynamic variables were well correlated to RG7697 average plasma concentration during MTT, with IC50 (average concentration required for 50% reduction) values of 49 and 24.5 ng/mL for glucose and insulin, respectively.ConclusionSingle s.c. injections of RG7697 up to 3.6 mg were generally well tolerated. Evidence of glycaemic effect and pharmacokinetic profiles consistent with once-daily dosing render this drug candidate suitable to be further tested in multiple-dose clinical trials in patients with type 2 diabetes.
      PubDate: 2017-07-25T06:41:20.635272-05:
      DOI: 10.1111/dom.13025
  • Glycaemic control and hypoglycaemia in people with type 2 diabetes
           switching from twice-daily basal insulin to once-daily insulin glargine
           300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup
    • Authors: Ronan Roussel; Michael C. d'Emden, Miles Fisher, Francisco Javier Ampudia-Blasco, Peter Stella, Florence Bizet, Anna M.G. Cali, Carol H. Wysham
      Abstract: This post hoc analysis compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla-300) and glargine 100 U/mL (Gla-100) administered once daily (QD) in people with T2DM from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials previously receiving twice-daily (BID) insulin.At randomisation, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving BID basal insulin. HbA1c change from baseline to month 6 was comparable over 6 months with Gla-300 or Gla-100 (LS mean difference −0.01 [95% CI: −0.27 to 0.24] % in EDITION 1 and 0.16 [−0.25 to 0.57] % in EDITION 2). Prior BID participants in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 versus Gla-100 at night (00:00–05:59 h), but not at any time (24 h); in EDITION 2 the risk was reduced at night and any time (24 h).In conclusion, Gla-300 provided comparable glycaemic control with less hypoglycaemia compared with Gla-100 in people with T2DM switching from BID to QD basal insulin.
      PubDate: 2017-07-24T00:15:22.997803-05:
      DOI: 10.1111/dom.13071
  • PCSK9 in context: A contemporary review of an important biological target
           for the prevention and treatment of atherosclerotic cardiovascular disease
    • Authors: Michael M Page; Gerald F Watts
      Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) and the identification of its critical role in lipoprotein metabolism has rapidly led to the development of PCSK9 inhibition with monoclonal antibodies (mAbs). PCSK9 mAbs are already in limited clinical use and are the subject of major cardiovascular outcomes trials, which if universally positive could see much wider clinical application of these agents. Patients with familial hypercholesterolaemia are the most obvious candidates for these drugs, but other patients with elevated cardiovascular risk, statin intolerance or hyperlipoproteinaemia(a) may also benefit. PCSK9 mAbs, administered once or twice monthly, reduce LDL-cholesterol levels by 50 - 70%, and appear to be safe and acceptable to patients over at least two years of treatment. However, treatment-emergent adverse effects are not always identified in clinical trials, as well-evidenced by statin myopathy. Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs but with a much longer duration of action. The cost-effectiveness and long-term safety of therapies targeted at inhibiting PCSK9 remains to be demonstrated if they are to be used widely in coronary prevention.
      PubDate: 2017-07-24T00:00:22.038038-05:
      DOI: 10.1111/dom.13070
  • Evaluation of the specific effects of intranasal glucagon on circulating
           glucose and lipid concentrations in healthy males during a pancreatic
    • Authors: Satya Dash; Changting Xiao, Priska Stahel, Khajag Koulajian, Adria Giacca, Gary F. Lewis
      Abstract: ContextIntravenous/intramuscular glucagon stimulates hepatic glucose production and adipose lipolysis. Intranasal glucagon (ING) has recently been shown to be an effective treatment for hypoglycaemia. Intranasal administration of hormones increases its central nervous system (CNS) concentration with metabolic effects independent of its plasma concentration, potentially via CNS action. Whether ING has metabolic effects independent of plasma glucagon is unknown.ObjectiveTo investigate the specific effects of intranasal glucagon (ING) on plasma glucose, endogenous glucose production (EGP) and lipid concentration.DesignSingle blind, randomized, crossover study.SettingAcademic investigation unit.Intervention1mg ING or intranasal placebo (INP) administered to 10 healthy men, under conditions of a pancreatic clamp with tracer infusion. As pilot studies showed ING transiently increased plasma glucagon, we infused intravenous glucagon for 30 minutes along with INP to ensure similar plasma glucagon concentrations between interventions.Main outcome measurePlasma glucose, EGP, free fatty acid (FFA) and triglyceride (TG) concentrationsResultsIn the presence of similar plasma glucagon concentrations, the increase in plasma glucose under these experimental conditions was attenuated with ING (mean plasma glucose by ANOVA < 0.001) with reduction in EGP (p = 0.027). No significant differences were seen in plasma FFA and triglyceride.ConclusionING raises plasma glucose but this route of administration attenuates the gluco-stimulatory effect of glucagon by reducing EGP. This observation invites speculation about a potential CNS effect of glucagon, which requires further investigation. If ING is developed as a treatment for hypoglycaemia, this attenuated effect on plasma glucose should be taken into account.Clinical trials Registration number ( NCT02740829
      PubDate: 2017-07-20T23:15:28.614263-05:
      DOI: 10.1111/dom.13069
  • Beneficial long-term antidiabetic actions of N- and C-terminally modified
           analogues of apelin-13 in diet-induced obese diabetic mice.
    • Authors: V. Parthsarathy; C. Hogg, P. R. Flatt, F. P. M. O'Harte
      Abstract: AimsThis study investigated the chronic effects of twice daily administration of stable apelin analogues, apelin-13 amide and (pGlu)apelin-13 amide, on metabolic parameters in glucose intolerant and insulin resistant diet-induced obese (DIO) mice fed a high-fat diet for 150 days.Study Design & MethodsGroups of mice received twice daily (09:00 and 17:00 h) injections of saline vehicle, apelin-13 amide, (pGlu)apelin-13 amide or exendin-4(1–39) for 28 days (all at 25 nmol/kg). Energy intake, body weight, non-fasting blood glucose, plasma insulin, glucose tolerance, metabolic response to feeding and insulin sensitivity together with pancreatic hormone content and biochemical parameters such as lipids and total GLP-1 were monitored. Dual-energy X-ray absorptiometry (DXA) analysis and indirect calorimetry were also performed.ResultsAdministration of apelin-13 amide, (pGlu)apelin-13 amide or exendin-4 significantly decreased bodyweight, food intake, blood glucose and increased plasma insulin compared with high-fat fed saline treated controls (P 
      PubDate: 2017-07-20T22:50:27.399288-05:
      DOI: 10.1111/dom.13068
  • Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses
           of the novel dual glucose-dependent insulinotropic
           polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2
           diabetes mellitus
    • Authors: Christophe Schmitt; Agnès Portron, Shirin Jadidi, Neena Sarkar, Richard DiMarchi
      Abstract: AimsTo investigate the pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in patients with type 2 diabetes mellitus (T2D).MethodsA total of 56 patients with T2D received once-daily subcutaneous (s.c.) injection of RG7697 (0.25-2.5 mg) or placebo for 14 days in a randomized, double-blind, dose-escalation study. Adverse events (AEs), vital signs, ECGs and routine laboratory variables were intensively monitored. Drug concentrations, fasting glycaemic variables, 24-hour glucose profiles, glycated haemoglobin (HbA1c) and antibody formation were measured. Several meal tolerance and gastric emptying tests were performed during the study.ResultsDaily s.c. injections of RG7697 were well tolerated by the majority of participants with T2D. The most frequently reported AEs with RG7697 were diarrhoea, nausea and decreased appetite. Asymptomatic events of hypoglycaemia were relatively uniformly distributed across dose groups including placebo. Pharmacokinetic steady-state was achieved within 1 week. Meaningful reductions in fasting, postprandial and 24-hour plasma glucose profile were observed at doses ≥0.75 mg, and were associated with numerical decreases in HbA1c (−0.67% [2.5-mg dose] vs −0.21% [placebo]). Decrease in postprandial insulin at doses ≥1.1 mg suggested improvement in insulin sensitivity. Minimum delay in gastric emptying and body weight reductions numerically greater than placebo (− 3.0 kg vs −0.9 kg) were seen at the highest dose of 2.5 mg.ConclusionsDaily doses of RG7697 for 2 weeks were well tolerated by the majority of patients with T2D. Pharmacokinetic data supported once-daily dosing and pharmacodynamic effect displayed dose-dependent reductions in fasting and postprandial plasma glucose, without increasing the risk of hypoglycaemia.
      PubDate: 2017-07-20T21:55:39.832146-05:
      DOI: 10.1111/dom.13024
  • Improving Type 2 Diabetes Mellitus glycaemic outcomes is possible without
           spending more on medication: Lessons from the UK National Diabetes Audit
    • Authors: Adrian H Heald; Mark Livingston, Nagaraj Malipatil, Michal Becher, Joyce Craig, Mike Stedman, Anthony A Fryer
      Abstract: ObjectivesThere is continuing discussion globally about how to optimise outcomes for type 2 diabetes (T2DM) patients. In the UK, national (NICE) guidance was updated in 2016 (NG28). We aimed to determine the factors at a GP practice level that relate to glycaemic control outcome.MethodsData was accessed from 4,050 GP practices (GPP) (50% of total) covering 1.6 million T2DM patients in the UK National Diabetes Audit 2013–14 and 2014–15. This reported T2DM population characteristics, services and outcomes, including % total glycaemic control (TGC) (at 67.2%; HbA1c results ≤58 mmol/mol) and % higher glycemic risk (HGR) (at 6.2%; HbA1c results>86 mmol/mol). The medication data were examined as annual Defined Daily Doses (DDD). Multi-variant linear regression analysis was used to identify associations between DDD and patient and practice characteristics.ResultsOver the period 2012/13–2015/16, patient numbers grew 4% annually and annual medication expenditure by 8% but glycaemic control outcomes did not improve.The main findings are that practices with better outcomes:Had higher percentage of patients aged over 65 years.Provided more effective diabetes services (including case identification, care checks, patient education, percentage of patients with blood pressure (BP) and cholesterol under control and more T1DM patients with HbA1c on target).Spend overall less on prescribing per T2DM patient.On average, prescribed:Less sulphonylureasLess insulin (for T2DM patients)Less glucagon-like peptide-1 agonists (GLP-1 agonists)More metforminMore dipeptidyl peptidase-4 inhibitors (DPP4i)More blood glucose monitoring stripsEthnicity and social disadvantage and levels of Thiazolidinediones (TZD/glitazones) prescribing had no significant impact on outcomes. Sodium-glucose co-transporter-2 (SGLT-2) inhibitor use was too small to see an effect in the period examined.ConclusionsIf all GPPs could provide service levels and medication mix similar to that provided by the top decile of practices this could, without raising spend on medication, increase the proportion of T2DM patients achieving TGC to 75.4% or 213,000 (11% of expected total TGC patients), and reduce T2DM patients at HGR to 3.8% or 63,000 (48% of expected total TGC patients) in the total T2DM population. This could have a major impact on the overall consequent healthcare costs of managing diabetes complications with attendant mortality risks.
      PubDate: 2017-07-20T21:20:45.136636-05:
      DOI: 10.1111/dom.13067
  • Development of a Cardiovascular Diseases Risk Prediction Model and Tools
           for Chinese Patients with Type 2 Diabetes Mellitus – A Population-based
           Retrospective Cohort Study
    • Authors: Eric Yuk Fai Wan; Daniel Yee Tak Fong, Colman Siu Cheung Fung, Esther Yee Tak Yu, Weng Yee Chin, Anca Ka Chun Chan, Cindy Lo Kuen Lam
      Abstract: AimsEvidence-based cardiovascular diseases(CVD) risk prediction models and tools specific for Chinese patients with type 2 diabetes mellitus(T2DM) are currently unavailable. This study aimed to develop and validate a CVD risk prediction model for Chinese T2DM patients.Materials and MethodsA retrospective cohort study was conducted on 137 935 Chinese patients aged 18-79 years with T2DM and without prior history of CVD, who had received public primary care services between 1 January 2010 and 31 December 2010. Using the derivation cohort over a median follow-up of 5 years, the interaction effect between predictors and age were derived using Cox proportional hazards regression with a forward stepwise approach. Harrell's C-statistic and calibration plot were used on the validation cohort to assess the discrimination and calibration of the models. The web calculator and chart were developed based on the developed models.ResultsAmongst both genders, predictors for higher risk of CVD were older age, smoking, longer diabetes duration, usage of anti-hypertensive drug and insulin, higher body mass index, haemoglobin A1c(HbA1c), systolic and diastolic blood pressure, total cholesterol to high-density lipoprotein-cholesterol(TC/HDL-C) ratio and urine albumin to creatinine ratio, and lower estimated glomerular filtration rate. Interaction factors with age demonstrated a greater weighting of TC/HDL-C ratio in both younger females and males, and smoking status and HbA1c in younger males.ConclusionsThe developed models, translated into a web calculator and color-coded chart, served as evidence-based visual aids that facilitate clinicians to quickly estimate the 5-year CVD risk for Chinese T2DM patients and guide intervention.
      PubDate: 2017-07-19T00:05:21.880386-05:
      DOI: 10.1111/dom.13066
  • Beyond glycemic control: a cross-over, double-blind, 24 week intervention
           with liraglutide in type 1 diabetes
    • Authors: M.-C. Dubé; M. D'Amours, S. J. Weisnagel
      Abstract: AimsTo investigate the effects of 24 weeks of treatment with liraglutide added to basal/bolus insulin on anthropometric and metabolic parameters in overweight participants with type 1 diabetes.MethodsIn a double-blind cross-over fashion, 15 participants were randomly assigned (1:1) to receive placebo (saline solution) or liraglutide for 24 weeks including a one-month titration period from 0.6 mg to 1.2 mg to 1.8 mg, in addition to their insulin. The treatment was followed by a 1 month wash-out period. Participants were then assigned to the other treatment for another 24 weeks. Paired rank tests were used to compare the metabolic parameters.ResultsThere was no treatment effect on HbA1c nor on insulin dose. Heart rate was increased by about 8 bpm with liraglutide. There were significant reductions in metabolic measures: weight, BMI, waist and hip circumferences, body fatness, CT-scan abdominal and midthigh measurements, systolic and diastolic blood pressure (BP) (all P ≤ 0.05). There was no increase in time spent in hypoglycemia with liraglutide.ConclusionsThe addition of liraglutide to basal/bolus insulin therapy for 24 weeks in overweight/obese individuals with type 1 diabetes improved the anthropometric and metabolic profiles without an increase in hypoglycemia.Clinical No: NCT01787916
      PubDate: 2017-07-18T23:55:20.612658-05:
      DOI: 10.1111/dom.13063
  • Therapeutic application of GPR119 ligands in metabolic disorders
    • Authors: Jin Won Yang; Hyo Seon Kim, Yong-Won Choi, Young-Mi Kim, Keon Wook Kang
      Abstract: GPR119 belongs to the G protein-coupled receptor family, and exhibits dual modes of action upon ligand-dependent activation: pancreatic secretion of insulin in a glucose-dependent manner, and intestinal secretion of incretins. Hence, GPR119 has emerged as a promising target for treating type 2 diabetes mellitus without causing hypoglycemia. However, despite continuous efforts by many major pharmaceutical companies, no synthetic GPR119 ligand has been approved as a new class of anti-diabetic agents thus far, nor has one passed beyond phase II clinical studies. Herein, we summarize recent advances in research about the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and speculate about future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease.
      PubDate: 2017-07-18T23:50:26.111398-05:
      DOI: 10.1111/dom.13062
  • The impact of exercise on sleep in adults with type 1 diabetes
    • Authors: Ravi Reddy; Joseph El Youssef, Kerri Winters-Stone, Deborah Branigan, Joseph Leitschuh, Jessica Castle, Peter G. Jacobs
      Abstract: The aim of this pilot study was to investigate the impact of exercise on sleep and nocturnal hypoglycemia in adults with type 1 diabetes (T1D). In a 3-week crossover trial, 10 adults with T1D were randomized to perform aerobic, resistance or no exercise. During each exercise week, participants completed two separate 45-minute exercise sessions at an academic medical center. Participants returned home and wore a continuous glucose monitor and a wrist based activity monitor to estimate sleep duration.Participants on average lost 70 (±49) minutes of sleep (p = 0.0015) on nights following aerobic exercise and 27 (±78) minutes (p=0.3) following resistance exercise relative to control nights. The odds ratio with confidence intervals of nocturnal hypoglycemia occurring on nights following aerobic and resistance exercise was 5.4 [1.3, 27.2] and 7.0 [1.7, 37.3], respectively.Aerobic exercise can cause sleep loss in T1D possibly from increased hypoglycemia.
      PubDate: 2017-07-18T07:25:25.740834-05:
      DOI: 10.1111/dom.13065
  • Insights into optimal basal insulin titration in type 2 diabetes: results
           of a quantitative survey
    • Authors: Lori Berard; Mireille Bonnemaire, Marie Mical, Steve Edelman
      Abstract: AimsBasal insulin (BI) treatment initiation and dose titration in type 2 diabetes (T2DM) are often delayed. Such “clinical inertia” results in poor glycemic control and high risk of long-term complications. This survey aimed to determine healthcare professional (HCP) and patient attitudes to BI initiation and titration.MethodsAn online survey (July–August 2015) including HCPs and patients with T2DM in the USA, France and Germany. Patients were ≥18 years old and had been on BI for 6–36 months, or discontinued BI within the previous 12 months.ResultsParticipants comprised 386 HCPs and 318 people with T2DM. While>75% of HCPs reported discussing titration at the initiation visit, only 16–28% of patients remembered such discussions, many (32–42%) were unaware of the need to titrate BI, and only 28–39% recalled mention of the time needed to reach glycemic goals. Most HCPs and patients agreed that more effective support tools to assist BI initiation/titration are needed; patients indicated that provision of such tools would increase confidence in self-titration. HCPs identified fear of hypoglycemia, failure to titrate in the absence of symptoms, and low patient motivation as important titration barriers. In contrast, patients identified weight gain, the perception that titration meant worsening disease, frustration over the time to reach HbA1c goals and fear of hypoglycemia as major factors.ConclusionA disconnect exists between HCP- and patient-perceived barriers to effective BI titration. To optimize titration, strategies should be targeted to improve HCP–patient communication, and provide support and educational tools.
      PubDate: 2017-07-18T07:02:35.080129-05:
      DOI: 10.1111/dom.13064
  • Luseogliflozin improves liver fat deposition compared to metformin in type
           2 diabetes patients with non-alcoholic fatty liver disease: A prospective
           randomized controlled pilot study
    • Authors: Takashi Shibuya; Nobutoshi Fushimi, Miyuka Kawai, Yohei Yoshida, Hiroki Hachiya, Shun Ito, Hiromi Kawai, Noritsugu Ohashi, Akihiro Mori
      Abstract: Non-alcoholic fatty liver disease (NAFLD) often coexists with type 2 diabetes (T2D), and its prevalence in patients with T2D is estimated to be approximately 50%–60% in Japan.1 In some patients with T2D, NAFLD can progress to non-alcoholic steatohepatitis (NASH) and further to liver cirrhosis and hepatocellular carcinoma (HCC).2 Moreover, NAFLD is considered an independent risk factor for cardiovascular events.3
      PubDate: 2017-07-18T04:00:21.311109-05:
      DOI: 10.1111/dom.13061
  • Comparative efficacy and safety of gemigliptin versus linagliptin in type
           2 diabetes patients with renal impairment: A 40-week extension of the
           GUARD randomized study
    • Authors: Sang Youb Han; Sun Ae Yoon, Byoung Geun Han, Sung Gyun Kim, Young-Il Jo, Kyung Hwan Jeong, Kook-Hwan Oh, Hyeong Cheon Park, Sun-Hee Park, Shin-Wook Kang, Ki-Ryang Na, Sun Woo Kang, Nam-Ho Kim, Younghwan Jang, Bogyeong Kim, Seonghye Shin, Dae Ryong Cha
      Abstract: AimsThe present extension study evaluated the long-term safety and efficacy of gemigliptin during a 40-week follow-up period after a 12-week study.MethodsThe main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) with moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7-11% and an estimated glomerular filtration rate (eGFR) of 15–59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, the patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas the patients in the placebo group were transitioned from placebo to linagliptin (N = 52). Each group received the indicated treatment over the subsequent 40-week period. A total of 102 patients consented to participate in the extension study, and 79 patients ultimately completed the study.ResultsThe HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change ± standard error in the HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00 ± 0.21% and 0.65 ± 0.22% lower at week 52 than at baseline (P 
      PubDate: 2017-07-18T03:00:38.831402-05:
      DOI: 10.1111/dom.13059
  • Walnut consumption increases activation of the insula to highly desirable
           food cues: A randomized, double-blind, placebo-controlled, cross-over fMRI
    • Authors: Olivia M. Farr; Dario Tuccinardi, Jagriti Upadhyay, Sabrina M. Oussaada, Christos S. Mantzoros
      Abstract: AimsThe use of walnuts is recommended for obesity and type 2 diabetes, although the mechanisms through which walnuts may improve appetite and/or glycemic control remain largely unknown.Materials and MethodsTo determine whether short-term walnut consumption could alter the neural control of appetite using functional magnetic resonance imaging, we performed a randomized, placebo-controlled, double-blind, cross-over trial of 10 patients who received, while living in the controlled environment of a clinical research center, either walnuts or placebo (using a validated smoothie delivery system) for 5 days each, separated by a wash-out period of one month.ResultsWalnut consumption decreased feelings of hunger and appetite assessed using visual analog scales and increased the activation of the right insula to highly desirable food cues.ConclusionsThese findings suggest that walnut consumption may increase salience and cognitive control processing of highly desirable food cues, leading to the beneficial metabolic effects NCT02673281
      PubDate: 2017-07-17T10:55:20.572442-05:
      DOI: 10.1111/dom.13060
  • Does SGLT2-inhibition with dapagliflozin overcome individual therapy
           resistance to RAAS inhibition'
    • Authors: Sergei Petrykiv; Goos Laverman, Dick de Zeeuw, Hiddo J.L. Heerspink
      Abstract: AimsIndividual patients show a large variation in their response to renin-angiotensin-aldosteron-system blockade both in surrogates like albuminuria and hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer cardiovascular and possibly renal protection. To establish whether individual therapy resistance to RAASi can be overcome by adding an SGLT2 inhibitor we assessed individual albuminuria responses in patients exposed both to RAASi and the SGLT2 inhibitor dapagliflozin.Materials and MethodsWe used data from a randomized controlled cross-over trial designed to assess the albuminuria lowering effect of 6-weeks treatment with dapagliflozin 10 mg/d. We extracted from the electronic medical records data on the albuminuria response upon start of RAASi before the trial period, and analyzed the individual albuminuria response to RAASi and to dapagliflozin.ResultsWe retrieved data on RAASi use from 26 patients (age 62 (SD 8); female gender 6 (23%); 24-hour urinary albumin excretion 521 [187 – 921] mg/24hr. The mean albuminuria lowering response to RAASi was 26.5% (range -76.1 to +135.1%). The addition of dapagliflozin resulted in a further reduction of 34.9%, (range -83.9 to +94.2). Interestingly, the albuminuria response to RAASi significantly correlated with response to dapagliflozin (Pearson correlation coefficient 0.635 (95%CI 0.328 to 0.821); p
      PubDate: 2017-07-07T07:25:20.484242-05:
      DOI: 10.1111/dom.13057
  • Efficacy and tolerability of the new autoinjected suspension of exenatide
    • Authors: Carol H. Wysham; Julio Rosenstock, Marion L. Vetter, Fang Dong, Peter Öhman, Nayyar Iqbal
      Abstract: AimsTo simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol® diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID).Materials and methodsThis randomized, open-label, controlled study in patients with type 2 diabetes on diet and exercise or stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28-week change in glycated hemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments.ResultsA total of 375 patients (mean HbA1c: 8.5% [69 mmol/mol]; body mass index: 33.2 kg/m2; diabetes duration: 8.5 years) received either exenatide QWS-AI (n=229) or exenatide BID (n=146); HbA1c was reduced by −1.4% and −1.0%, respectively (least-squares mean difference: −0.37%; p=0.0072). More patients achieved HbA1c
      PubDate: 2017-07-07T07:15:24.643104-05:
      DOI: 10.1111/dom.13056
  • Apelin administration improves insulin sensitivity in overweight men
           during an hyperinsulinemic euglycemic clamp
    • Authors: Pierre Gourdy; Laurent Cazals, Claire Thalamas, Agnès Sommet, Fabienne Calvas, Monique Galitzky, Claire Vinel, Cédric Dray, Hélène Hanaire, Isabelle Castan-Laurell, Philippe Valet
      Abstract: AimsApelin is a recently identified adipokine known to improve glucose tolerance and insulin sensitivity in murine models. This study was dedicated to the proof of concept that apelin administration also enhances insulin sensitivity in humans.Materials and methodsHealthy overweight men were enrolled in this randomized, double-blind, placebo-controlled, cross-over study that successively considered the efficacy and the tolerance of two doses of (pyr1)-Apelin-13. A first group of subjects received 9 nmol/kg (n=8) of (pyr1)-Apelin-13 and, after examination of safety data, a second group received 30 nmol/kg (n=8). Each volunteer underwent two hyperinsulinemic-euglycemic clamps where the basal level of glucose infusion rate (GIR) was measured from the 90th to the 120th minutes (level 1). Apelin or placebo continuous i.v. administration was then started for 2 hours and GIR was finally evaluated from the 210th to the 240th minutes (level 2). Primary evaluation endpoint was the difference in GIR between level 2 and level 1 (ΔGIR).ResultsA slight increase in ΔGIR was observed with the low apelin dose (+0.65 ± 0.71 mg/kg/min, p=0.055) whereas the highest dose significantly improved insulin sensitivity (+0.82 ± 0.71 mg/kg/min, p=0.033). Cardiovascular monitoring and safety reports did not reveal any side effect of apelin administration.ConclusionAs the first demonstration of the insulin sensitizing action of apelin in humans alongside numerous rodent studies, this trial confirms that the apelin/APJ pathway should be considered as a new target to design alternative therapeutic strategies to control insulin resistance in type 2 diabetic patients.
      PubDate: 2017-07-06T04:55:28.969781-05:
      DOI: 10.1111/dom.13055
  • Metformin-associated prevention of weight gain in insulin-treated type 2
           diabetic patients cannot be explained by decreased energy intake: A Post
           hoc Analysis of a Randomized Placebo-Controlled 4.3 year Trial.
    • Authors: Mattijs Out; Ida Miedema, Harriët Jager-Wittenaar, Cees van der Schans, Wim Krijnen, Philippe Lehert, Coen Stehouwer, Adriaan Kooy
      Abstract: Metformin prevents weight gain in patients with type 2 diabetes (T2D). However, the mechanisms involved are still unknown. In this post-hoc analysis of the HOME trial, we aimed to determine whether metformin affects energy intake. Patients with T2D were treated with 850 mg metformin or placebo (1-3 times daily) added to insulin for 4.3 years. Dietary intake was assessed at baseline, after 1 year and after 4.3 years, according to the dietary history method. Of the 310 included participants, 179 completed (93 placebo, 86 metformin) all three dietary assessments. We found no significant difference in energy intake after 4.3 years between the groups (metformin vs placebo: -31.0 kcal/day; 95% CI -107.4 to +45.4; F-value 1.3, df=415, p=0.27). Body weight in placebo-users increased significantly more than in metformin-users during 4.3 years (4.9± 4.9 vs 1.1±5.2kg; t-test: p≤0.001).Linear mixed models did not show a significant effect of energy intake as explanation for the difference in weight gain between the groups (F-value 0.1, df=1, p=0.82). In conclusion, the prevention from weight gain by metformin cannot be explained by reduced energy intake.
      PubDate: 2017-07-06T04:35:18.424343-05:
      DOI: 10.1111/dom.13054
  • Effect of Liraglutide on Ectopic Fat in Polycystic Ovary Syndrome: A
           Randomized Clinical Trial
    • Authors: Signe Frøssing; Malin Nylander, Elizaveta Chabanova, Jan Frystyk, Jens Juul Holst, Caroline Kistorp, Sven O. Skouby, Jens Faber
      Abstract: Women with polycystic ovary syndrome (PCOS) were treated with the GLP-1 receptor agonist liraglutide to investigate the effect on liver fat content, visceral adipose tissue (VAT), and the prevalence of nonalcoholic fatty liver disease (NAFLD).In a double-blind, placebo-controlled, randomized clinical trial 72 women with PCOS and BMI>25 kg/m2 and/or insulin resistance were treated with liraglutide or placebo 1.8 mg/day (2:1) for 26 weeks. Liver fat content was assessed by 1HMR spectroscopy, VAT by MRI, body composition by DXA, and glucose metabolism by oral glucose tolerance test.Compared with placebo, liraglutide treatment reduced body weight by 5.2 kg (5.6%), liver fat content by 44%, VAT by 18%, and the prevalence of NAFLD with two-thirds (all p
      PubDate: 2017-07-06T04:05:19.628835-05:
      DOI: 10.1111/dom.13053
  • The challenges of Achieving Postprandial Glucose Control using Closed-Loop
           Systems in Patients with Type 1 Diabetes
    • Authors: Véronique Gingras; Nadine Taleb, Amélie Roy-Fleming, Laurent Legault, Rémi Rabasa-Lhoret
      Abstract: For patients with type 1 diabetes, closed-loop delivery systems (CLS) combining an insulin pump, a glucose sensor and a dosing algorithm allowing a dynamic hormonal infusion have been shown to improve glucose control when compared to conventional therapy. Yet, reducing glucose excursion as well as simplification of prandial insulin doses remains a challenge. The objective of this literature review is to examine current meal-time strategies in the context of automated delivery systems in adults and children with type 1 diabetes. Current challenges and considerations for post-meal glucose control will also be discussed. Despite promising results with meal detection, the fully automated CLS has yet failed to provide comparable glucose control to CLS with CHO-matched bolus in the post-meal period. The latter strategy has been efficient to control post-meal glucose control using different algorithms and in various settings; yet, at the cost of meal carbohydrate counting burden for patients. Further improvements in meal detection algorithms or simplified meal priming boluses may represent interesting avenues. The greatest challenges remain in regards to the pharmacokinetic and –dynamic profiles of available rapid insulins as well as sensor accuracy and lag-time. New and upcoming faster acting insulins could provide important benefits. Multi-hormone CLS (e.g. dual-hormone combining insulin with glucagon or pramlintide) and adjunctive therapy (e.g. GLP-1 and SGLT2 inhibitors) also represent promising options. Meal glucose control with the artificial pancreas remains an important challenge for which the optimal strategy is still to be determined.
      PubDate: 2017-07-04T10:40:20.122554-05:
      DOI: 10.1111/dom.13052
  • Glycaemic outcomes of an Individualised treatMent aPproach for oldER
           vulnerable patIents: A randomised, controlled stUdy in type 2 diabetes
           Mellitus (IMPERIUM)
    • Authors: Simon R. Heller; Richard E. Pratley, Alan Sinclair, Andreas Festa, Jacek Kiljanski, Cynthia S. Brusko, Ran Duan, Robert J. Heine
      Abstract: AimTo compare the glycaemic outcomes of 2 glucose-lowering treatment strategies in vulnerable (moderately ill and/or frail) patients aged ≥65 years with type 2 diabetes whose individual HbA1c targets were not met with diet/exercise and/or oral antihyperglycaemic medications (OAMs).MethodsThe primary endpoint of this study was a composite of achieving/maintaining individualised HbA1c targets without ‘clinically significant’ hypoglycaemia (severe hypoglycaemia or repeated hypoglycaemia causing interruption of patients’ activities or blood glucose
      PubDate: 2017-07-03T08:55:21.325291-05:
      DOI: 10.1111/dom.13051
  • Body fat distribution is more predictive of all-cause mortality than
           overall adiposity
    • Authors: Sung Woo Lee; Jee Young Son, Jeong Min Kim, Seung-sik Hwang, Jin Suk Han, Nam Ju Heo
      Abstract: AimsThe relationship between directly measured body fat and all-cause mortality has been rarely studied. The aim of this study was to evaluate the predictive significance of computed tomography (CT)-measured body fat, including both visceral fat area (VFA) and subcutaneous fat area (SFA), for mortality.MethodsThe study included 36,656 participants who underwent abdominal CT as part of a health check-up at a single university-affiliated healthcare centre in 2007–2015. Of those, 32,593 participants with data regarding vital status as of May 2016 were included in the final analysis. The main factors evaluated were VFA, SFA and visceral-to-subcutaneous fat area ratio (VSR), and the primary outcome was all-cause mortality.ResultsThere were 253 deaths during a mean follow-up of 5.7 years. Increased SFA was associated with decreased all-cause mortality, whereas an increased VFA and VSR were related to increased all-cause mortality. Compared with the predictive power of body mass index (BMI), SFA and VSR showed a larger area under the curve than did BMI. In Kaplan-Meier survival curve analysis, increased SFA and VSR were associated with decreased and increased hazard of all-cause death, respectively. However, in multivariate Cox proportional hazard regression analysis, only VSR was independently associated with all-cause mortality. Moreover, this relationship was paralleled by the harmful impact of increased VSR on metabolic profiles.ConclusionsIncreased VSR was an independent predictor of all-cause mortality. This suggests that the location of fat deposits may be more important than the actual amount of body fat.
      PubDate: 2017-07-03T08:50:21.449688-05:
      DOI: 10.1111/dom.13050
  • Comparative Safety of Pioglitazone versus Clinically Meaningful Treatment
           Alternatives on the Risk of Bladder Cancer in Older US Adults with Type 2
    • Authors: Elizabeth M. Garry; John B. Buse, Jennifer L. Lund, Virginia Pate, Til Stürmer
      Abstract: AimsCompare bladder cancer incidence between patients initiating pioglitazone and patients initiating dipeptidyl-peptidase-4 inhibitors [DPP-4 s] or sulfonylureas.MethodsWe identified Medicare beneficiaries aged>65 initiating pioglitazone (N = 38,700), DPP-4 s (N = 82,552), or sulfonylureas (N = 126,104) 2007–2014 after at least 6 months without prescriptions for these drug classes. Patients were followed from second prescription until bladder cancer outcome (2 claims within 60 days) using a 6-month induction/latency period, censoring for treatment change, death, or end of 2014. We used propensity score weighted Cox proportional-hazards models to obtain adjusted hazard ratios (aHR) and their 95% confidence intervals.ResultsOverall mean age was 75 and 41% were men. Over a median of 1.2 treatment years, 727 beneficiaries developed bladder cancer. Pioglitazone initiators had an increased bladder cancer incidence (308 vs 204 (DPP-4 s) or 231 (sulfonylureas) per 100,000 person-years; aHR = 1.57 [1.23-2.00]) vs DPP-4 s and 1.32 [1.02-1.70] vs sulfonylureas. The increased risk emerged within the first 2 years of treatment (aHR = 1.63 [1.22-2.17] vs DPP-4 s and 1.32 [0.98-1.78] vs sulfonylureas). If treatment was stopped within the first 2 years, the risk after 2 years post-initiation was attenuated (aHR = 0.89 [0.61-1.28]) compared with patients treated for more than 2 years (aHR = 1.45 [0.93-2.26], both vs DPP-4 s). Findings were consistent across secondary and sensitivity analyses.ConclusionsPioglitazone was associated with an elevated bladder cancer risk compared with DPP-4 s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after stopping. Pioglitazone's relative effectiveness should be weighed against a small absolute increase in bladder cancer risk.
      PubDate: 2017-06-29T10:45:20.181058-05:
      DOI: 10.1111/dom.13049
  • Glycaemic control and hypoglycaemia during 12 months of randomized
           treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in
           people with type 1 diabetes (EDITION 4)
    • Authors: Philip D Home; Richard M Bergenstal, Geremia B Bolli, Monika Ziemen, Maria Rojeski, Melanie Espinasse, Matthew C Riddle
      Abstract: AimsInsulin glargine 300 U/mL (Gla-300) offers a flatter pharmacodynamic profile than insulin glargine 100 U/mL (Gla-100). We have compared these insulins over 1 year in people with type 1 diabetes (T1DM).MethodsEDITION 4 was a 6-month, multicentre, randomized, open-label phase 3 study. People with T1DM completing the 6 months continued their randomized Gla-300 or Gla-100 once daily, morning or evening, for a further 6 months.ResultsOf 549 participants randomized, 444 completed the 12-month study period (Gla-300, 80%; Gla-100, 82%). Mean HbA1c decreased similarly from baseline to month 12 in the two treatment groups (difference 0.02 [95% CI: −0.13 to 0.17]) %-units [0.2 (−1.5 to 1.9) mmol/mol]), to a mean of 7.86 % (62.4 mmol/mol) in both groups. For morning versus evening injection, there was no difference in HbA1c change over 12 months for Gla-100, but a significantly larger decrease in HbA1c was observed in the Gla-300 morning than the Gla-300 evening group (difference: −0.25 [−0.47 to −0.04] %-units [−2.7 (−5.2 to −0.4) mmol/mol]). Mean glucose from the 8-point SMPG profiles decreased from baseline, and was similar between the two treatment groups. Basal insulin dose was 20% higher with Gla-300 than Gla-100, while hypoglycaemia event rates, analysed at night, over 24 hours, or according to different glycaemic thresholds, did not differ between treatment groups, regardless of injection time. Adverse event profiles did not differ between groups.ConclusionsIn T1DM, Gla-300 provides comparable glucose control to Gla-100, and can be given at any time of day.Clinical trial registration: NCT01683266,
      PubDate: 2017-06-29T10:20:26.153771-05:
      DOI: 10.1111/dom.13048
  • Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus
           dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in
           patients with type 2 diabetes mellitus: a systematic review and
    • Authors: Zhiying Wang; Jiahui Sun, Ruobing Han, Dongzhu Fan, Xinyi Dong, Zenghui Luan, Rongwu Xiang, Mingyi Zhao, Jingyu Yang
      Abstract: AimsTo compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) as monotherapy or add-on to metformin (Met) in patients with type 2 diabetes mellitus (T2DM).Materials and MethodsPubMed, Embase, and were systematically searched for randomized controlled trials to assess the efficacy and safety of DPP-4is and SGLT-2is in patients with T2DM. Risk ratio (RR) and weighted mean difference (WMD) were used to evaluate the outcomes.ResultsIn the analysis of 25 randomized trials, which involved 14619 patients, SGLT-2is were associated with a significantly stronger reduction in hemoglobin A1c (HbA1c) [WMD 0.13%, 95% credible interval (CI) 0.04 to 0.22%, p = 0.005] and fasting plasma glucose (FPG) (WMD 0.80 mmol/L, 95% CI 0.58 to 1.01 mmol/L, p 
      PubDate: 2017-06-28T02:55:19.198745-05:
      DOI: 10.1111/dom.13047
  • Interaction between variants in the CYP2C9 and POR genes and the risk of
           sulfonylurea-induced hypoglycaemia: A GoDARTS Study
    • Authors: Tanja Dujic; Kaixin Zhou, Louise A. Donnelly, Graham Leese, Colin N.A. Palmer, Ewan R. Pearson
      Abstract: Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)-induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes, on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1,770 patients were included in the analysis of SU efficacy assessed as the combined outcome of the HbA1c reduction and prescribed SU daily dose. Sixty nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR=2.81, 95%CI 1.30-6.09, P=0.009) and better response to SU treatment (β = −0.218, SE=0.074, P=0.003) only in patients carrying POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.
      PubDate: 2017-06-28T02:25:33.51849-05:0
      DOI: 10.1111/dom.13046
  • Therapeutic Inertia in Patients Treated With Two or More Antidiabetics in
           Primary Care: Factors Predicting Intensification of Treatment
    • Authors: Manel Mata-cases; Josep Franch-Nadal, Jordi Real, Mònica Gratacòs, Flora López-Simarro, Kamlesh Khunti, Dídac Mauricio
      Abstract: AimsTo determine the patterns and predictors of treatment intensification in patients with type 2 diabetes on ≥2 non-insulin antidiabetic drugs (NIADs) and inadequate glycemic control in primary care in Catalonia, Spain.Material and MethodsRetrospective analysis using electronic medical records from patients with HbA1c ≥7% and a first prescription for a new NIAD or insulin recorded from January 2010 to December 2014. Therapeutic inertia was defined as no intensification if HbA1c ≥8% at baseline or during follow-up. Time to first intensification was evaluated by time-to-event analysis, and factors predicting intensification through a competing-risk regression model.ResultsAmong 23,678 patients with HbA1c ≥7%, 26.2% were censored without treatment intensification after a median follow up of 4.2 years. Out of the 12,730 patients in the subgroup with HbA1c ≥8% at baseline or during follow-up, therapeutic inertia was present in 18.1% of cases. In the overall cohort, the mean HbA1c at initiation of insulin and NIAD were 9.4% ± 1.5 and 8.7% ± 1.3, respectively. The median time to first intensification was 17.1 months in patients with HbA1c 8.0-9.9%, and 10.1 months in those with HbA1c>10%. Variables strongly associated with intensification were HbA1c values 8.0-9.9% (subhazard ratio [SHR] 1.7; 95%CI: 1.65-1.78) and>10% (SHR 2.5; 95%CI: 2.37-2.68); diabetes duration ≥20 years (SHR 1.25; 95CI: 1.11-1.41), and to a lesser extent female gender, presence of comorbidities, chronic kidney disease, and microvascular complications.ConclusionsLack of intensification was present in 1 in 5 patients. Both the HbA1c thresholds and the time until therapy intensification exceeded current recommendations.
      PubDate: 2017-06-28T01:50:50.207138-05:
      DOI: 10.1111/dom.13045
  • Red wine polyphenols do not improve obesity associated insulin-resistance:
           a randomized controlled trial
    • Authors: Jorn Woerdeman; Daniele Del Rio, Luca Calani, Etto C. Eringa, Yvo. M. Smulders, Erik H. Serné
      Abstract: Preclinical studies have suggested that polyphenols extracted from red wine (RWPs) favorably affect insulin sensitivity, but controversy exists on whether RWPs exert similar effects in humans. This study aimed to determine whether RWPs improve insulin sensitivity in obese volunteers. Obese (BMI>30) volunteers were randomly allocated to RWPs 600 mg/day (n = 14) or matched placebo (n = 15) in a double-blind fashion (parallel-arm) for 8 weeks. Subjects were investigated at baseline and at the end of the study (EOS). Insulin sensitivity was determined using a hyperinsulinemic-euglycemic clamp (M-value), a mixed-meal test (Matsuda index), and homeostatic model assessment of insulin resistance (HOMA-ir). RWPs elicited no significant changes in M-value (RWPs: baseline: 3.0 [2.4;3.6] (median [interquartile range]); EOS: 3.3 [2.4;4.8] vs. placebo: baseline: 3.4 [2.8;4.4]; EOS: 2.9 [2.8;5.9] mg/kg/min; p = 0.65), in Matsuda index: (RWPs: baseline: 3.3 [2.2;4.8];EOS: 3.6 [2.4;4.8] vs. placebo: baseline: 4.0 [3.0;6.0]; EOS: 4.0 [3.0;5.2]; p = 0.88), or in HOMA-ir. This study shows that eight weeks of RWPs supplementation did not improve insulin sensitivity in 29 obese volunteers. Our findings are not consistent with the hypothesis that RWPs ameliorate insulin resistance in human obesity. (NCT01518764)
      PubDate: 2017-06-23T03:55:18.314237-05:
      DOI: 10.1111/dom.13044
  • IDegLira was effective across a range of dysglycaemia and BMI categories
           in the DUAL V randomized trial
    • Authors: Ildiko Lingvay; Stewart Harris, Elmar Jaeckel, Keval Chandarana, Mattis F Ranthe, Esteban Jódar
      Abstract: This study assessed the efficacy of insulin degludec/liraglutide (IDegLira) versus insulin glargine U100 (IGlar) across categories of baseline HbA1c (≤7.5%,>7.5– ≤ 8.5% and>8.5%), body mass index (BMI;
      PubDate: 2017-06-23T03:21:21.250713-05:
      DOI: 10.1111/dom.13043
  • Bimagrumab improves body composition and insulin sensitivity in
           insulin-resistant subjects
    • Authors: Tania Garito; Ronenn Roubenoff, Marcus Hompesch, Linda Morrow, Katherine Gomez, Daniel Rooks, Charles Meyers, Monte Buchsbaum, Srikanth Neelakantham, Therese Swan, Lee Anne Filosa, Didier Laurent, Olivier Petricoul, Marjorie Zakaria
      Abstract: BackgroundSkeletal muscle is a key mediator of insulin resistance. Bimagrumab, an antibody against activin receptor type II (ActRII), prevents binding of negative muscle regulators, like myostatin, and increases lean mass and decreases fat mass in animal models.ObjectiveWe hypothesized that an improving body composition in insulin resistant individuals could enhance insulin sensitivity.MethodsSixteen individuals with mean body mass index (BMI) = 29.3 kg/m2 and insulin resistance, received a single dose of bimagrumab or placebo and were assessed at Week 10 for insulin sensitivity, with hyperinsulinemic euglycemic (H-E) clamp and intravenous glucose tolerance test (IVGTT), and for body composition, with dual energy X-ray absorptiometry (DXA) and Positron emission tomography (PET) scan.ResultsBimagrumab increased lean mass by 2.7% (p 
      PubDate: 2017-06-23T02:52:00.422603-05:
      DOI: 10.1111/dom.13042
  • Favourable Changes in Mortality in People with Diabetes – U.S.
           NHANES 1999–2010
    • Authors: Tetsuro Tsujimoto; Hiroshi Kajio, Takehiro Sugiyama
      Abstract: AimsDiabetes-related complications have declined during the past two decades. We aimed to examine whether mortality in people with diabetes improved overtime in the 1999–2010 NHANES.MethodsWe conducted a prospective cohort study using 1999–2004 and 2005–2010 data from the National Health and Nutrition Examination Survey. For primary analyses, we compared the unadjusted, age-adjusted, and multivariable-adjusted hazard ratios (HR) for mortality outcomes (total, cardiovascular, cardiac, and cancer deaths) of the participants with diabetes with those without diabetes using Cox proportional hazard models.ResultsFor each mortality outcome, HR (95% confidence interval) in diabetic participants in the years 2005–2010 was lower than that in the years 1999–2004 (all-cause death, 2.76 [1.87–4.08] vs. 4.23 [2.57–6.98]; cardiovascular death, 2.70 [1.20–6.04] vs. 8.82 [3.28–23.70]; cardiac death, 2.45 [0.98–6.09] vs. 15.55 [7.01–34.50]; cancer death, 2.33 [0.87–6.23] vs. 3.03 [1.20–7.65]). Compared with those in 1999–2004, greater declines in mortality in 2005–2010 were observed for cardiovascular (−54.0%) and cardiac deaths (−64.8%). In age-adjusted and multivariable-adjusted models, the cumulative event rates for total, cardiovascular, and cardiac death were not significantly different between participants with and without diabetes in 2005–2010; this was not the case in 1999–2004. The leading cause of death was malignant neoplasm in 2005–2010.ConclusionConsiderably improved outcomes for total, cardiovascular and cardiac death were observed for the 2005–2010 NHANES compared to the 1999–2004 NHANES.
      PubDate: 2017-06-22T10:50:19.370768-05:
      DOI: 10.1111/dom.13039
  • Glycemic Improvement with a Fixed-dose combination of DPP-4
           inhibitor + metformin in patients with Type 2 Diabetes (GIFT study)
    • Authors: Harpreet S. Bajaj; Chenglin Ye, Esha Jain, Karri Venn, Eden Stein, Ronnie Aronson
      Abstract: This study investigates changes in A1C following a switch from dual therapy of metformin and DPP-4 inhibitor to a fixed-dose combination (FDC) of metformin + DPP-4 inhibitor following the introduction of the FDC in the provincial formulary. LMC Diabetes Registry was queried retrospectively for patients with type 2 diabetes, aged between 18–80 years with at least one A1C recorded prior and ≥3 months post-switch. 568 subjects with mean age 64 ± 12 years and mean A1C 7.7% ± 1.2% met study criteria. Overall, A1C was 0.3% lower post-switch to FDC (p 
      PubDate: 2017-06-22T10:46:22.160281-05:
      DOI: 10.1111/dom.13040
  • Linagliptin and its effects on hyperglycaemia and albuminuria in patients
           with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D™
    • Authors: P.-H. Groop; M.E. Cooper, V. Perkovic, B. Hocher, K. Kanasaki, M. Haneda, G. Schernthaner, K. Sharma, R.C. Stanton, R. Toto, J. Cescutti, M. Gordat, T. Meinicke, A. Koitka-Weber, S. Thiemann, M. von Eynatten
      Abstract: AimsThe MARLINA-T2D™ study (, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria.Methods360 individuals with type 2 diabetes, HbA1c 6.5 − 10.0% (48 − 86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio (UACR) 30–3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively.ResultsBaseline mean HbA1c and geometric mean (gMean) UACR were 7.8 ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was −0.60% (−6.6 mmol/mol) (95% confidence interval [CI] −0.78 to −0.43 [−8.5 to −4.7 mmol/mol]; P < .0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was −6.0% (95% CI −15.0 to 3.0; P = .1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups.ConclusionsIn individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.
      PubDate: 2017-06-21T11:21:32.611279-05:
      DOI: 10.1111/dom.13041
  • Long-term safety and efficacy of canagliflozin as add-on therapy to
           teneligliptin in Japanese patients with type 2 diabetes
    • Authors: Takashi Kadowaki; Nobuya Inagaki, Kazuoki Kondo, Kenichi Nishimura, Genki Kaneko, Nobuko Maruyama, Nobuhiro Nakanishi, Yumi Watanabe, Maki Gouda, Hiroaki Iijima
      Abstract: AimTo evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy.MethodsThis open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included the changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to week 52 (with last observation carried forward).ResultsOverall, 153 patients entered the treatment period and 142 completed the study. The overall incidence of AEs and drug-related AEs was 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean (95% confidence interval) changes in HbA1c, FPG, and body weight were −0.99% (−1.12% to −0.85%), −38.6 mg/dL (−43.4 to −33.9 mg/dL), and −3.92% (−4.53% to −3.31%), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52.ConclusionsNo new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG, and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese T2DM patients with inadequate glycaemic control on teneligliptin alone.
      PubDate: 2017-06-13T05:10:20.990826-05:
      DOI: 10.1111/dom.13038
  • The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in
    • Authors: Juraj Koska; Lizette Lopez, Karen D'Souza, Tracy Osredkar, James Deer, Julie Kurtz, Arline D. Salbe, S. Mitchell Harman, Peter D. Reaven
      Abstract: AimsHigh saturated fatty acid (SFA) diets blunt peripheral insulin action. GLP-1 receptor agonists suppress postprandial lipids and endothelial dysfunction, which may counter SFA-induced insulin resistance. This study tested whether liraglutide suppresses postprandial elevations in lipids and thus protects against high SFA-diet induced insulin resistance.Materials and methodsIn a randomized placebo-controlled cross-over study, 32 subjects with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and following a 24-hr SFA-enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non-esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants had ex vivo measurements of insulin-mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle.ResultsLiraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA-diet (by 50, 25 and 9% respectively), and the SFA-diet increased plasma glucose during the IST (by 36%) (all p 
      PubDate: 2017-06-12T11:05:21.200371-05:
      DOI: 10.1111/dom.13037
  • Comment on Tang, et al. Sodium-glucose cotransporter 2 inhibitors and risk
           of adverse renal outcomes among type 2 diabetes patients: a network and
           cumulative meta-analysis of randomized controlled trials. Diabetes Obes
           Metab. 2017; doi: 10.1111/dom.12917.
    • Authors: William Canovatchel; Jennifer Davidson, Norm Rosenthal
      Abstract: In a recent article, Tang et al. described the effects of sodium glucose co-transporter 2 (SGLT2) inhibitors on renal outcomes in patients with type 2 diabetes mellitus (T2DM) based on a meta-analysis of data from randomized, controlled clinical trials [1]. The authors concluded that among the 3 currently approved SGLT2 inhibitors, dapagliflozin and canagliflozin may be associated with an increased risk of harmful renal outcomes, while empagliflozin may provide benefits on renal function [1].
      PubDate: 2017-06-09T08:06:58.001084-05:
      DOI: 10.1111/dom.13035
  • A novel GIP analog, ZP4165, enhances GLP-1-induced body weight loss and
           improves glycemic control in rodents
    • Authors: P. K. Nørregaard; M. A. Deryabina, P. Tofteng Shelton, J. U. Fog, J. R. Daugaard, P. Eriksson, L.F. Larsen, L. Jessen
      Abstract: AimTo investigate the effects of the novel GIP analog, ZP4165, on body weight and glycemic control in rodents. Additionally, to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycemic effects of a GLP-1 agonist (liraglutide).MethodsThe acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. Long-term effects of ZP4165 on body weight and glycemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice.ResultsZP4165 showed insulinotropic action in rats. The GIP analog did not alter body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4-weeks dosing with ZP4165 reduced HbA1c% levels versus vehicle to a similar extent as the GLP-1 agonist.ConclusionsZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity.
      PubDate: 2017-06-09T05:40:20.549281-05:
      DOI: 10.1111/dom.13034
  • Prevention of Cardiovascular Disease by the Reduction of Glycemic Exposure
           in Type 2 Diabetes: A Perspective on Glucose-Lowering Interventions
    • Authors: Ronan Roussel; Philippe Gabriel Steg, Kamel Mohammedi, Michel Marre, Louis Potier
      Abstract: Type 2 diabetes is a leading cause of cardiovascular disease (CVD). Observational studies showed consistently an association between glycemic level and risk of major cardiovascular events (MACE). However, the intervention studies provided limited evidence supporting the reduction of cardiovascular burden of diabetes by intensive glucose control. Here, we propose to apply the concept of cumulative glycemic exposure to protection against CVD in diabetes. We address how we can move from a binary approach in trials, to a more quantitative approach based on differences in cumulative glycemic exposure. We plotted the association between differential glycemic exposure between the study arms and Hazard Ratio for MACE in randomized controls trials comparing intensive vs. conventional glycemic control in type 2 diabetes. We found a strikingly good correlation between differential exposure and cardiovascular risk reduction. Similar results were obtained with trials comparing antidiabetes drugs vs. placebo. They suggest that a minimum study duration and a minimum gain in HbA1c reduction are necessary to drive a relevant risk reduction in CVD risk, and we provide a quantitative perspective in that respect. This analysis underlines that the duration of the intensification, and the amplitude of the resulting reduction in HbA1c, are important notions for clinical decision making.
      PubDate: 2017-06-09T02:10:22.768571-05:
      DOI: 10.1111/dom.13033
  • Severe Hypoglycemia Among Patients With Type 2 Diabetes Requiring
           Emergency Hospital Admission: The HIPOS-ER Study
    • Authors: João Conceição; Jorge Dores, Francisco Araújo, Pedro Laires, Richard D. Carr, Kimberly Brodovicz, Larry Radican, Ana Maria Nogueira
      Abstract: AimsIn this study we analysed the prevalence of severe hypoglycaemia in patients with type 2 diabetes treated with antihyperglycemic agents (AHA) and requiring emergency room (ER) assistance. This analysis was also done by AHA therapy.Materials and methodsThe HIPOS-ER study was a cross-sectional, observational, multicenter, nationwide, study with specific hypoglycemia source data collection.ResultsWithin the study period, a total of 425,706 admissions were recorded at the ER of participating hospitals. The prevalence of severe hypoglycemic episodes with T2DM was 0.074%. 238 patients were included, more than half of them were on insulin-based therapy (55.0%) and a third (31.5%) on oral secretagogue-based therapy. In 61.2% primary care was the main diabetes care setting. Median age was 77.5 years and mean duration of diabetes 19 years. Missing a meal or low carbohydrate meal content was the most frequent triggering cause of hypoglycemia (55.9%) and the most frequent triggers for seeking emergency assistance were pre-syncope (19.2%) and transient loss of consciousness (17.4%). 44.1% of patients were hospitalized for a median of 5.1 days. Patients on the secretagogue group were more often admitted than patients in the insulin group (70.7% vs 29.0%; p 
      PubDate: 2017-06-05T05:55:19.065389-05:
      DOI: 10.1111/dom.13030
  • The effect of continuous exenatide infusion on cardiac function and
           perioperative glucose control in cardiac surgery patients: a single-blind,
           randomized, controlled trial
    • Authors: Michal Lipš; Miloš Mráz, Jana Kloučková, Petr Kopecký, Miloš Dobiáš, Jarmila Křížová, Jaroslav Lindner, Michaela Diamant, Martin Haluzík
      Abstract: To intensify perioperative glucose control while minimizing the risk of hypoglycemia and to evaluate the suggested cardioprotective effects of GLP-1-based treatments we performed a randomized controlled trial with the GLP-1 receptor agonist exenatide as add-on to standard perioperative insulin therapy in subjects undergoing elective cardiac surgery. 38 subjects with decreased left ventricular systolic function (ejection fraction ≤50%) scheduled for elective CABG (coronary artery by-pass grafting) were randomized to receive either exenatide or placebo in a continuous 72-hour i.v. infusion on top of standard perioperative insulin therapy. While no significant difference in postoperative echocardiographic parameters was found between the groups, subjects receiving exenatide showed improved perioperative glucose control as compared with the placebo group (average glycemia 6.4 ± 0.5 vs. 7.3 ± 0.8 mmol/l, p 
      PubDate: 2017-06-05T05:31:57.886521-05:
      DOI: 10.1111/dom.13029
  • Design and Baseline Characteristics of Participants in the Researching
           cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) Trial of
           Dulaglutide's Cardiovascular Effects
    • Authors: Hertzel C. Gerstein; Helen M. Colhoun, Gilles R. Dagenais, Rafael Diaz, Mark Lakshmanan, Prem Pais, Jeffrey Probstfield, Matthew C Riddle, Lars Rydén, Denis Xavier, Charles Messan Atisso, Alvaro Avezum, Jan Basile, Namsik Chung, Ignacio Conget, William C. Cushman, Edward Franek, Nicolae Hancu, Markolf Hanefeld, Shaun Holt, Petr Jansky, Matyas Keltai, Fernando Lanas, Lawrence A. Leiter, Patricio Lopez-Jaramillo, Ernesto German Cardona Munoz, Valdis Pirags, Nana Pogosova, Peter J. Raubenheimer, Jonathan Shaw, Wayne H-H Sheu, Theodora Temelkova-Kurktschiev
      Abstract: BackgroundDulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 (GLP1) analogue lowers blood glucose, body weight, appetite, and blood pressure. Its effect on cardiovascular outcomes is unknown.MethodsPeople with type 2 diabetes, aged 50 or older, a HbA1c ≤9.5%, and either a previous cardiovascular (CV) event, evidence of CV disease or ≥ 2 CV risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal MI or nonfatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes.ResultsRecruitment of 9901 participants (mean age 66, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3 %, and 31% had prior cardiovascular disease.ConclusionThe REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease, and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.
      PubDate: 2017-06-01T23:50:28.498925-05:
      DOI: 10.1111/dom.13028
  • Projected Long-Term Outcomes in Patients With Type 1 Diabetes Treated With
           Fast-Acting Insulin Aspart Versus Conventional Insulin Aspart in the Uk
    • Authors: D Russell-Jones; S Heller, S Buchs, A Sandberg, WJ Valentine, B Hunt
      Abstract: AimsMany patients with type 1 diabetes mellitus (T1DM) fail to achieve optimal glycemic control and mealtime insulins that more closely match physiological insulin secretion can help improve treatment. In the onset 1 trial, fast-acting insulin aspart (faster aspart) was shown to improve glycemic control in patients with T1DM compared with conventional insulin aspart (insulin aspart). In the UK, faster aspart and insulin aspart are associated with the same acquisition cost, and therefore the present analysis assessed the impact of faster aspart versus insulin aspart on long-term clinical outcomes and costs for patients with T1DM in the UK setting.MethodsThe QuintilesIMS CORE Diabetes Model was used to project clinical outcomes and costs over patient lifetimes in a cohort with baseline characteristics from the onset 1 trial. Treatment effects were taken from the 26-week main phase of the onset 1 trial, with costs and utilities based on literature review. Future costs and clinical benefits were discounted at 3.5% annually.ResultsProjections indicated that faster aspart was associated with improved discounted quality-adjusted life expectancy (by 0.13 quality-adjusted life years) versus insulin aspart). Improved clinical outcomes resulted from fewer diabetes-related complications and a delayed time to their onset with faster aspart. Faster aspart was found to be associated with reduced costs versus insulin aspart (cost savings of GBP 1,715), resulting from diabetes-related complications avoided and reduced treatment costs.ConclusionsFaster aspart was associated with improved clinical outcomes and cost savings versus insulin aspart for patients with T1DM in the UK setting.
      PubDate: 2017-06-01T22:56:26.403552-05:
      DOI: 10.1111/dom.13026
  • Variability in and predictors of glycaemic responses after 24 weeks of
           treatment with exenatide twice daily and exenatide once weekly
    • Authors: Jonathan E. Shaw; Baptist Gallwitz, Jenny Han, Elise Hardy, Guntram Schernthaner
      Abstract: The range of glycated haemoglobin (HbA1c) responses and characteristics associated with above-average response to exenatide twice daily (BID) and once weekly (QW) were examined. Data were pooled from 8 exenatide BID and 5 exenatide QW studies. A baseline HbA1c-corrected measure of change in HbA1c after 24 weeks identified high, average, and low responses. Multiple linear regression and multivariate generalized estimating equation models identified factors associated with high response. Among 2355 participants (exenatide BID, n = 1414; exenatide QW, n = 941), baseline HbA1c correlated with change in HbA1c (P
      PubDate: 2017-06-01T22:45:30.665698-05:
      DOI: 10.1111/dom.13022
  • Once-weekly administration of a long-acting FGF21 analogue modulates
           lipids, bone turnover markers, blood pressure, and body weight differently
           in obese hypertriglyceridemic subjects and in non-human primates
    • Authors: Albert M. Kim; Veena R. Somayaji, Jennifer Q. Dong, Timothy P. Rolph, Yan Weng, Jeffrey R. Chabot, Kathryn E. Gropp, Saswata Talukdar, Roberto A. Calle
      Abstract: AimsTo assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting FGF21 analogue, in obese, hypertriglyceridemic subjects on atorvastatin with or without type 2 diabetes.MethodsSubjects received PF-05231023 or placebo intravenously once-weekly for 4 weeks. Safety (12-lead electrocardiogram [ECGs], vital signs, adverse events [AEs], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure (mean, systolic, and diastolic) and ECGs were monitored.ResultsOne hundred and seven (107) subjects were randomised. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33–43%) and increased high-density lipoprotein cholesterol (day 25, 15.7–28.6%) and adiponectin (day 25, 1574–3272 ng/ml) across all doses, without significant changes in body weight (day 25, −0.45 to −1.21%). Modest decreases from baseline were observed for N-terminal propeptides of type 1 collagen at day 25, although C-telopeptide cross-linking of type 1 collagen increased minimally. Systolic, diastolic blood pressure, and pulse rate increased in a dose- and time-related manner. There were five serious AEs (one treatment-related) and no deaths. Three subjects discontinued due to AEs. The majority of AEs were gastrointestinal. PF-05231023 increased blood pressure and heart rate in rats, but not in monkeys.ConclusionsOnce-weekly PF-05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report demonstrating increases in blood pressure and pulse rate in humans and rats upon pharmacological administration of a long-acting FGF21 NCT01673178
      PubDate: 2017-06-01T22:20:39.364555-05:
      DOI: 10.1111/dom.13023
  • Breaking up sedentary time with seated upper body activity can regulate
           metabolic health in obese high risk adults: A randomised crossover trial
    • Authors: Matthew McCarthy; Charlotte L Edwardson, Melanie J Davies, Joseph Henson, Alex Rowlands, James King, Danielle H Bodicoat, Kamlesh Khunti, Thomas Yates
      Abstract: AimsTo investigate the impact of performing short bouts of seated upper body activity on postprandial blood glucose and insulin levels during prolonged sitting.Materials and methodsParticipants undertook two 7 · 5 hour experimental conditions in a randomised order: 1) prolonged sitting only 2) sitting interspersed with 5 minutes of seated arm ergometry every 30 minutes. Blood samples were obtained while fasting and throughout the postprandial period following ingestion of two standardised meals. Incremental Area Under the Curve (iAUC) was calculated for glucose and insulin throughout each experimental condition. Paired samples t-test assessed the difference in iAUC data between conditions for glucose (primary outcome) and insulin (secondary outcome).ResultsThirteen obese adults (7 female; 6 male; age: 66 ± 6 years, BMI: 33.8 ± 3.8 kg/m2 (mean ± SD) completed this investigation. Compared with the prolonged sitting only condition, the implementation of seated arm ergometry every 30 minutes significantly reduced mean [95% CI] blood glucose iAUC (from 7.4 [5.2, 9.5] mmol · L−1 · h to 3.1 [1.3, 5.0] mmol · L−1 · h, p = 0.001). Significant reductions in mean insulin iAUC (from 696 [359, 1032] mU⋅L−1 ⋅h to 554 [298, 811] mU⋅L−1 ⋅h, p = 0.047) were also observed.ConclusionPerforming short bouts of arm ergometry during prolonged sitting attenuated postprandial glycaemia despite maintaining a seated posture. This may have clinical significance for those with weight bearing difficulty who may struggle with postural change.Trial (NCT02909894)
      PubDate: 2017-05-23T04:00:24.588727-05:
      DOI: 10.1111/dom.13016
  • Comment on: “Strengths and Limitations of Healthcare Databases in the
           Evaluation of Hypoglycaemia”
    • Authors: Francesco Zaccardi; Nafeesa N Dhalwani, Melanie J Davies, Kamlesh Khunti
      Abstract: We thank Loke and Mattishent for their commentary on our paper investigating risk factors for hospitalisation for hypoglycaemia in England.1, 2In their editorial, they further underlined the challenges we recognised in the manuscript over the use of administrative databases for epidemiological research and, in particular, for identifying potential risk factors for hypoglycaemia.
      PubDate: 2017-05-18T23:15:34.726902-05:
      DOI: 10.1111/dom.13014
  • Comparative effects of liraglutide 3 mg versus structured lifestyle
           modification on body weight, liver fat and liver function in obese
    • Authors: Joan Khoo; John Hsiang, Ranu Taneja, Ngai-Moh Law, Tiing-Leong Ang
      Abstract: We compared effects of weight loss induced by the glucagon-like peptide 1-agonist liraglutide with a structured lifestyle intervention in obese adults with non-alcoholic fatty liver disease (NAFLD). Obese (BMI ≥ 30 kg/m2, mean weight 96.0 ± 16.3 kg) non-diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on MRI without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/day) plus moderate-intensity aerobic exercise (~200 minutes/week) (DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (p 
      PubDate: 2017-05-14T23:50:52.852129-05:
      DOI: 10.1111/dom.13007
  • Hypoglycaemia seriousness and weight gain as determinants of
           cardiovascular disease outcomes among sulfonylurea users
    • Authors: Anthony P. Nunes; Kristy Iglay, Larry Radican, Samuel S. Engel, Jing Yang, Michael C. Doherty, David D. Dore
      Abstract: AimsCertain treatments for type 2 diabetes mellitus cause hypoglycaemia and weight gain, and thus might counteract the benefits of intensive glucose control. We quantify the association of cardiovascular disease (CVD) outcomes with hypoglycaemia and weight gain among patients with type 2 diabetes treated with sulfonylureas.Materials and MethodsThis cohort study included patients from January 2009 through December 2014 identified within a deidentified nationwide electronic health records repository, including multiple provider networks and electronic medical records systems. Hypoglycaemia measures from structured data fields and free text clinical notes were categorized as serious or non-serious. Covariate adjusted Poisson regression analysis was used to assess the association between the frequency of hypoglycaemia (by severity), or magnitude of weight change, and incidence of acute myocardial infarction (AMI), congestive heart failure (CHF), and stroke.ResultsAmong 143,635 eligible patients, we observed 5,669 cases of AMI, 14,109 incident cases of CHF, and 7,017 strokes. Overall incidence rates were 1.53, 4.26, and 1.92 per 100 person-years for AMI, CHF, and stroke, respectively. The associations between overall hypoglycaemia and each of the CVD outcomes were positive, with stronger associations observed for serious hypoglycaemia and attenuated or null associations observed for non-serious hypoglycaemia. Weight change exhibited a U-shaped association with increased risks associated with both weight loss and weight gain relative to stable weight.ConclusionsThis study provides evidence of increased CVD risk associated with hypoglycaemia, especially serious hypoglycaemia events. While associations were attenuated with non-serious hypoglycaemia, the results were suggestive of a potential increased risk.
      PubDate: 2017-05-12T01:29:46.037103-05:
      DOI: 10.1111/dom.13000
  • Sodium-glucose (SGLT) and Glucose (GLUT) Transporter Expression in the
           Kidney of Type 2 Diabetic Subjects
    • Authors: Luke Norton; Christopher Shannon, Marcel Fourcaudot, Cheng Hu, Niansong Wang, Wei Ren, Jun Song, Muhammad Abdul-Ghani, Ralph A DeFronzo, Jimmy Ren, Weiping Jia
      Abstract: The sodium-glucose cotransporters (SGLTs) are responsible for the tubular reabsorption of filtered glucose from the kidney into the bloodstream. The inhibition of SGLT2-mediated glucose reabsorption is a novel and highly effective strategy to alleviate hyperglycemia in patients with type 2 diabetes mellitus (T2DM). However, the effectiveness of SGLT2 inhibitor therapy is diminished due, in part, to a compensatory increase in the maximum reabsorptive capacity (Tm) for glucose in patients with T2DM. We hypothesized that this increase in Tm could be explained by an increase in the tubular expression of SGLT and GLUT transporters in these patients. To examine this, we obtained human kidney biopsy specimens from patients with or without T2DM and examined the mRNA expression of SGLTs and GLUTs. The expression of SGLT1 is markedly increased in the kidney of patients with T2DM, and SGLT1 mRNA is highly and significantly correlated with fasting and postprandial plasma glucose and HbA1C. In contrast our data demonstrate that the levels of SGLT2 and GLUT2 mRNA are downregulated in diabetic patients, but not to a statistically significant level. These important findings are clinically significant and may have implications for the treatment of T2DM using strategies that target SGLT transporters in the kidney.
      PubDate: 2017-05-06T04:07:53.160094-05:
      DOI: 10.1111/dom.13003
  • Relationship Between Diabetes and Ischemic Injury Among Patients with
           Revascularized ST-Elevation Myocardial Infarction
    • Authors: Sebastian J Reinstadler; Thomas Stiermaier, Charlotte Eitel, Bernhard Metzler, Suzanne de Waha, Georg Fuernau, Steffen Desch, Holger Thiele, Ingo Eitel
      Abstract: AimsStudies comparing reperfusion efficacy and myocardial damage between diabetic and non-diabetic patients with ST-elevation myocardial infarction (STEMI) are scarce and have reported conflicting results. Aim was to investigate the impact of preadmission diabetic status on myocardial salvage and damage as determined by cardiac magnetic resonance (CMR) and to evaluate its prognostic relevance.Materials and methodsWe enrolled 792 patients with STEMI at eight sites. CMR core laboratory analysis was performed to determine infarct characteristics. Major adverse cardiac events (MACE), defined as a composite of all-cause death, nonfatal re-infarction and new congestive heart failure were recorded at 12 months. Patients were categorized according to preexisting diabetes mellitus (DM) and according to insulin-treated DM (ITDM) and non-insulin-treated DM (NITDM).ResultsOne hundred sixty (20%) patients had DM and 74 (9%) were insulin-treated. There was no difference in the myocardial salvage index, infarct size, microvascular obstruction, and left ventricular ejection fraction between all patient groups (all p > 0.05). DM patients were at higher risk for MACE (11%vs.6%, p = 0.03) than non-DM patients. After stratification according to preadmission antidiabetic therapy, MACE rate was comparable between NITDM and non-DM (p > 0.05), whereas the group of ITDM patients had significantly worse outcome (p 
      PubDate: 2017-05-05T04:02:22.09349-05:0
      DOI: 10.1111/dom.13002
  • Cost-Effectiveness of Exenatide twice daily versus Insulin Glargine as
           add-on Therapy to Oral Anti-diabetic Agents in Type 2 Diabetes in China
    • Authors: Shuyan Gu; Xiaoyong Wang, Qing Qiao, Weiguo Gao, Jian Wang, Hengjin Dong
      Abstract: AimsThis study aimed to estimate long-term cost-effectiveness of exenatide twice daily (EBID) versus insulin glargine once daily (IGQD) as add-on therapy to oral anti-diabetic agents (OADs) for Chinese patients with type 2 diabetes (T2DM).Materials and methodsCardiff Diabetes Model was used to simulate disease progression and estimate long-term effects of EBID versus IGQD. Model-required patient profiles and treatment effects were obtained from literature reviews (English and Chinese databases) and meta-analysis of eight randomized clinical trials comparing EBID versus IGQD add-on to OADs for T2DM in China. Medical expenditure were mainly collected from 639 T2DM patients (≥18 years) with and without complications incurred between 1/1/2014 and 12/31/2015 from claims databases in Shandong, China. From payers’ perspective, costs (2014 Chinese Yuan, ¥) and benefits were estimated over 40 years at discount rate of 3%. A series of sensitivity analyses were performed.ResultsPatients on EBID+OAD had lower predicted incidences of most cardiovascular events and hypoglycemia events and lower total costs compared with those on IGQD+OAD. There were increased numbers of quality adjusted life years (QALY; 1.94) at a cost saving of ¥117706 gained with EBID versus IGQD (i.e. cost saving of ¥60764/QALY) per patient.ConclusionsIn Chinese T2DM patients inadequately controlled by OADs, EBID is a cost-effective add-on therapy alternative compared with IGQD, which may address an excess of medical needs attributed to weight gain and hypoglycemia in T2DM treatment.
      PubDate: 2017-04-28T03:05:51.339268-05:
      DOI: 10.1111/dom.12991
  • Effects of age, gender, and body mass index on efficacy and hypoglycaemia
           outcomes across treat-to-target trials with insulin glargine 100 U/ml
           added to oral antidiabetes agents in type 2 diabetes
    • Authors: D. Owens; G. Bolli, B. Charbonnel, T. Haak, W. Landgraf, F. Porcellati, L. Traylor, A. Kautzky-Willer
      Abstract: AimsAnalyse effects of patient characteristics and different OAD use on standardised clinical outcomes in type 2 diabetes patients initiating insulin glargine 100 U/ml (Gla-100).Materials and MethodsPatient-level data were analysed from 16 randomised, treat-to-target clinical trials that added Gla-100 to existing metformin (MET), sulfonylurea (SU), or metformin plus sulfonylurea (MET+SU) in insulin-naïve patients inadequately controlled on oral therapy and followed for ≥24 weeks. Change in glycated haemoglobin A1c (HbA1c) from baseline to Week 24, other glycaemic endpoints, and incidence of hypoglycaemia (overall, nocturnal, and severe) were analysed by age (
      PubDate: 2017-04-27T13:27:37.966978-05:
      DOI: 10.1111/dom.12966
  • Strengths and Limitations of Healthcare Databases in the Evaluation of
    • Authors: Yoon Kong Loke; Katharina Mattishent
      Abstract: In this issue of DOM, Zaccardi et al. present an analysis of hypoglycaemia-related hospitalizations in the Hospital Episodes Statistics (HES) administrative database of the English National Health Service. [1] Notable strengths of the work include a large sample size involving more than 100 000 cases of hypoglycaemia, and nationwide capture spanning a duration of ten years. Key conclusions include the possibility of a U-shaped relationship between risk of hypoglycaemia and age, as well as possible associations between social deprivation and ethnicity with greater risk of hypoglycaemia.
      PubDate: 2017-04-27T12:13:10.971792-05:
      DOI: 10.1111/dom.12984
  • Postprandial renal haemodynamic effect of lixisenatide versus once-daily
           insulin glulisine in type 2 diabetes patients on insulin-glargine: an
           8-week, randomised, open-label trial
    • Authors: Lennart Tonneijck; Marcel H.A. Muskiet, Mark M. Smits, Trynke Hoekstra, Mark H.H. Kramer, A.H. Jan Danser, Michaela Diamant, Jaap A. Joles, Daniël H. van Raalte
      Abstract: AimsTo determine whether lixisenatide, a prandial short-acting glucagon-like peptide receptor agonist (GLP-1RA), ameliorates postprandial glomerular hyperfiltration in type 2 diabetes mellitus (T2DM)-patients compared to insulin-glulisine (iGlu) .MethodsPostprandial renal haemodynamic effects of 8-week treatment with lixisenatide 20 µg versus once-daily titrated iGlu were measured in 35 overweight T2DM-patients inadequately controlled on insulin-glargine, with or without metformin (mean±SD age 62 ± 7years, HbA1c 8.0 ± 0.9%, estimated GFR 85 ± 12 ml/min/1.73 m2, median[IQR] urinary albumin/creatinine ratio 1.5 [0.9-3.0] mg/mmol). After a standardised breakfast, GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid renal clearance, respectively, based on timed urine sampling. Intrarenal haemodynamic functions were estimated using Gomez’-equations.ResultsCompared to iGlu, lixisenatide did not affect GFR (+0.1 ml/min/1.73 m2 [95% CI −9 to 9]), ERPF (−17 ml/min/1.73 m2 [−61 to 26]), other (intra-)renal haemodynamics or renal damage markers, but increased fractional sodium excretion (+0.25% [0.09 to 0.41]) and urinary pH (+0.7 [0.3 to 1.2]). Plasma renin, angiotensin-II and aldosterone were unchanged. Lixisenatide and iGlu reduced HbA1c similarly, by 0.8 ± 0.1% and 0.6 ± 0.1%, respectively, while postprandial glucose was lower with lixisenatide (p = 0.002). Compared to iGlu, lixisenatide reduced bodyweight (−1.4 kg [−2.5 to −0.2]), and increased postprandial mean arterial pressure (+9 mmHg [4 to 14]).ConclusionEight-week lixisenatide-treatment does not affect postprandial (intra-)renal haemodynamics compared to iGlu when added to insulin glargine in T2DM-patients without overt nephropathy. Prolonged lixisenatide treatment has a sustained natriuretic effect –which contrast previous reports on long-acting GLP-1RA–, reduces bodyweight and increases postprandial blood pressure compared to iGlu.Trial registration identifier NCT02276196
      PubDate: 2017-04-27T11:40:43.614749-05:
      DOI: 10.1111/dom.12985
  • Neuropsychiatric safety with liraglutide 3.0 mg for weight management:
           results from randomized controlled phase 2 and 3a trials
    • Authors: P.M. O'Neil; V. R. Aroda, A. Astrup, R. Kushner, D.C.W. Lau, T.A. Wadden, J. Brett, A. Cancino, J.P.H. Wilding,
      Abstract: AimsLiraglutide, a GLP-1 receptor agonist, regulates appetite via receptors in the brain. Due to concerns over the potential of centrally-acting anti-obesity medications to affect mental health, pooled neuropsychiatric safety data from all phase 2 and 3a randomized, double-blind trials with liraglutide 3.0 mg were evaluated post hoc.MethodsData from the liraglutide weight-management programme were pooled. Across trials, individuals with a body mass index ≥30 kg/m2 or ≥27 kg/m2 with weight-related comorbidities were randomized to once-daily subcutaneous liraglutide 3.0 mg (n = 3384) or placebo (n = 1941), both with a 500 kcal/day deficit diet plus exercise. Adverse events related to neuropsychiatric safety were collected in all trials. Additionally, in the phase 3a trials, validated mental-health questionnaires were prospectively and systematically administered.ResultsIn the pooled analysis of 5325 randomized and exposed individuals, rates of depression (2.1 versus 2.1 events/100 person-years) and anxiety (1.9 versus 1.7 events/100 person-years) through adverse event reporting were similarly low in the liraglutide group and the placebo group. Nine (0.3%) individuals on liraglutide and two (0.1%) on placebo reported adverse events of suicidal ideation or behaviour. In phase 3a trials, mean baseline Patient Health Questionnaire-9 scores of 2.8 ± 3.0 versus 2.9 ± 3.1 for liraglutide versus placebo improved to 1.8 ± 2.7 versus 1.9 ± 2.7 at treatment end; 34/3291 individuals (1.0%) on liraglutide 3.0 mg versus 19/1843 (1.0%) on placebo reported suicidal ideation on the Columbia-Suicide Severity Rating Scale.ConclusionsThe results of this exploratory pooled analysis do not provide any cause for concern regarding the neuropsychiatric safety of treatment with liraglutide 3.0 mg in patients similar to those individuals included in the examined trials. Although there was a small numerical imbalance in suicidal ideation with liraglutide through adverse event reporting, no between-treatment imbalances in suicidal ideation/behaviour or depression were noted through prospective questionnaire assessments.
      PubDate: 2017-04-06T22:45:27.581849-05:
      DOI: 10.1111/dom.12963
  • Factors associated with improved glycemic control following continuous
           subcutaneous insulin infusion therapy in patients with type 2 diabetes
           uncontrolled with bolus-basal insulin regimens: an analysis from the
           OpT2mise randomized trial
    • Authors: Muriel Metzger; Javier Castañeda, Yves Reznik, Francesco Giorgino, Ignacio Conget, Ronnie Aronson, Simona de Portu, Sarah Runzis, Scott W Lee, Ohad Cohen
      Abstract: This analysis investigated factors associated with the decrease in HbA1c in patients receiving continuous subcutaneous insulin infusion (CSII) in the OpT2mise randomized trial. In this study, patients with type 2 diabetes and HbA1C >8% following multiple daily injections (MDI) optimization were randomized to receive CSII (n = 168) or MDI (n = 163) for 6 months. Patient-related and treatment-related factors associated with decreased HbA1c in the CSII arm were identified by univariate and multivariate analyses. CSII produced a significantly greater reduction in HbA1c than MDI, and the treatment difference increased with baseline HbA1c . In the CSII arm, the only factors significantly associated with decreased HbA1C were higher baseline HbA1C (P
      PubDate: 2017-04-04T03:21:11.58997-05:0
      DOI: 10.1111/dom.12960
  • Cardiovascular safety of vildagliptin in patients with type 2 diabetes: a
           European multi-database, non-interventional post-authorization safety
    • Authors: R. Williams; F. de Vries, W. Kothny, C. Serban, S. Lopez-Leon, C. Chu, R. Schlienger
      Abstract: This non-interventional, multi-database, analytical cohort study assessed the cardiovascular (CV) safety of vildagliptin vs. other non-insulin antidiabetic drugs (NIADs) using real-world data from five European electronic healthcare databases. Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) for the outcomes of interest (myocardial infarction [MI], acute coronary syndrome [ACS], stroke, congestive heart failure [CHF], individually and as a composite) were estimated using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738,054) used vildagliptin at any time during the study with an average follow-up time of 1.4 years, resulting in a cumulative current vildagliptin exposure of 28,330 person-years. The adjusted IRRs (vildagliptin [± other NIADs] vs. other NIADs) were in the range of 0.61–0.97 (MI), 0.55–1.60 (ACS), 0.02–0.77 (stroke), 0.49–1.03 (CHF), and 0.22–1.02 (composite CV outcomes). The IRRs and their 95% CIs were close to 1, demonstrating no increased risk of adverse CV events, including the risk of CHF, with vildagliptin vs. other NIADs under real-world conditions.
      PubDate: 2017-03-24T05:10:04.363757-05:
      DOI: 10.1111/dom.12951
  • Improving glycemic control in type 2 diabetes: stimulate insulin secretion
           or provide beta-cell rest'
    • Authors: Daniël H van Raalte; C. Bruce Verchere
      Abstract: Type 2 diabetes (T2D) is characterized by a gradual decline of pancreatic beta cell function that determines the progressive course of the disease. While beta-cell failure is an important contributor to hyperglycemia, chronic hyperglycemia itself is also detrimental for beta-cell function, likely by inducing prolonged secretory stress on the beta cell as well as through direct glucotoxic mechanisms that have not been fully defined. For years, research has been carried out in search of therapies targeting hyperglycemia that preserve long-term beta-cell function in T2D, a quest that is still ongoing. Current strategies aim to improve glycemic control either by promoting endogenous insulin secretion, such as sulfonylureas, or by mechanisms that may impact the beta cell indirectly, for example providing beta-cell rest through insulin treatment. Although overall long-term success is limited with currently available interventions, in this review we argue that strategies that induce beta-cell rest have considerable potential to preserve long-term beta-cell function. This is based on laboratory-based studies involving human islets as well as clinical studies employing intensive insulin therapy, thiazolidinediones, bariatric surgery, short-acting glucagon-like peptide (GLP)-1 receptor agonists, and a promising new class of diabetes drugs, sodium-glucose linked transporter (SGLT)-2 inhibitors. Nevertheless, a lack of long-term clinical studies that focus on beta-cell function for the newer glucose-lowering agents as well as commonly used combination therapies preclude a straightforward conclusion; this gap in our knowledge should be a focus of future studies.
      PubDate: 2017-03-14T08:10:46.897953-05:
      DOI: 10.1111/dom.12935
  • Diabetes, Obesity and Metabolism
    • Pages: 1199 - 1200
      PubDate: 2017-08-23T04:22:45.504799-05:
      DOI: 10.1111/dom.12774
  • Cardiovascular safety of insulin: Between real-world data and reality
    • Authors: Edoardo Mannucci; Ele Ferrannini
      Pages: 1201 - 1204
      PubDate: 2017-05-24T23:40:25.394128-05:
      DOI: 10.1111/dom.12967
  • Evidence connecting old, new and neglected glucose-lowering drugs to bile
           acid-induced GLP-1 secretion: A review
    • Authors: Martin L. Kårhus; Andreas Brønden, David P. Sonne, Tina Vilsbøll, Fillip K. Knop
      Pages: 1214 - 1222
      Abstract: Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G-protein-coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells. The present article critically reviews current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion, and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid sequestrants – old, new and neglected glucose-lowering drugs – improve glucose metabolism.
      PubDate: 2017-04-27T12:49:08.772919-05:
      DOI: 10.1111/dom.12946
  • Short- and long-term mortality after bariatric surgery: A systematic
           review and meta-analysis
    • Authors: Luís Cardoso; Dírcea Rodrigues, Leonor Gomes, Francisco Carrilho
      Pages: 1223 - 1232
      Abstract: AimsThe objective of this study was to investigate short- (≤ 30 days) and long-term (≥ 2 years) all-cause mortality after bariatric surgery among adult patients with obesity.Materials and methodsFor short-term mortality, eligible studies comprised randomized controlled trials (RCTs) reporting perioperative mortality. For long-term mortality, eligible studies comprised RCTs and observational studies comparing mortality between obese patients after bariatric surgery and non-operated controls. Random-effects models using a Bayesian or frequentist approach were used to pool effect estimates of short- and long-term mortality, respectively.ResultsShort-term all-cause mortality based on 38 RCTs involving 4030 patients was 0.18% (95% CI, 0.04%-0.38%) and was higher for open surgeries (0.31%; 95% CI, 0.03%-0.97%) and similar in mixed surgeries (0.17%; 95% CI, 0.03%-0.43%) and restrictive surgeries (0.17%; 95% CI, 0.03%-0.45%). For long-term mortality, 12 observational studies involving 27 258 operated patients and 97 154 non-operated obese controls were included. Of these, 8 studies were eligible for the meta-analysis, which showed a reduction of 41% in all-cause mortality (hazard ratio, 0.59; 95% CI, 0.52-0.67; P 
      PubDate: 2017-05-31T06:15:51.508382-05:
      DOI: 10.1111/dom.12922
  • Safety issues with glucagon-like peptide-1 receptor agonists
           (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized
           controlled trials
    • Authors: Matteo Monami; Besmir Nreu, Alessia Scatena, Barbara Cresci, Francesco Andreozzi, Giorgio Sesti, Edoardo Mannucci
      Pages: 1233 - 1241
      Abstract: AimGlucagon-like peptide 1 receptor agonists (GLP1-RA) have been associated with an increased risk of pancreatitis and pancreatic cancer. Prior meta-analyses of randomized controlled trials failed to show any significant increase of risk; however, those meta-analyses did not include the recently published cardiovascular outcome trials (CVOT) with GLP1-RA, which provide a substantial additional body of data. The aim of the present meta-analysis is to assess the effect of GLP1-RA on pancreatitis, pancreatic cancers and cholelithiasis.Materials and methodsA Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide or semaglutide) was performed, collecting all randomized clinical trials with a duration>11 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug.ResultsOf the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported no events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms (MH-OR [95% CI] 0.93 [0.65-1.34], P = .71, and 0.94 [0.52-1.70], P = .84, respectively), whereas, a significantly increased risk of cholelithiasis (MH-OR [95% CI] 1.30 [1.01-1.68], P = .041) was detected.ConclusionsPresently available data confirm the safety of GLP-1 receptor agonists for pancreatitis. Conversely, therapy with those drugs is associated with an increased risk of cholelithiasis, which deserves further investigation.
      PubDate: 2017-06-20T03:42:32.921661-05:
      DOI: 10.1111/dom.12926
  • Effects of once-weekly semaglutide on appetite, energy intake, control of
           eating, food preference and body weight in subjects with obesity
    • Authors: John Blundell; Graham Finlayson, Mads Axelsen, Anne Flint, Catherine Gibbons, Trine Kvist, Julie B. Hjerpsted
      Pages: 1242 - 1251
      Abstract: AimThe aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide.Materials and methodsThis randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks of treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed.ResultsAfter a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (−1255 kJ; P 
      PubDate: 2017-05-05T05:51:26.547948-05:
      DOI: 10.1111/dom.12932
  • Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment
           in Japanese patients with type 2 diabetes on background insulin glargine:
           A randomized phase IV study (NEXTAGE Study)
    • Authors: Yuichiro Yamada; Masayuki Senda, Yusuke Naito, Masahiro Tamura, Daisuke Watanabe, Yujin Shuto, Yoshihisa Urita
      Pages: 1252 - 1259
      Abstract: AimTo evaluate the pharmacodynamics of lixisenatide once daily vs sitagliptin once daily in Japanese patients with type 2 diabetes receiving insulin glargine U100.Materials and methodsThis multicentre, open-label, phase IV study (NEXTAGE Study; number, NCT02200991) randomly assigned 136 patients to either lixisenatide once daily via subcutaneous injection (10 µg initially increased weekly by 5 up to 20 µg) or once-daily oral sitagliptin 50 mg. The primary endpoint was the change in postprandial glucose (PPG) exposure 4 hours after a standardized breakfast (PPG area under the plasma glucose concentration–time curve [AUC0:00-4:00h]) from baseline to day 29.ResultsLixisenatide reduced PPG exposure to a statistically significantly greater extent than sitagliptin: least squares (LS) mean change from baseline in PPG AUC0:00-4:00h was −347.3 h·mg/dL (−19.3 h·mmol/L) in the lixisenatide group and −113.3 h·mg/dL (−6.3 h·mmol/L) in the sitagliptin group (LS mean between-group difference −234.0 h·mg/dL [−13.0 h·mmol/L], 95% confidence interval −285.02 to −183.00 h·mg/dL [−15.8 to −10.2 h·mmol/L]; P 
      PubDate: 2017-04-27T12:46:30.62172-05:0
      DOI: 10.1111/dom.12945
  • Evaluation of the modified FINDRISC to identify individuals at high risk
           for diabetes among middle-aged white and black ARIC study participants
    • Authors: Manjusha Kulkarni; Randi E. Foraker, Ann M. McNeill, Cynthia Girman, Sherita H. Golden, Wayne D. Rosamond, Bruce Duncan, Maria Ines Schmidt, Jaakko Tuomilehto
      Pages: 1260 - 1266
      Abstract: ObjectiveTo evaluate a modified Finnish Diabetes Risk Score (FINDRISC) for predicting the risk of incident diabetes among white and black middle-aged participants from the Atherosclerosis Risk in Communities (ARIC) study.Research design and methodsWe assessed 9754 ARIC cohort participants who were free of diabetes at baseline. Logistic regression and receiver operator characteristic (ROC) curves were used to evaluate a modified FINDRISC for predicting incident diabetes after 9 years of follow-up, overall and by race/gender group. The modified FINDRISC used comprised age, body mass index, waist circumference, blood pressure medication and family history.ResultsThe mean FINDRISC (range, 2 [lowest risk] to 17 [highest risk]) for black women was higher (9.9 ± 3.6) than that for black men (7.6 ± 3.9), white women (8.0 ± 3.6) and white men (7.6 ± 3.5). The incidence of diabetes increased generally across deciles of FINDRISC for all 4 race/gender groups. ROC curve statistics for the FINDRISC showed the highest area under the curve for white women (0.77) and the lowest for black men (0.70).ConclusionsWe used a modified FINDRISC to predict the 9-year risk of incident diabetes in a biracial US population. The modified risk score can be useful for early screening of incident diabetes in biracial populations, which may be helpful for early interventions to delay or prevent diabetes.
      PubDate: 2017-05-22T01:40:27.631461-05:
      DOI: 10.1111/dom.12949
  • Metabolic responses to exogenous ghrelin in obesity and early after
           Roux-en-Y gastric bypass in humans
    • Authors: Robyn A. Tamboli; Joseph Antoun, Reem M. Sidani, Austin Clements, Emily E. Harmata, Pam Marks-Shulman, Bruce D. Gaylinn, Brandon Williams, Ronald H. Clements, Vance L. Albaugh, Naji N. Abumrad
      Pages: 1267 - 1275
      Abstract: AimsGhrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB).Materials and methodsWe assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg−1 min−1) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp.ResultsGhrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion.ConclusionsThese data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.
      PubDate: 2017-05-31T06:20:44.99734-05:0
      DOI: 10.1111/dom.12952
  • Dapagliflozin once daily plus exenatide once weekly in obese adults
           without diabetes: Sustained reductions in body weight, glycaemia and blood
           pressure over 1 year
    • Authors: Per Lundkvist; Maria J. Pereira, Petros Katsogiannos, C. David Sjöström, Eva Johnsson, Jan W. Eriksson
      Pages: 1276 - 1288
      Abstract: AimsDapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24 weeks. Here, we examined these effects over 1 year in obese adults without diabetes.Materials and methodsObese adults without diabetes (N = 50; aged 18-70 years; body mass index, 30-45 kg/m2) were initially randomized to double-blind oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or to placebo. They entered an open-label extension from 24 to 52 weeks during which all participants received active treatment.ResultsOf the original 25 dapagliflozin + exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52 weeks of treatment. At baseline, mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (−4.5 and −5.7 kg), total adipose tissue volume (−3.8 and −5.3 L), proportion with prediabetes (34.8% and 35.3%), and SBP (−9.8 and −12.0 mm Hg). Effects on body weight, SBP and glycaemia at 52 weeks with placebo  dapagliflozin + exenatide were similar to those observed with continuation of dapagliflozin + exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin + exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed.ConclusionsDapagliflozin + exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52 weeks and was well tolerated in obese adults without diabetes.
      PubDate: 2017-05-31T06:15:37.30821-05:0
      DOI: 10.1111/dom.12954
  • Sodium-glucose co-transporter (SGLT)2 and SGLT1 renal expression in
           patients with type 2 diabetes
    • Authors: Anna Solini; Chiara Rossi, Chiara M. Mazzanti, Agnese Proietti, Hermann Koepsell, Ele Ferrannini
      Pages: 1289 - 1294
      Abstract: AimTo quantify the expression of sodium-glucose co-transporter (SGLT)2 and SGLT1, their cognate basolateral transporters, GLUT2 and GLUT1, and the transcriptional regulator of SGLTs in renal tissue obtained from people with T2DM and a group of well-matched people without diabetes.MethodsWe measured SGLT2 and SGLT1 expression in unaffected renal tissue from 19 people with T2DM and 20 people without diabetes, matched for age and estimated glomerular filtration rate (controls), undergoing unilateral nephrectomy. Expression of SGLT2 and SGLT1, as well as that of GLUT2 and GLUT1, was quantified using real-time and digital PCR; an affinity-purified antibody against human SGLT2 was used to localize SGLT2 by immunohistochemistry.ResultsSGLT2 expression was higher in control than T2DM tissue (median [interquartile range] target/β-actin 1.62 [2.02] vs 0.67 [0.61]; P 
      PubDate: 2017-05-22T01:50:50.287483-05:
      DOI: 10.1111/dom.12970
  • Effect of weight reduction on glycated haemoglobin in weight loss trials
           in patients with type 2 diabetes
    • Authors: Anders Gummesson; Elisabeth Nyman, Mikael Knutsson, Martin Karpefors
      Pages: 1295 - 1305
      Abstract: AimTo quantify the effect of weight loss on glycated haemoglobin (HbA1c) at group level, based on data from published weight loss trials in overweight and obese patients with type 2 diabetes (T2D).MethodsA systematic literature search in MEDLINE, EMBASE and Cochrane CENTRAL (January 1990 through December 2012) was conducted to identify prospective trials of energy-reduced diets, obesity drugs or bariatric surgery in adult, overweight and obese patients with T2D. Based on clinical data with follow-up from 3 to 24 months, a linear model was developed to describe the effect of weight reduction on HbA1c.ResultsThe literature search identified 58 eligible articles consisting of 124 treatment groups and 17 204 subjects, yielding a total of 250 data points with concurrent mean changes from baseline in weight and HbA1c. The model-based analyses indicated a linear relationship between weight loss and HbA1c reduction, with an estimated mean HbA1c reduction of 0.1 percentage points for each 1 kg of reduced body weight for the overall population. Baseline HbA1c was a significant covariate for the relationship between weight loss and HbA1c: high HbA1c at baseline was associated with a greater reduction in HbA1c for the same degree of weight loss. The collected trial data also indicated weight-loss-dependent reductions in antidiabetic medication.ConclusionsAt group level, weight loss in obese and overweight patients with T2D was consistently accompanied by HbA1c reduction in a dose-dependent manner. The model developed in the present study estimates that for each kg of mean weight loss, there is a mean HbA1c reduction of 0.1 percentage points. HbA1c-lowering is greater in populations with poor glycaemic control than in well controlled populations with the same degree of weight loss. This summary of data from previous trials regarding the effect of weight reduction on HbA1c may be used to support the design and interpretation of future studies that aim to demonstrate the efficacy of weight loss interventions for T2D treatment.
      PubDate: 2017-05-22T01:35:40.150019-05:
      DOI: 10.1111/dom.12971
  • Liraglutide acutely suppresses glucagon, lipolysis and ketogenesis in type
           1 diabetes
    • Authors: Manisha Garg; Husam Ghanim, Nitesh D. Kuhadiya, Kelly Green, Jeanne Hejna, Sanaa Abuaysheh, Barrett Torre, Manav Batra, Antoine Makdissi, Ajay Chaudhuri, Paresh Dandona
      Pages: 1306 - 1311
      Abstract: In view of the occurrence of diabetic ketoacidosis associated with the use of sodium-glucose transport protein-2 inhibitors in patients with type 1 diabetes (T1DM) and the relative absence of this complication in patients treated with liraglutide in spite of reductions in insulin doses, we investigated the effect of liraglutide on ketogenesis. Twenty-six patients with inadequately controlled T1DM were randomly divided into 2 groups of 13 patients each. After an overnight fast, patients were injected, subcutaneously, with either liraglutide 1.8 mg or with placebo. They were maintained on their basal insulin infusion and were followed up in our clinical research unit for 5 hours. The patients injected with placebo maintained their glucose and glucagon concentrations without an increase, but there was a significant increase in free fatty acids (FFA), acetoacetate and β-hydoxybutyrate concentrations. In contrast, liraglutide significantly reduced the increase in FFA, and totally prevented the increase in acetoacetate and β-hydroxybutyrate concentrations while suppressing glucagon and ghrelin concentrations. Thus, a single dose of liraglutide is acutely inhibitory to ketogenesis.
      PubDate: 2017-05-18T05:46:43.656251-05:
      DOI: 10.1111/dom.12944
  • Five-year cost-effectiveness of the Patient Empowerment Programme (PEP)
           for type 2 diabetes mellitus in primary care
    • Authors: Jinxiao Lian; Sarah M. McGhee, Ching So, June Chau, Carlos K. H. Wong, William C. W. Wong, Cindy L. K. Lam
      Pages: 1312 - 1316
      Abstract: This study evaluated the short-term cost-effectiveness of the Patient Empowerment Programme (PEP) for diabetes mellitus (DM) in Hong Kong. Propensity score matching was used to select a matched group of PEP and non-PEP subjects. A societal perspective was adopted to estimate the cost of PEP. Outcome measures were the cumulative incidence of all-cause mortality and diabetic complication over a 5-year follow-up period and the number needed to treat (NNT) to avoid 1 event. The incremental cost-effectiveness ratio (ICER) of cost per event avoided was calculated using the PEP cost per subject multiplied by the NNT. The PEP cost per subject from the societal perspective was US$247. There was a significantly lower cumulative incidence of all-cause mortality (2.9% vs 4.6%, P < .001), any DM complication (9.5% vs 10.8%, P = .001) and CVD events (6.8% vs 7.6%, P = .018), in the PEP group. The costs per death from any cause, DM complication or case of CVD avoided were US$14 465, US$19 617 and US$30 796, respectively. The extra amount allocated to managing PEP was small and it appears cost-effective in the short-term as an addition to RAMP.
      PubDate: 2017-05-05T05:30:43.238607-05:
      DOI: 10.1111/dom.12919
  • Lixisenatide reduces glycaemic variability in insulin-treated patients
           with type 2 diabetes
    • Authors: Guillermo E. Umpierrez; David O'Neal, Andres DiGenio, Ronald Goldenberg, Eric Hernandez-Triana, Jay Lin, Cheol-Young Park, Eric Renard, Boris Kovatchev
      Pages: 1317 - 1321
      Abstract: Chronic hyperglycaemia and glucose variability are associated with the development of chronic diabetes-related complications. We conducted a pooled analysis of patient-level data from three 24-week, randomized, phase III clinical trials to evaluate the impact of lixisenatide (LIXI) on glycaemic variability (GV) vs placebo as add-on to basal insulin. The main outcome GV measures were standard deviation (s.d.), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG) level, area under the curve for fasting glucose (AUC-F), and high (HBGI) and low blood glucose index (LBGI). The change in GV metrics over 24 weeks and relationships among baseline GV, patient characteristics and outcomes were assessed. Data were pooled from 1198 patients (665 LIXI, 533 placebo). Values for s.d., MAG level, MAGE, HBGI, and AUC-F significantly decreased with LIXI vs placebo, while LBGI values were unchanged. Higher baseline GV measures correlated with older age, longer type 2 diabetes duration, lower body mass index, higher baseline glycated/haemogobin, greater reduction in postprandial glucose (PPG) level, and higher rates of symptomatic hypoglycaemia. These data show that LIXI added to basal insulin significantly reduced GV and PPG excursions vs placebo, without increasing the risk of hypoglycaemia (LBGI).
      PubDate: 2017-05-05T06:53:50.955326-05:
      DOI: 10.1111/dom.12930
  • Incretin-based glucose-lowering medications and the risk of acute
           pancreatitis and/or pancreatic cancer: Reassuring data from
           cardio-vascular outcome trials
    • Authors: Michael A. Nauck; Juris J. Meier, Wolfgang E. Schmidt
      Pages: 1327 - 1328
      PubDate: 2017-05-22T01:40:56.60839-05:0
      DOI: 10.1111/dom.12981
  • Highlights from the 77th Scientific Sessions of the American Diabetes
           Association Scientific Meeting, 9-13 June 2017, San Diego, USA
    • Authors: Iskandar Idris
      Pages: 1329 - 1331
      PubDate: 2017-08-23T04:22:48.610867-05:
      DOI: 10.1111/dom.13058
  • Corrigendum
    • Pages: 1332 - 1332
      PubDate: 2017-08-23T04:22:44.722342-05:
      DOI: 10.1111/dom.13074
  • Corrigendum
    • Pages: 1333 - 1333
      PubDate: 2017-08-23T04:22:46.840579-05:
      DOI: 10.1111/dom.13076
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