Journal Cover Diabetes, Obesity and Metabolism
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   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  [1579 journals]
  • Saxagliptin add-on therapy in Chinese patients with type 2 diabetes
           inadequately controlled by insulin with or without metformin: results from
           the SUPER study, a randomized, double-blind, placebo-controlled trial
    • Authors: Yingli Chen; Xiaomin Liu, Quanmin Li, Jianhua Ma, Xiaofeng Lv, Lixin Guo, Changjiang Wang, Yongquan Shi, Yanbing Li, Eva Johnsson, Mei Wang, June Zhao, Linong Ji
      Abstract: This prospective, multicentre, phase 3 study (NCT02104804) evaluated the efficacy and safety of saxagliptin add-on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin ± metformin. Patients with glycated haemoglobin (HbA1c) 7.5%–10.5% and fasting plasma glucose (FPG)
      PubDate: 2017-11-16T06:30:21.509547-05:
      DOI: 10.1111/dom.13161
       
  • A comparison of adherence and persistence by medication class in type 2
           diabetes: A systematic review and meta-analysis
    • Authors: Andrew McGovern; Zayd Tippu, William Hinton, Neil Munro, Martin Whyte, Simon de Lusignan
      Abstract: Limited medication adherence and persistence are barriers to successful treatment in type 2 diabetes (T2D). We searched MEDLINE, EMBASE, The Cochrane Library, The Register of Controlled Trials, PsychINFO, and CINAHL for observational and interventional studies comparing medication adherence or persistence between two or more glucose lowering medications in people with T2D. Where several studies (n≥5) provided the same comparison a random effects meta-analysis was performed reporting mean difference (MD), odds ratio (OR), or hazard ratio (HR) depending on the pooled study outcomes.We included 48 studies. Compared with metformin, adherence (%) was better for sulfonylureas (n=5; MD 10.6%; 95%CI 6.5 to 14.7%) and thiazolidinediones (n=6; MD 11.3%; 95%CI 2.7 to 20.0%). Thiazolidinedione adherence was marginally better than sulfonylureas (n=5; MD 1.5%; 95%CI 0.1 to 2.9%). DPP4 inhibitors had better adherence than sulfonylureas and thiazolidinediones. GLP1 receptor agonists had higher OR for discontinuation than long acting analogue insulins (n=6; 1.95; 95%CI 1.17 to 3.27). Long acting insulin analogues had better persistence than human insulins (n=5; MD 43.1; 95%CI 22.0 to 64.2 days). Methods for defining adherence and persistence were highly variable.
      PubDate: 2017-11-14T05:40:23.506857-05:
      DOI: 10.1111/dom.13160
       
  • Acute oral sodium propionate supplementation raises resting energy
           expenditure and lipid oxidation in fasted humans
    • Authors: Edward S. Chambers; Claire S. Byrne, Karen Aspey, Yanjie Chen, Saadiyah Khan, Douglas J. Morrison, Gary Frost
      Abstract: Short chain fatty acids (SCFAs), produced from fermentation of dietary fibre by the gut microbiota, have been suggested to modulate energy metabolism. Previous work using rodent models have demonstrated that oral supplementation of the SCFA propionate raises resting energy expenditure (REE) by promoting lipid oxidation. The objective of this study was to investigate the effects of oral sodium propionate on REE and substrate metabolism in humans. Eighteen healthy volunteers (9 females and 9 males; Age: 25±1 y; Body Mass Index: 24.1±1.2 kg/m2) completed two study visits following an overnight fast. Tablets containing a total of 6845mg sodium propionate or 4164mg sodium chloride were provided over the 180 min study period in a random order. REE and substrate oxidation was assessed by indirect calorimetry. Oral sodium propionate administration increased REE (0.045±0.020 kcal/min; P=0.036) accompanied with elevated rates of whole-body lipid oxidation (0.012 ± 0.006 g/min; P=0.048) and independent of changes in glucose and insulin concentrations. Future studies are warranted to determine whether the acute effects of oral sodium propionate on REE translate into positive improvements in long-term energy balance in humans.
      PubDate: 2017-11-13T23:40:22.918616-05:
      DOI: 10.1111/dom.13159
       
  • The impact of differing glucose-lowering regimens on the pattern of
           association between glucose control and survival
    • Authors: Craig J. Currie; Sarah Holden, Sara Jenkins-Jones, Christopher Ll. Morgan, Bernd Voss, Swapnil N. Rajpathak, Berhanu Alemayehu, John R. Peters, Samuel S. Engel
      Abstract: AimsTo characterise survival in relation to achieved HbA1c within alternative glucose-lowering regimens with differing risks of hypoglycaemia.Materials and methodsData were extracted from the UK Clinical Practice Research Datalink and the Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin were identified between 2004 and 2013. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent variable.ResultsThere were 6,646 deaths with follow-up of 374,591 years. Survival for lower (
      PubDate: 2017-11-09T03:05:51.860517-05:
      DOI: 10.1111/dom.13155
       
  • Metformin for the Management of Peri-operative Hyperglycemia
    • Authors: Russell Brown; James Paul
      Abstract: Perioperative hyperglycemia is an all too common issue (incidence 20-40%) associated with significant surgical morbidity and mortality [1]. Often defined as a blood glucose>11.1mmol/L, peri-operative hyperglycemia increases the risk for developing costly surgical site infections, sepsis, impairs wound healing, promotes endothelial dysfunction, thrombus formation, myocardial ischemia, stroke, neurocognitive dysfunction, prolongs length of hospitalization, and even death [2-7].
      PubDate: 2017-11-09T00:00:30.495241-05:
      DOI: 10.1111/dom.13154
       
  • Glucocorticoids Suppress Brown Adipose Tissue Function In Humans: A
           Double-Blind Placebo-Controlled Study
    • Authors: Moe Thuzar; W Phillip Law, Jeyakantha Ratnasingam, Christina Jang, Goce Dimeski, Ken KY Ho
      Abstract: AimTo investigate the effect of glucocorticoids on BAT function in humansMaterials & MethodsIn a randomised double-blind cross-over design, 13 healthy adults underwent 1 week of oral prednisolone (15mg/day) and placebo treatment with an intervening 2-week wash-out period. BAT function was assessed in response to cooling (190C) and to a standardised meal, by measuring fluoro-deoxyglucose (FDG) uptake using Positron Emission Tomography-Computed Tomography and skin temperatures overlying the supraclavicular (SCL) BAT depots using infrared thermography. Postprandial energy and substrate metabolism was assessed by indirect calorimetry.ResultsDuring cooling, prednisolone significantly reduced BAT FDG uptake (standardised uptake value, SUVmax, 6.1±2.2 vs 3.7±1.2; P
      PubDate: 2017-11-08T23:40:36.69069-05:0
      DOI: 10.1111/dom.13157
       
  • Impact of delaying treatment intensification with a glucagon-like
           peptide-1 receptor agonist in patients with type 2 diabetes uncontrolled
           on basal insulin: a longitudinal study of a US administrative claims
           database
    • Authors: L. Tong; C. Pan, H. Wang, M. Bertolini, E. Lew, L.F. Meneghini
      Abstract: AimTo evaluate the effect of delaying treatment intensification with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) on clinical and economic outcomes in patients with type 2 diabetes (T2D).MethodsWe conducted a retrospective observational claims study using IMPACTTM, in adult patients with T2D who initiated basal insulin between 1 January 2005 and 31 December 2012 with or without OADs, but remained uncontrolled (glycated haemoglobin [HbA1c] ≥7.0%). Patients were categorized into three groups: early, delayed, and no intensification with a GLP-1 RA. We evaluated changes from baseline to 12 months’ follow-up for HbA1c level, rate of hypoglycaemic events, and healthcare costs, and assessed the association between baseline patient characteristics and subsequent treatment intensification.Results139 (9.0% of 1552 eligible patients) met the criteria for inclusion in the early intensification group, 588 (37.9%) in the delayed intensification group, and 825 (53.2%) in the no intensification group. Mean baseline HbA1c values were 9.16%, 9.07%, and 9.34%, respectively. At follow-up, delayed intensification was associated with significantly smaller decreases in HbA1c from baseline (−0.68%) compared with early intensification (−1.01%). Rates of overall hypoglycaemia was numerically greater in delayed intensification group than in early intensification group (0.26 vs 0.06 events/patient-years of exposure, respectively).The change in semi-annual total healthcare costs was greater in the no intensification group (+US$5266) compared with the early intensification (−US$560) and delayed intensification groups (+US$1943).ConclusionsTimely addition of a GLP-1 RA to therapy for patients with T2D not adequately controlled on basal insulin is associated with better clinical and economic outcomes.
      PubDate: 2017-11-08T23:20:25.979407-05:
      DOI: 10.1111/dom.13156
       
  • Long-term efficacy and safety of canagliflozin in combination with insulin
           in Japanese patients with type 2 diabetes mellitus
    • Authors: Nobuya Inagaki; Shin-ichi Harashima, Kohei Kaku, Kazuoki Kondo, Nobuko Maruyama, Makiko Otsuka, Yutaka Kawaguchi, Hiroaki Iijima
      Abstract: AimThe aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin.Materials and methodsThe study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N=70) or canagliflozin (100 mg, CAN; N=76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values.ResultsThe changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were –1.09% ± 0.85% and –0.88% ± 0.86% for HbA1c, −1.40% ± 2.54% and −2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001).Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period.ConclusionsThis study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients.
      PubDate: 2017-11-07T04:40:28.389742-05:
      DOI: 10.1111/dom.13152
       
  • NHE3 Blockade Ameliorates Type 2 Diabetes Mellitus via Inhibition of
           SGLT1-Mediated Glucose Absorption in the Small Intestine
    • Authors: Leo K.Y. Chan; Yi Wang, Enders K.W. Ng, Po Sing Leung
      Abstract: AimNa+/H+ exchanger 3 (NHE3) is an exchanger localized to the small intestinal brush border membrane (BBM). Here, we unraveled the role of NHE3 in SGLT1-mediated small intestinal BBM glucose absorption and functional implication in type 2 diabetes mellitus (T2DM).Materials and methodsHuman jejunal samples were obtained from patients undergoing gastrectomy. 14C-glucose absorption was measured by liquid scintillation counting. NHE3 expression was suppressed by siRNA-mediated knockdown or augmented in Caco2 cells. Glucose and insulin tolerance in db/db and m+/db mice were assessed with oral and intraperitoneal glucose tolerance tests, and intraperitoneal insulin tolerance test. Insulin resistance and β-cell function were assessed with the homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-β).ResultsNHE3 expression was upregulated in db/db mouse jejunal BBM and high-glucose-treated Caco2 cells. NHE3 blockade impaired SGLT1-mediated glucose absorption in human jejunum, m+/db and db/db mouse jejunums, and Caco2 cells, via serum/glucocorticoid-regulated kinase 1 (SGK1). NHE3 knockdown suppressed SGLT1-mediated glucose uptake and reduced mRNA and protein levels of SGK1 and SGLT1, which were conversely enhanced by NHE3 overexpression. Chronic S3226 treatment diminished postprandial glucose levels and ameliorated glucose intolerance in db/db mice.ConclusionNHE3 is essential in the modulation of small intestinal BBM glucose absorption. Our findings provide a rationale for future possible clinical application of NHE3 for treatment of T2DM through reducing intestinal glucose uptake and counteracting post-prandial hyperglycemia.
      PubDate: 2017-11-07T04:25:39.598771-05:
      DOI: 10.1111/dom.13151
       
  • Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and
           tubular dysfunction in a mouse model of diabetic nephropathy
    • Authors: Tony Jourdan; Joshua K. Park, Zoltán V. Varga, János Pálóczi, Nathan J. Coffey, Avi Z. Rosenberg, Grzegorz Godlewski, Resat Cinar, Ken Mackie, Pal Pacher, George Kunos
      Abstract: AimsTo determine the specific role of podocyte-expressed cannabinoid-1 receptor (CB1R) in the development of diabetic nephropathy (DN), relative to CB1R in other renal cell types.Material and methodsWe developed a mouse model with a podocyte-specific deletion of CB1R (pCB1Rko) and challenged this model with streptozotocin (STZ)-induced type-1 DN. We also assessed the podocyte response to high glucose in vitro and its effects on CB1R activation.ResultsHigh glucose exposure for 48h led to an increase in CB1R gene expression (CNR1) and endocannabinoid production in cultured human podocytes. This was associated with podocyte injury reflected by decreased podocin and nephrin expression. These changes could be prevented by Cnr1-silencing, thus identifying CB1R as a key player in podocyte injury. After 12 weeks of chronic hyperglycemia, STZ-treated pCB1Rko mice showed similar elevated blood glucose as their wild-type littermates. However, they displayed less albuminuria and less podocyte loss than STZ-treated wild-type mice. Unexpectedly, pCB1Rko mice also have milder tubular dysfunction, fibrosis and reduction of cortical microcirculation compared to wild-type controls, which is partly mediated by podocyte-derived endocannabinoids acting via CB1R on proximal tubular cells.ConclusionsActivation of CB1R in podocytes contributes to both glomerular and tubular dysfunction in type-1 DN, which highlights the therapeutic potential of peripheral CB1R blockade.
      PubDate: 2017-11-06T05:11:21.610803-05:
      DOI: 10.1111/dom.13150
       
  • A European, multicentre, retrospective, non-interventional study
           (EU-TREAT) of the effectiveness of insulin degludec after switching basal
           insulin in a population with type 1 or type 2 diabetes
    • Authors: Thorsten Siegmund; Nikolaos Tentolouris, Søren T. Knudsen, Annunziata Lapolla, Rudolf Prager, Tra-Mi Phan, Michael Lyng Wolden, Bernd Schultes,
      Abstract: AimsTo evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin-treated patients with either T1DM or T2DM, in conditions of routine clinical care.Materials and methodsThis was a multicentre, retrospective, chart review study. All patients had their basal insulin switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are mean [95%CI].ResultsT1DM (n=1717): HbA1c decreased by −2.2 [−2.6; −2.0] mmol/mol (−0.20 [−0.24; −0.17]%) at 6 months versus baseline (P
      PubDate: 2017-11-06T04:55:50.405755-05:
      DOI: 10.1111/dom.13149
       
  • Cover Image, Volume 19, Issue 12
    • Authors: Eyal Dassau; Eric Renard, Jérôme Place, Anne Farret, Marie-José Pelletier, Justin Lee, Lauren M. Huyett, Ankush Chakrabarty, Francis J. Doyle, Howard C. Zisser
      Abstract: The cover image, by Eyal Dassau et al., is based on the Original Article Intraperitoneal insulin delivery provides superior glycaemic regulation to subcutaneous insulin delivery in model predictive control-based fully-automated artificial pancreas in patients with type 1 diabetes: a pilot study,
      DOI : 10.1111/dom.12999. Design Credit: Harvard University.The cover image, by Eyal Dassau et al., is based on the Original Article Intraperitoneal insulin delivery provides superior glycaemic regulation to subcutaneous insulin delivery in model predictive control-based fully-automated artificial pancreas in patients with type 1 diabetes: a pilot study,
      DOI : 10.1111/dom.12999. Design Credit: Harvard University.
      PubDate: 2017-11-06T03:29:38.668095-05:
       
  • A risk score of BMI, HbA1c and triglycerides predicts future glycemic
           control in type 2 diabetes
    • Authors: Dorijn FL Hertroijs; Arianne MJ Elissen, Martijn CGJ Brouwers, Nicolaas C. Schaper, Sebastian Köhler, Mirela C Popa, Stylianos Asteriadis, Steven H Hendriks, Henk J Bilo, Dirk Ruwaard
      Abstract: AimTo identify, predict and validate distinct glycemic trajectories among patients with newly diagnosed type 2 diabetes treated in primary care, as a first step towards more effective patient-centred care.Material and methodsWe conducted a retrospective study on two cohorts using routinely collected individual patient data in primary care practices from two large Dutch diabetes patient registries. Participants included newly diagnosed, adult patients with type 2 diabetes between January 2006 and December 2014 (n = 10,528, development cohort; n = 3,777, validation cohort). Latent growth mixture modeling (LGMM) identified distinct glycemic 5-year trajectories. Machine learning models were built to predict the trajectories with easily obtainable patient characteristics in daily clinical practice.ResultsThree different glycemic trajectories were identified: 1) stable, adequate glycemic control (76.5% of patients); 2) improved glycemic control (21.3% of patients) and 3) deteriorated glycemic control (2.2% of patients). Similar trajectories could be discerned in the validation cohort. BMI, HbA1c and triglycerides were the most important predictors of trajectory membership. The predictive model, trained on the development cohort, had a receiver operating characteristic area under the curve (ROC-AUC) of 0.96 in the validation cohort, indicating excellent accuracy.ConclusionsThe developed model can effectively explain heterogeneity in future glycemic response of patients with type 2 diabetes. It can therefore be used in clinical practice as a quick and easy tool to provide tailored diabetes care.
      PubDate: 2017-11-02T07:55:21.285712-05:
      DOI: 10.1111/dom.13148
       
  • Direct head-to-head comparison of glycemic durability of dipeptidyl
           peptidase-4 inhibitors and sulphonylureas in patients with type 2 diabetes
           mellitus: a meta-analysis of long-term randomized controlled trials
    • Authors: Kang Chen; Deying Kang, Miao Yu, Ruya Zhang, Ye Zhang, Guojuan Chen, Yiming Mu
      Abstract: We performed a meta-analysis of randomized controlled trials (RCTs) to compare the long-term glycemic durability between dipeptidyl-peptidase 4 (DPP4) inhibitors and sulfonylureas (SUs) in patients with type 2 diabetes mellitus (T2DM), in terms of the changes in glycosylated hemoglobin (HbA1c) levels from an intermediate time point (26 weeks or 52 weeks) to 104 weeks of treatment. The Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library) databases were searched for relevant RCTs. Eight RCTs were included. Compared with SUs, DPP4 inhibitors were associated with significantly smaller increases in the HbA1c level from 24 ~ 28 weeks (mean difference [MD]: −0.16%, 95% confidence interval [CI]: −0.21 to −0.11, P 
      PubDate: 2017-11-02T07:47:19.039214-05:
      DOI: 10.1111/dom.13147
       
  • All-Cause and Diabetes-Related Healthcare Costs among U.S. Adults with
           Type 2 Diabetes Initiating Exenatide Once Weekly or Insulin Glargine
    • Authors: Eric Wittbrodt; Amanda M. Kong, Laura Moore-Schiltz, Paul Juneau
      Abstract: AimsTo compare healthcare utilization and costs between patients with type 2 diabetes (T2D) treated with exenatide (Bydureon®) once weekly (EQW) and patients treated with insulin glargine (IG).Materials and MethodsUsing the MarketScan® Commercial and Medicare Supplemental databases, we conducted a retrospective cohort study of adult US patients with ≥1 claim for T2D initiating EQW or IG from 2/1/2012 to 6/30/2014 (first claim=index date). All-cause and diabetes-related utilization and costs were measured in the 12 months after index date. EQW patients were matched 1:1 to IG patients using propensity scores. Logistic and ordinary least-squares regression models were fit to model differences between the matched cohorts.ResultsThere were 7,749 EQW patients matched to 7,749 IG patients. EQW patients had significantly (p
      PubDate: 2017-10-30T10:25:25.261724-05:
      DOI: 10.1111/dom.13145
       
  • On the etiology of type 1 diabetes: Physiological growth in children
           impacts disease progression
    • Authors: Oskar Skog; Olle Korsgren
      Abstract: The prevailing view is that Type 1 Diabetes (T1D) develops as a consequence of a severe fall in beta-cell mass resulting from T-cell mediated autoimmunity. However, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of c-peptide production occurs in most affected subjects only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total beta cell mass of only 0.2 – 1.5 g in non-diabetic adults.Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in subjects with recent onset T1D and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis; dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30-fold increase in beta-cell mass that normally should occur during the first 20 years of life in order to maintain glucose metabolism during physiological increases in insulin production required to balance the 20-fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand beta-cell mass during childhood would lead to clinically overt T1D and can help to explain the apparently more aggressive form of T1D occurring in growing children when compared to that observed in affected adults.
      PubDate: 2017-10-30T09:55:29.101574-05:
      DOI: 10.1111/dom.13144
       
  • Recent Trends in the Prevalence of Type 2 Diabetes and the Association
           With Abdominal Obesity Lead to Growing Health Disparities in the United
           States
    • Authors: Herve Caspard; Serge Jabbour, Niklas Hammar, Peter Fenici, John J. Sheehan, Mikhail Kosiborod
      Abstract: The prevalence of obesity and type 2 diabetes have increased concomitantly in the United States (US) during the last thirty years.1,2,3 Obesity, in particular abdominal obesity, is also a major risk factor for type 2 diabetes,4,5 suggesting that the increase in the prevalence of obesity has contributed, at least in part, to the increase in the prevalence of type 2 diabetes.
      PubDate: 2017-10-27T09:35:30.913093-05:
      DOI: 10.1111/dom.13143
       
  • SGLT 2 inhibitors and cardiovascular outcome studies in Type 2 diabetes:
           From efficacy to effectiveness
    • Authors: K Khunti; M Kosiborod
      Abstract: Cardiovascular disease remains the main cause of morbidity and mortality in people with diabetes, and is also the largest contributor to healthcare costs in this population(1).
      PubDate: 2017-10-27T09:00:34.508175-05:
      DOI: 10.1111/dom.13142
       
  • Targeting Postprandial Glycaemia in Children with Diabetes: Opportunities
           and Challenges
    • Authors: Myfanwy Clare Geyer; Christopher Keith Rayner, Michael Horowitz, Jennifer Jocelyn Couper
      Abstract: The microvascular complications of diabetes have an irrefutable link to overall glycaemic control and achieving optimal management of glycaemia from the onset of diabetes in children is critical in minimising the risk of complications [1-3].
      PubDate: 2017-10-26T09:10:29.955731-05:
      DOI: 10.1111/dom.13141
       
  • Anti-interleukin-1 therapy has mild hypoglycemic effect in type 2 diabetes
    • Authors: Jinya Huang; Yehong Yang, Renming Hu, Lili Chen
      Abstract: ObjectiveTo systematically evaluate the efficacy and safety of anti-interleukin-1 therapy for type 2 diabetes.MethodsA literature search from Pubmed and Embase for available trials on anti-interleukin-1 therapy in type 2 diabetes was performed. The baseline characteristics, changes of HbA1c and other metabolic parameters and adverse events were extracted from included randomized controlled trials (RCTs) and analyzed with Review Manager. Mean differences (MDs) and 95% CIs were calculated to measure differences of metabolic parameters. Odds ratio and 95% CIs were calculated for adverse event rates.ResultsFive RCTs were included in the current meta-analysis with 357 subjects under anti-interleukin-1 therapy (IL-1 receptor antagonist or anti-IL-1beta antibody) and 221 controls treated with placebo. The HbA1c decrement (%) of anti-interleukin-1 group was significantly higher than that of placebo group (MD=-0.23; 95%CI [-0.39 to -0.07]; P =0.005). AUC of C-peptide was improved too (MD=14.55; 95%CI [1.81 to 27.28]; P=0.03) after anti-interleukin-1 intervention. There was no difference in adverse events rate (odds ratio=1.16; 95%CI[0.90-1.49]; P =0.25) between two groups.ConclusionsAnti-interleukin-1 therapy has mild hypoglycemic effect in type 2 diabetes.
      PubDate: 2017-10-26T09:00:48.098604-05:
      DOI: 10.1111/dom.13140
       
  • A Semi-Physiologic Model of Postprandial Triglyceride Response in Lean,
           Obese and Very Obese Subjects Following a High Fat Meal
    • Authors: Jennifer Leohr; Michael Heathman, Maria C. Kjellsson
      Abstract: AIMSTo quantify the postprandial triglyceride response of chylomicrons and very low-density lipoprotein-V6 (VLDL-V6) following a high fat meal in lean, obese and very obese healthy subjects, using a mechanistic population lipokinetic modeling approach.METHODSHealthy subjects from three BMI population categories: lean (18.5-24.9), obese (30-33), and very obese (34-40) were enrolled in a clinical study to assess the triglyceride response after a high-fat meal, containing 60% fat. Nonlinear mixed-effect modeling was used to analyze the triglyceride concentrations of chylomicrons and large VLDL-V6 particles.RESULTSThe triglycerides in chylomicrons and VLDL-V6 particles had a prominent postprandial peak and represented the majority of the postprandial response. A turn-over model successfully described the triglyceride concentration versus time profiles of both chylomicron and large VLDL-V6 particles post the high fat meal. This model consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of triglycerides in the blood and one compartment for the chylomicron and large VLDL-V6, respectively. The rate constants for the production of chylomicron and elimination of large VLDL-V6 along with the conversion rate of chylomicron to large VLDL-V6 were well defined.CONCLUSIONSThis is the first lipokinetic model that describes the absorption of triglycerides from dietary fats into the blood stream and compares the dynamics of triglycerides in chylomicron and large VLDL-V6 among lean, obese and very obese subjects. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies.
      PubDate: 2017-10-26T08:45:40.447587-05:
      DOI: 10.1111/dom.13138
       
  • Effect of Sitagliptin on Glucose Control in Type 2 Diabetes Mellitus after
           Roux-en-Y Gastric Bypass Surgery
    • Authors: Ankit Shah; Kiarra Levesque, Esmeralda Pierini, Betsy Rojas, Michael Ahlers, Sarah Stano, Marlena Holter, Roxanne Dutia, Scott Belsley, James McGinty, Blandine Laferrère
      Abstract: This is a 4-week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl-peptidase-4 inhibitor, in persistent or recurring type 2 diabetes after gastric bypass surgery (RYGB). Subjects (n=32) completed a mixed meal test (MMT) and home glucose monitoring (SPMG) before and 4 weeks after randomization to either sitagliptin 100 mg daily (S) or placebo daily (P). Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active GLP-1 and β-cell function during the MMT and glucose levels during SPMG.Age (56.3 ± 8.2 y), BMI (34.4±6.7 kg/m2), HbA1c (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 y), years since RYGB (5.6 ± 3.3 y) and β-cell function did not differ between P and S groups at pre-intervention. Sitagliptin was well tolerated, decreased post-prandial glucose during the MMT (135.2±34.3 to 122.3±29.1 mg/dL, p=0.03) and mean home glucose, but had no effect on β-cell function.In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided small but significant glucose-lowering effect with no identified improvement in β-cell function.Clinical trial registration number: NCT01512797
      PubDate: 2017-10-26T08:45:23.638751-05:
      DOI: 10.1111/dom.13139
       
  • High-sensitivity C-reactive Protein, Low-Density Lipoprotein Cholesterol,
           and Cardiovascular Outcomes in Patients with Type 2 Diabetes in the
           EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus
           Standard of Care) Trial
    • Authors: You-Cheol Hwang; David A. Morrow, Christopher P. Cannon, Yuyin Liu, Richard Bergenstal, Simon Heller, Cyrus Mehta, William Cushman, George L Bakris, Faiez Zannad, William B White
      Abstract: ObjectiveWe sought to assess the risk of major adverse cardiovascular events (MACE) by utilizing high-sensitivity C-reactive protein (hsCRP) level and low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and recent acute coronary syndrome.Research Design and MethodsStudy participants enrolled in the EXAMINE trial, were stratified by baseline hsCRP levels (3 mg/l) and were also sub-divided into 4 groups according to baseline hsCRP (≤3 or>3 mg/l) and achieved LDL-C (
      PubDate: 2017-10-24T10:01:44.959758-05:
      DOI: 10.1111/dom.13136
       
  • Effects of Common Cold and Concomitant Administration of Nasal
           Decongestant on the Pharmacokinetics and Pharmacodynamics of Nasal
           Glucagon in Otherwise Healthy Participants: a randomized clinical trial
    • Authors: Cristina B. Guzman; Helene Dulude, Claude Piché, Marianne Rufiange, Aziz A Sadoune, Emmanouil Rampakakis, Dolores Carballo, Myriam Triest, Michelle Xiaotian Zhang, Shuyu Zhang, Maryam Tafreshi, Eric Sicard
      Abstract: AimsNasal glucagon (NG) is a nasally-administered glucagon powder, absorbed through the nasal mucosa, designed for treatment of severe hypoglycaemia. This study evaluated safety, pharmacokinetics (PK), and pharmacodynamics (PD) of NG in otherwise healthy participants with common colds and after recovery from cold symptoms, with and without concomitant nasal decongestant.Materials and MethodsThis was a single-centre, open-label study. Cohort 1 participants (N=18) received two NG doses: one while experiencing nasal congestion and another after recovery from cold symptoms. Cohort 2 participants (N=18), who also had colds with nasal congestion, received a single dose of NG 2 hours after treatment with the decongestant oxymetazoline. Total symptoms score and other safety measures were assessed before and after NG administration.ResultsNG was well tolerated, without serious adverse events. Common adverse events (transient lacrimation, nasal discomfort, rhinorrhea, and nausea) were more frequent in Cohorts 1 and 2 during nasal congestion. Glucagon levels peaked 18 minutes post-dose and glucose levels peaked 30 to 42 minutes post-dose for all groups. Nasal congestion, with or without concomitant nasal decongestant, did not significantly affect PK of NG. Although glucose AUECs0-t were different between Cohort 1 with nasal congestion and Cohort 2, glucose concentrations at 30 minutes appeared similar for all groups.ConclusionsThere were no clinically relevant differences in safety or PK/PD of NG associated with nasal congestion or concomitant administration of nasal decongestant, suggesting that NG can be used to treat severe hypoglycaemia in people experiencing nasal congestion.
      PubDate: 2017-10-20T09:01:24.945953-05:
      DOI: 10.1111/dom.13134
       
  • Treatment Satisfaction with ITCA 650, a Novel Drug-device Delivering
           Continuous Exenatide versus Twice-Daily Injections of Exenatide in Type 2
           Diabetics on Metformin
    • Authors: Robert Henry; Julio Rosenstock, John F. McCarthy, Ginger Carls, Tom Alessi, John Yee, Michelle Baron
      Abstract: AimsTo evaluate treatment satisfaction in patients with type 2 diabetes (T2D), not adequately controlled by metformin, randomized to ITCA 650 (continuous exenatide in osmotic mini-pump) versus twice-daily exenatide injections (Ex-BID).Materials and MethodsThe Diabetes Medication Satisfaction Tool (DM-SAT) was administered and assessments made at baseline, week 8, and week 20 in a 24 week open-label phase 2 trial. In Stage I (weeks 1-12), 155 patients, comprising the ITT population, were randomized to three groups: ITCA 650 20 μg/day, ITCA 650 40 μg/day and Ex-BID 10 μg BID. In Stage II (weeks 13-24), ITCA 650 groups were re-randomized to remain on the Stage I dose or receive a higher dose. Patients treated with Ex-BID were randomized to 40 or 60 μg/day ITCA 650.ResultsPatients taking ITCA 650 reported significant increases in overall treatment satisfaction by week 8 versus those taking Ex-BID (p
      PubDate: 2017-10-20T08:50:25.071429-05:
      DOI: 10.1111/dom.13133
       
  • The identification of barriers to insulin therapy and approaches for
           overcoming them
    • Authors: D. Russell-Jones; F. Pouwer, K. Khunti
      Abstract: Poor glycaemic control in type 2 diabetes (T2D) is a global problem despite the availability of numerous glucose-lowering therapies and clear guidelines for T2D management. Tackling clinical or therapeutic inertia, where the person with diabetes and/or their healthcare providers do not intensify treatment regimens despite this being appropriate, is key to improving patients’ long-term outcomes. This gap between best practice and current level of care is most pronounced when considering insulin regimens, with studies showing that insulin initiation/intensification is frequently and inappropriately delayed for several years. Patient- and physician-related factors both contribute to this resistance at the stages of insulin initiation, titration and intensification, impeding achievement of optimal glycaemic control. This review evaluates the evidence and reasons for this delay, together with available methods for facilitation of insulin initiation or intensification.
      PubDate: 2017-10-20T08:45:53.116828-05:
      DOI: 10.1111/dom.13132
       
  • Preoperative Weight Loss With GLP-1 Receptor Agonist Treatment Predicts
           Greater Weight Loss Achieved by the Combination of Medical Weight
           Management And Bariatric Surgery In Patients With Type 2 Diabetes: A
           Longitudinal Analysis
    • Authors: Tien Tang; Sally Abbott, Carel W le Roux, Violet Wilson, Rishi Singhal, Srikanth Bellary, Abd Tahrani
      Abstract: We examined the relationship between weight changes following preoperative glucagon-like peptide-1 receptor agonist (GLP-1 RA) and weight changes from the start of medical weight management (MWM) till 12 months after bariatric surgery in patients with Type 2 diabetes in a retrospective cohort study. Forty-five patients (64.4% women, median age 49 (IQR 45-60) years) were included. The median weight loss from start of MWM until 12 months post-surgery was 17.9% (13.0%-29.3%). GLP-1 RA during MWM resulted in 5.0% (1.9%-7.7%) weight loss. Weight loss during GLP-1 RA treatment predicted weight loss from the start of MWM till 12 months post-surgery; but not post-operative weight loss following adjustment. The proportion of weight loss from start of MWM to 12 months post-surgery attributed to GLP-1 RA was negatively associated with that attributed to surgery following adjustment. In conclusion, weight change following GLP-1 RA predicted the weight loss achieved by a combination of MWM and bariatric surgery, but not weight loss induced by surgery only. Failure to lose weight following GLP-1 RA should not be considered a barrier to having bariatric surgery.
      PubDate: 2017-10-20T08:36:21.179822-05:
      DOI: 10.1111/dom.13131
       
  • DPP-4 inhibitors moderate the risk of genitourinary tract infections
           associated with SGLT2 inhibitors
    • Authors: Gian Paolo Fadini; Benedetta Maria Bonora, Mayur Sarangdhar, Mauro Rigato, Angelo Avogaro
      Abstract: Genito-urinary tract infections (GUTI) are the most common adverse event (AE) during therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i). We evaluated whether dipeptidyl peptidase 4 inhibitors (DPP4i) moderate the risk of GUTI during therapy with SGLT2i, using two approaches. First, we screened the literature for randomized controlled trials (RCTs) directly comparing the frequency of GUTI in patients receiving a DPP4i/SGLT2i combination therapy versus those receiving a SGLT2i only. In the 5 trials we retrieved, the pooled RR for genital tract infections (GTI) in patients on a DPP4i/SGLT2i combination therapy versus those on SGLT2i alone was 0.51 (95% C.I. 0.28-0.92). Second, we found that within the Food and Drug Administration AE Reporting System (FAERS), the frequency of GUTI among reports listing both SGLT2i and DPP4i as suspect or concomitant drugs was significantly lower than among reports listing SGLT2i without DPP4i, with a proportional reporting ratio (PRR) of 0.74 (95% C.I. 0.61-0.90). In conclusion, in RCTs and in a large pharmacovigilance database, the combination with a DPP4i appears to reduce the frequency of G(U)TI associated with SGLT2i.
      PubDate: 2017-10-20T08:26:37.562278-05:
      DOI: 10.1111/dom.13130
       
  • Effects of glucagon-like peptide-1 (GLP-1) receptor agonists on
           cardiovascular risk factors: a narrative review of head-to-head
           comparisons
    • Authors: Niels B. Dalsgaard; Tina Vilsbøll, Filip K. Knop
      Abstract: Cardiovascular (CV) disease is the leading cause of death and morbidity in patients with type 2 diabetes. Five CV risk factors (blood pressure, resting heart rate [HR], body weight, cholesterol levels and blood glucose) are monitored routinely as safety and efficacy endpoints in randomised clinical trials for diabetes therapies. To determine if different glucagon-like peptide-1 receptor agonists (GLP-1RAs) had varying effects on these CV risk factors, we reviewed 16 head-to-head trials directly comparing GLP-1RAs that included at least one of the five factors. Few trials reported statistical differences between GLP-1RAs in terms of systolic blood pressure (SBP), body weight and total cholesterol. Liraglutide increased heart rate versus its comparators in three separate trials. All GLP-1RAs reduced glycated haemoglobin (HbA1c), but exenatide twice daily and lixisenatide had statistically smaller effects compared with other GLP-1RAs. These descriptive data indicate that individual GLP-1RAs affect CV risk factors differently, potentially due to their individual pharmacokinetics and/or size. Short-acting GLP-1RAs appeared to result in smaller changes in SBP and total cholesterol compared with continuous-acting treatments, while large GLP-1RAs had a reduced effect on body weight compared with small GLP-1RAs. For glycaemic control, short-acting GLP-1RAs had a greater impact on post-prandial glucose levels versus continuous-acting GLP-1RAs, but for fasting plasma glucose levels and HbA1c, continuous-acting treatments had the greater effect. No differentiating trends were obvious in HR data. These diverse actions of GLP-1RAs on CV risk factors should aid individualised patient treatment.
      PubDate: 2017-10-12T08:20:27.051651-05:
      DOI: 10.1111/dom.13128
       
  • Influence of Metabolic Syndrome and Race on the Relationship between
           Intensive Blood Pressure Control and Cardiovascular Outcomes in the SPRINT
           Cohort
    • Authors: Kathleen Dungan; Timothy E. Craven, Kyaw Soe, Jackson T. Wright, Jan Basile, William E. Haley, Nancy R. Kressin, Uzma Rani, Leonardo Tamariz, Jeff Whittle, Alan Wiggers, Kwame Osei
      Abstract: AimsTo determine whether baseline metabolic syndrome (MetS) modifies the effect of intensive blood pressure control on cardiovascular (CV) outcomes, and whether effects varied by race/ethnicity.Materials and MethodsWe performed post-hoc analyses among Non-Hispanic Black (NHB), Non-Hispanic White (NHW), and Hispanic participants with and without MetS in the Systolic Blood Pressure Intervention Trial (SPRINT) randomized to a systolic blood pressure (SBP) target of less than 120 mm Hg (intensive group, N = 4544) or one less than 140 mm Hg (standard group, N = 4553). Median follow-up was 3.26 years. The primary outcome was the composite of the first occurrence of myocardial infarction (MI), stroke, heart failure, non-MI acute coronary syndrome, or (CV) death.ResultsOverall, 3521/9097 (38.7%) of subjects met criteria for MetS at baseline. Baseline characteristics were similar between SBP groups within each MetS subgroup except BMI was slightly higher in the Standard arm of the MetS subgroup (33.3+/−5.6 vs. 33.0+/−5.3, p 
      PubDate: 2017-10-12T08:10:44.19603-05:0
      DOI: 10.1111/dom.13127
       
  • Why do SGLT2 inhibitors reduce heart failure hospitalization' A
           differential volume regulation hypothesis
    • Authors: K. Melissa Hallow; Gabriel Helmlinger, Peter J. Greasley, John J. V. McMurray, David W. Boulton
      Abstract: The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than other diuretic classes, results in greater electrolyte-free water clearance, and ultimately in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling, and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects administered either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling due to low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.
      PubDate: 2017-10-12T07:50:44.491786-05:
      DOI: 10.1111/dom.13126
       
  • Metformin and beta cell function in insulin-treated patients with type 2
           diabetes : a randomized placebo-controlled 4.3 year trial
    • Authors: Wiebe Top; Coen Stehouwer, Philippe Lehert, Adriaan Kooy
      Abstract: Metformin is a key drug in the treatment of type 2 diabetes. In our ‘Hyperinsulinaemia: the Outcome of its Metabolic Effects (HOME) Study’ we showed that metformin vs placebo improved glycemic control and decreased insulin requirements in insulin-treated patients with advanced type 2 diabetes (1).
      PubDate: 2017-10-02T01:40:20.665565-05:
      DOI: 10.1111/dom.13123
       
  • Liraglutide and cardiovascular outcomes in adults with overweight or
           obesity: A post hoc analysis from SCALE randomized controlled trials
    • Authors: MJ Davies; LJ Aronne, ID Caterson, AB Thomsen, PB Jacobsen, SP Marso,
      Abstract: The cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist approved for weight management at a dose of 3.0 mg, was evaluated post hoc using data from 5908 participants in 5 randomized, double-blind, placebo-controlled clinical trials. Participants were randomized to liraglutide or a comparator group (placebo or orlistat). The objective was to evaluate whether cardiovascular risk was increased with liraglutide treatment. The primary composite outcome of this time-to-event analysis was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. These cardiovascular events were adjudicated prospectively for three of the trials and retrospectively for two trials by an event adjudication committee. The primary outcome was analyzed using a Cox proportional hazards model, stratified by trial. With liraglutide 3.0 mg, 8 participants had positively adjudicated cardiovascular events (1.54 events/1000 person-years) compared to 10 participants in the comparators group (3.65 events/1000 person-years). The hazard ratio for liraglutide 3.0 mg compared to comparators was 0.42 (95% confidence interval, 0.17 to 1.08). In this analysis, liraglutide 3.0 mg treatment was not associated with excess cardiovascular risk. However, the wide confidence intervals and retrospective adjudication of events in two of the trials are limitations of the analysis.
      PubDate: 2017-09-26T10:40:26.492325-05:
      DOI: 10.1111/dom.13125
       
  • Dapagliflozin in patients with type 2 diabetes mellitus: a pooled analysis
           of safety data from Phase 2b/3 clinical trials
    • Authors: Serge Jabbour; Jochen Seufert, Andre Scheen, Clifford J Bailey, Cathrina Karup, Anna Maria Langkilde
      Abstract: AimDapagliflozin is a highly selective sodium–glucose cotransporter-2 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). This pooled analysis evaluated the safety and tolerability of dapagliflozin in patients with T2DM.MethodsData were pooled from 13 placebo-controlled trials of up to 24 weeks’ duration (dapagliflozin, n=2360; placebo, n=2295). Larger placebo/comparator-controlled pools of 21 (≤208 week; dapagliflozin, n=5936; control, n=3403) and 30 trials (≥12 week; dapagliflozin, n=9195; control, n=4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower-limb amputation, respectively.ResultsOver 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was comparable for dapagliflozin and placebo; 60.0% versus 55.7% and 5.1% versus 5.4%, respectively. Rates of hypoglycemia, volume depletion AEs, urinary tract infections (UTIs) and fractures were balanced between groups. Genital infections were more frequent with dapagliflozin (5.5%) versus placebo (0.6%) and renal function AEs occurred in 3.2% versus 1.8% of patients (most common renal AE was decreased creatinine clearance: 1.1% versus 0.7%). In the 21-study pool, one SAE of DKA and three AEs of ketonuria/metabolic acidosis occurred with dapagliflozin versus none with control; estimated combined incidence for these events was 0.03% (95% CI:0.010–0.089). In the 30-study pool, lower-limb amputation occurred in eight (0.1%) and seven (0.2%) patients receiving dapagliflozin and control, respectively.ConclusionThe overall incidence of AEs and SAEs was comparable in the dapagliflozin and placebo/control groups, including the incidence of hypoglycemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.http:ClinicalTrials.gov identifiers:NCT00263276, NCT00357370, NCT00528372, NCT00528879, NCT00643851, NCT00660907, NCT00663260, NCT00831779; NCT00673231, NCT00680745, NCT00683878, NCT00736879, NCT00855166, NCT00859898, NCT00972244, NCT00976495, NCT00984867, NCT01031680, NCT01042977, NCT01095653, NCT01095666, NCT01137474, NCT01195662, NCT01217892, NCT01294423, NCT01294436, NCT01392677, NCT01606007, NCT01619059, NCT01646320
      PubDate: 2017-09-26T10:35:26.772422-05:
      DOI: 10.1111/dom.13124
       
  • Non–ST-Elevation Myocardial Infarction (NSTEMI) outcome in type 2
           diabetic patients with non-obstructive coronary artery stenosis: effects
           of incretin treatment
    • Authors: Raffaele Marfella; Celestino Sardu, Paolo Calabrò, Mario Siniscalchi, Fabio Minicucci, Giuseppe Signoriello, Maria Luisa Balestrieri, Ciro Mauro, Maria Rosaria Rizzo, Giuseppe Paolisso, Michelangela Barbieri
      Abstract: No proper data on prognosis and management of type-2 diabetic patients with non-obstructive coronary artery stenosis (NOCS)-Non–ST-Elevation Myocardial Infarction (NSTEMI) exist. We evaluated the 12-months prognosis of NOCS-diabetics (20-49% luminal stenosis) with first NSTEMI as compared with non-diabetics. Moreover, we investigated the 12-months prognosis in NSTEMI-NOCS diabetics, previously treated with incretin-based therapy, compared with a matched cohort of NSTEMI-NOCS never treated with such therapy. Furthermore, we categorized the diabetic patients in current-incretin-users (6 months, GLP-1 agonists or DPP-4 inhibitors), and never-incretin-users. The endpoint was all-cause death, cardiac death, recurrent acute coronary (ACS) syndrome, and heart failure (HF). The unadjusted Kaplan-Meier, and a risk-adjusted hazard analysis evidenced that, all death, cardiac death, readmission for ACS, and HF through 12 months were higher in diabetic than non-diabetic NOCS-NSTEMI patients. Among diabetic patients, the current-incretin-users, presented a significantly lower rate of all death, cardiac death, and readmission for ACS through 12-months. In type 2 diabetic patients with NOCS-NSTEMI, we observed higher incidence of 1-year mortality, and adverse cardiovascular outcomes, as compared to non-diabetic NOCS-NSTEMI patients. In diabetic patients, never-incretin-users have worse prognosis as compared to current-incretin-users.
      PubDate: 2017-09-26T10:21:55.54623-05:0
      DOI: 10.1111/dom.13122
       
  • Different intervention strategies for preventing type 2 diabetes mellitus
           in China: A systematic review and network meta-analysis of randomized
           controlled trials
    • Authors: Bing Pang; Lin-hua Zhao, Xin-long Li, Jun Song, Qing-wei Li, Xing Liao, Shuo Feng, Xi-yan Zhao, Yu-jiao Zheng, Xiao-wen Gou, Qing Ni, Xiao-lin Tong
      Abstract: Different strategies are increasingly used for early intervention on prediabetes in China, but the effects of these strategies on incident diabetes have not yet been confirmed. This study was to systematically assess the effects of different strategies on preventing diabetes, aimed at Chinese prediabetic subjects. Seven electronic databases were searched to identify eligible trials published from inception to Sep 20, 2016. Randomized controlled trials with a minimum follow-up duration of 6 months were included. Standard pairwise meta-analysis with a random-effects model and network meta-analysis with a frequentist framework were performed. Sixty-three studies with 11 intervention strategies were included. Compared with placebo, all strategies, except for lipid-affecting drugs and sitagliptin, reduced the incident diabetes with different levels of effectiveness, ranging from 0.18 (95%CI 0.12, 0.27) to 0.39 (95%CI 0.20, 0.75). Ranking probability analysis indicated that metformin and β-cell simulating drugs reduced the risk of diabetes most, with probabilities of 87.4 and 81%, respectively. Ethnicity and cultural factors should be considered for diabetes prevention. However, most of the included trials were of poor methodological quality; the results should be interpreted with caution.
      PubDate: 2017-09-23T08:21:36.496821-05:
      DOI: 10.1111/dom.13121
       
  • Semaglutide improves postprandial glucose and lipid metabolism, and delays
           first-hour gastric emptying in subjects with obesity
    • Authors: JB Hjerpsted; A Flint, A Brooks, MB Axelsen, T Kvist, J Blundell
      Abstract: AimTo investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying.Materials and MethodsThis was a randomised, double-blind, placebo-controlled, two-period, crossover trial. Subjects with obesity (N = 30) received once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, or placebo. After each 12-week treatment period, glucose and lipid metabolism were assessed before and after standardised meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed.ResultsSemaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin versus placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide versus placebo (incremental area under the curve 0–5 hours [iAUC0-5h]; estimated treatment difference: glucose −1.34 mmol*h/L [−2.42, −0.27]; insulin −921 pmol*h/L [−1461, −381]; C-peptide −1.42 nmol*h/L [−2.33, −0.51]). Fasting and postprandial lipid metabolism improved with semaglutide versus placebo. First-hour gastric emptying after the meal was delayed versus placebo (AUC0-1h; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide-treated subjects. Overall gastric emptying (AUC0-5h) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide versus placebo (p=0.0397 and p=0.0097, respectively).ConclusionSemaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to placebo; however, the observed first-hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.
      PubDate: 2017-09-23T08:00:20.950298-05:
      DOI: 10.1111/dom.13120
       
  • Islet neuropeptide Y receptors are functionally conserved and novel
           targets for the preservation of beta-cell mass
    • Authors: ZJ Franklin; A Tsakmaki, P Fonseca Pedro, AJ King, GC Huang, SJ Persaud, GA Bewick
      Abstract: ObjectiveTwo unmet therapeutic strategies for diabetes treatment are prevention of beta-cell death and stimulation of beta-cell replication. Our aim was to characterise the role of Neuropeptide Y receptors in the control of beta-cell mass.MethodsWe used endogenous and selective agonists of the NPY receptor system to explore its role in the prevention of beta-cell apoptosis and proliferation in islets isolated from both mouse and human donors. We further explored the intra-cellular signalling cascades involved using chemical inhibitors of key signalling pathways. As proof of principle we designed a long-acting analogue of [Leu31Pro34]-NPY, an agonist of the islet expressed Y receptors, to validate if targeting this system could preserve beta-cell mass in vivo.ResultsOur data reveal NPY Y1, 4 and 5 receptor activation engages a generalised and powerful anti-apoptotic pathway which protects mouse and human islets from damage. This anti-apoptotic effects were dependent on stimulating a Gαi-PLC-PKC signalling cascade, which prevented cytokine induced NFkB signalling. NPY receptor activation functionally protected islets by restoring glucose responsiveness following chemically induced injury in both species. NPY receptor activation attenuated beta-cell apoptosis, preserved functional beta-cell mass and attenuated the hyperglycaemic phenotype in a low dose streptozotocin model of diabetes.ConclusionTaken together, our observations identify the islet Y receptors as promising targets for the preservation of beta-cell mass. As such targeting these receptors could help to maintain beta-cell mass in both Type 1 and 2 diabetes and may also be useful for improving islet transplantation outcomes.
      PubDate: 2017-09-22T09:10:49.686327-05:
      DOI: 10.1111/dom.13119
       
  • Perioperative continuation of metformin does not improve glycemic control
           in patients with type 2 diabetes; a randomized controlled trial
    • Authors: A.H. Hulst; J.A.W. Polderman, E. Ouweneel, A.J. Pijl, M.W. Hollmann, J.H. DeVries, B. Preckel, J. Hermanides
      Abstract: Historically, metformin was withheld before surgery in fear of metformin associated lactic acidosis. Now, this risk is deemed low and guidelines move towards continuation of metformin. We hypothesized that continuing metformin perioperatively would lower postoperative serum glucose without an effect on plasma lactate.We performed a single-blind multicenter RCT in type 2 diabetes mellitus patients scheduled for non-cardiac surgery and continued (MF+) or withheld (MF–) metformin before surgery. Main outcome parameters were the differences in perioperative plasma glucose and lactate levels. We randomized 70 patients (37 MF+ group and 33 MF– group) with type 2 diabetes mellitus. Postoperative glucose levels were similar between groups (148 ± 32 (MF+) vs. 149 ± 41 mg dl-1 (MF–), p=0.95) Although preoperative lactate levels were slightly higher in the MF+ group compared to the MF– group (1.5 vs. 1.2 mmol l-1, p=0.02), the postoperative lactate levels were not significantly different (1.2 vs. 1.0 mmol l-1, p=0.18).In conclusion, continuation of metformin during elective non-cardiac surgery does not improve glucose control or raise lactate levels to a clinically relevant degree.MESH Keywords: Metformin; Diabetes Mellitus, Type 2; Perioperative Period.Trial registry number: NTR5254 Nederlands Trial Register
      PubDate: 2017-09-20T06:00:30.146455-05:
      DOI: 10.1111/dom.13118
       
  • Efficacy and Safety of Saxagliptin in Combination with Metformin as
           Initial Therapy in Chinese Patients with Type 2 diabetes: Results from the
           START Study, a Multicenter, Randomized, Double-blind, Active-controlled,
           Phase 3 Trial
    • Authors: Jingtao Dou; Jianhua Ma, Jun Liu, Changjiang Wang, Eva Johnsson, Hui Yao, June Zhao, Changyu Pan
      Abstract: OBJECTIVETo assess the efficacy and safety of saxagliptin plus metformin over 24 weeks in pharmacotherapy-naïve Chinese patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c 8.0–12.0%).RESEARCH DESIGN AND METHODSIn this multicenter, double-blind, active-controlled study (The START study: NCT02273050), patients were randomized (1:1:1) to saxagliptin 5 mg plus metformin, saxagliptin 5 mg plus placebo, or metformin plus placebo. Saxagliptin was taken once daily; metformin was taken once/twice daily and was titrated from 500 mg to a maximum of 2000 mg/day over 8 weeks. The primary end point was change in HbA1c from baseline to week 24.RESULTSData from 630 patients (66.5% men; mean age 50.1 years; mean body mass index, 26.6 kg/m2; mean HbA1c 9.4%; mean diabetes duration, 0.81 years) were analyzed. Mean HbA1c reduction was greater with saxagliptin plus metformin (−3.0%) than with saxagliptin plus placebo (−2.1%; P < 0.001) or metformin plus placebo (−2.8%; P = 0.034). Changes in mean fasting plasma glucose, 120-min postprandial glucose, and 180-min postprandial glucose area under curve were greater, and more patients achieved a therapeutic glycemic response, with saxagliptin plus metformin than with either monotherapy. Hypoglycemic events were infrequent (
      PubDate: 2017-09-19T09:55:27.586131-05:
      DOI: 10.1111/dom.13117
       
  • 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
           diabetes
    • 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
           Diabetes
    • 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 ClinicalTrials.gov 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
       
  • 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. (ClinicalTrials.gov: 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
           study
    • 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
           Volunteers
    • 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 (clinicaltrials.gov).
      PubDate: 2017-07-25T10:20:22.694091-05:
      DOI: 10.1111/dom.13072
       
  • 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
           analysis)
    • 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
           clamp
    • 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 (clinicaltrials.gov): 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
       
  • 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 Trials.gov 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
           study
    • 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 observed.ClinicalTrials.gov: NCT02673281
      PubDate: 2017-07-17T10:55:20.572442-05:
      DOI: 10.1111/dom.13060
       
  • 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
       
  • 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
       
  • 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
       
  • 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
           meta-analysis
    • 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 ClinicalTrials.gov 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
       
  • 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. Clinicaltrials.gov (NCT01518764)
      PubDate: 2017-06-23T03:55:18.314237-05:
      DOI: 10.1111/dom.13044
       
  • Diabetes, Obesity and Metabolism
    • Pages: 1643 - 1644
      PubDate: 2017-11-06T03:29:41.062573-05:
      DOI: 10.1111/dom.12777
       
  • A review of glucagon-like peptide-1 receptor agonists and their effects on
           lowering postprandial plasma glucose and cardiovascular outcomes in the
           treatment of type 2 diabetes mellitus
    • Authors: David R. Owens; Louis Monnier, Markolf Hanefeld
      Pages: 1645 - 1654
      Abstract: Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular (CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose (PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all-cause and CV-related mortality. Although GLP-1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short-lived effect on gastric emptying and, hence, lower PPG substantially. However, current long-term data on CV outcomes with GLP-1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes.
      PubDate: 2017-07-11T06:01:21.347432-05:
      DOI: 10.1111/dom.12998
       
  • Insulin-associated weight gain in obese type 2 diabetes mellitus patients:
           What can be done'
    • Authors: Adrian Brown; Nicola Guess, Anne Dornhorst, Shahrad Taheri, Gary Frost
      Pages: 1655 - 1668
      Abstract: Insulin therapy (IT) is initiated for patients with type 2 diabetes mellitus when glycaemic targets are not met with diet and other hypoglycaemic agents. The initiation of IT improves glycaemic control and reduces the risk of microvascular complications. There is, however, an associated weight gain following IT, which may adversely affect diabetic and cardiovascular morbidity and mortality. A 3 to 9 kg insulin-associated weight gain (IAWG) is reported to occur in the first year of initiating IT, predominantly caused by adipose tissue. The potential causes for this weight gain include an increase in energy intake linked to a fear of hypoglycaemia, a reduction in glycosuria, catch-up weight, and central effects on weight and appetite regulation. Patients with type 2 diabetes who are receiving IT often have multiple co-morbidities, including obesity, that are exacerbated by weight gain, making the management of their diabetes and obesity challenging. There are several treatment strategies for patients with type 2 diabetes, who require IT, that attenuate weight gain, help improve glycaemic control, and help promote body weight homeostasis. This review addresses the effects of insulin initiation and intensification on IAWG, and explores its potential underlying mechanisms, the predictors for this weight gain, and the available treatment options for managing and limiting weight gain.
      PubDate: 2017-07-13T05:35:39.807193-05:
      DOI: 10.1111/dom.13009
       
  • Postprandial renal haemodynamic effect of lixisenatide vs once-daily
           insulin-glulisine in patients with type 2 diabetes 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
      Pages: 1669 - 1680
      Abstract: AimTo determine whether lixisenatide, a prandial short-acting glucagon-like peptide receptor agonist (GLP-1RA), ameliorates postprandial glomerular hyperfiltration in patients with type 2 diabetes mellitus (T2DM) compared with insulin-glulisine (iGlu).MethodsPostprandial renal haemodynamic effects of 8-week treatment with lixisenatide 20 µg vs once-daily titrated iGlu were measured in 35 overweight patients with T2DM inadequately controlled on insulin-glargine, with or without metformin [mean ± SD age 62 ± 7 years, HbA1c 8.0% ± 0.9%, estimated glomerular filtration rate (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 with 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% (0.09-0.41)] and urinary pH [+0.7 (0.3-1.2)]. 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 = .002). Compared with iGlu, lixisenatide reduced bodyweight [−1.4 kg (−2.5 to −0.2)] and increased postprandial mean arterial pressure [+9 mm Hg (4-14)].ConclusionEight-week lixisenatide treatment does not affect postprandial (intra-)renal haemodynamics compared with iGlu when added to insulin-glargine in patients with T2DM without overt nephropathy. Prolonged lixisenatide treatment has a sustained natriuretic effect, which is in contrast to previous reports on long-acting GLP-1RA, reduces body weight and increases postprandial blood pressure compared with iGlu.Trial registration: ClinicalTrials.gov identifier NCT02276196
      PubDate: 2017-07-25T23:35:42.463623-05:
      DOI: 10.1111/dom.12985
       
  • Efficacy and safety of evogliptin monotherapy in patients with type 2
           diabetes and moderately elevated glycated haemoglobin levels after diet
           and exercise
    • Authors: Juri Park; Sung Woo Park, Kun Ho Yoon, Sung Rae Kim, Kyu Jeung Ahn, Jae Hyuk Lee, Ji Oh Mok, Choon Hee Chung, Kyung Ah Han, Gwan Pyo Koh, Jun Goo Kang, Chang Beom Lee, Seong Hwan Kim, Na Young Kwon, Doo Man Kim
      Pages: 1681 - 1687
      Abstract: AimsTo evaluate the efficacy and safety of evogliptin, a newly developed dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes (T2D) inadequately controlled by diet and exercise.Materials and MethodsIn this randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase III study, 160 patients with T2D were assigned to either evogliptin 5 mg or placebo for 24 weeks. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline to week 24.ResultsThe mean baseline HbA1c levels were similar in the evogliptin and the placebo groups (7.20% ± 0.56% vs 7.20% ± 0.63%, respectively). At week 24, evogliptin significantly reduced HbA1c levels from baseline compared with placebo (−0.23% vs 0.05%, respectively, P < .0001). Additionally, the proportion of patients achieving HbA1c
      PubDate: 2017-07-07T03:35:42.162581-05:
      DOI: 10.1111/dom.12987
       
  • Cost-effectiveness of exenatide twice daily vs insulin glargine as add-on
           therapy to oral antidiabetic agents in patients with type 2 diabetes in
           China
    • Authors: Shuyan Gu; Xiaoyong Wang, Qing Qiao, Weiguo Gao, Jian Wang, Hengjin Dong
      Pages: 1688 - 1697
      Abstract: AimsTo estimate the long-term cost-effectiveness of exenatide twice daily vs insulin glargine once daily as add-on therapy to oral antidiabetic agents (OADs) for Chinese patients with type 2 diabetes (T2DM).MethodsThe Cardiff Diabetes Model was used to simulate disease progression and estimate the long-term effects of exenatide twice daily vs insulin glargine once daily. Patient profiles and treatment effects required for the model were obtained from literature reviews (English and Chinese databases) and from a meta-analysis of 8 randomized controlled trials comparing exenatide twice daily with insulin glargine once daily add-on to OADs for T2DM in China. Medical expenditure data were collected from 639 patients with T2DM (aged ≥18 years) with and without complications incurred between January 1, 2014 and December 31, 2015 from claims databases in Shandong, China. Costs (2014 Chinese Yuan [¥]) and benefits were estimated, from the payers’ perspective, over 40 years at a discount rate of 3%. A series of sensitivity analyses were performed.ResultsPatients on exenatide twice daily + OAD had a lower predicted incidence of most cardiovascular and hypoglycaemic events and lower total costs compared with those on insulin glargine once daily + OAD. A greater number of quality-adjusted life years (QALYs; 1.94) at a cost saving of ¥117 706 gained was associated with exenatide twice daily vs insulin glargine once daily. (i.e. cost saving of ¥60 764/QALY) per patient.ConclusionsIn Chinese patients with T2DM inadequately controlled by OADs, exenatide twice daily is a cost-effective add-on therapy alternative to insulin glargine once daily, and may address the problem of an excess of medical needs resulting from weight gain and hypoglycaemia in T2DM treatment.
      PubDate: 2017-07-20T09:01:37.028758-05:
      DOI: 10.1111/dom.12991
       
  • Intraperitoneal insulin delivery provides superior glycaemic regulation to
           subcutaneous insulin delivery in model predictive control-based
           fully-automated artificial pancreas in patients with type 1 diabetes: a
           pilot study
    • Authors: Eyal Dassau; Eric Renard, Jérôme Place, Anne Farret, Marie-José Pelletier, Justin Lee, Lauren M. Huyett, Ankush Chakrabarty, Francis J. Doyle, Howard C. Zisser
      Pages: 1698 - 1705
      Abstract: AimsTo compare intraperitoneal (IP) to subcutaneous (SC) insulin delivery in an artificial pancreas (AP).Research design and methodsTen adults with type 1 diabetes participated in a non-randomized, non-blinded sequential AP study using the same SC glucose sensing and Zone Model Predictive Control (ZMPC) algorithm adjusted for insulin clearance. On first admission, subjects underwent closed-loop control with SC delivery of a fast-acting insulin analogue for 24 hours. Following implantation of a DiaPort IP insulin delivery system, the identical 24-hour trial was performed with IP regular insulin delivery. The clinical protocol included 3 unannounced meals with 70, 40 and 70 g carbohydrate, respectively. Primary endpoint was time spent with blood glucose (BG) in the range of 80 to 140 mg/dL (4.4-7.7 mmol/L).ResultsPercent of time spent within the 80 to 140 mg/dL range was significantly higher for IP delivery than for SC delivery: 39.8 ± 7.6 vs 25.6 ± 13.1 (P = .03). Mean BG (mg/dL) and percent of time spent within the broader 70 to 180 mg/dL range were also significantly better for IP insulin: 151.0 ± 11.0 vs 190.0 ± 31.0 (P = .004) and 65.7 ± 9.2 vs 43.9 ± 14.7 (P = .001), respectively. Superiority of glucose control with IP insulin came from the reduced time spent in hyperglycaemia (>180 mg/dL: 32.4 ± 8.9 vs 53.5 ± 17.4, P = .014;>250 mg/dL: 5.9 ± 5.6 vs 23.0 ± 11.3, P = .0004). Higher daily doses of insulin (IU) were delivered with the IP route (43.7 ± 0.1 vs 32.3 ± 0.1, P < .001) with no increased percent time spent
      PubDate: 2017-07-06T06:55:33.145562-05:
      DOI: 10.1111/dom.12999
       
  • Relationship between diabetes and ischaemic 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
      Pages: 1706 - 1713
      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. The 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 8 sites. CMR core laboratory analysis was performed to determine infarct characteristics. Major adverse cardiac events (MACE), defined as a composite of all-cause death, non-fatal 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 and 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> .05). Patients with DM were at higher risk of MACE (11% vs 6%, P = .03) than non-DM patients. After stratification according to preadmission anti-diabetic therapy, MACE rate was comparable between NITDM and non-DM (P> .05), whereas the group of ITDM patients had significantly worse outcome (P < .001).ConclusionsDiabetic patients with STEMI, especially those having ITDM, had an increased risk of MACE. The adverse clinical outcome was, however, not explained by an impact of DM on reperfusion success or myocardial damage.Clinical trial registry number: NCT00712101.
      PubDate: 2017-07-25T06:40:55.017393-05:
      DOI: 10.1111/dom.13002
       
  • Fasiglifam for glycaemic control in people with type 2 diabetes: A phase
           III, placebo-controlled study
    • Authors: John Marcinak; Charles Cao, Douglas Lee, Zhan Ye
      Pages: 1714 - 1721
      Abstract: AimTo investigate the effect of fasiglifam on glycaemic control in people with type 2 diabetes mellitus (T2DM).MethodsIn total, 421 people with T2DM and glycated haemoglobin (HbA1c) ≥7.0% and ≤10.5% who had received only diet and exercise treatment for ≥12 weeks prior to screening were randomized to receive fasiglifam 25 or 50 mg or placebo. The primary efficacy endpoint was change from baseline in HbA1c at week 24.ResultsThe mean participant age was 53.5 years, mean baseline body mass index 32.3 kg/m2, and mean baseline HbA1c level 8.05%. Least squares mean changes in HbA1c from baseline to week 24 were: −0.93% (fasiglifam 50 mg), −0.65% (fasiglifam 25 mg) and −0.17% (placebo). Treatment-emergent adverse events (TEAEs) occurred in 53.3%, 48.2% and 39.9% of participants receiving fasiglifam 25 mg, fasiglifam 50 mg, and placebo, respectively. Three participants in each group experienced a serious adverse event (AE). Nine participants had alanine aminotransferase (ALT) elevations>3× upper limit of normal: 5 (3.6%) in the fasiglifam 25-mg group, 4 (2.8%) in the fasiglifam 50-mg group, and none in the placebo group.ConclusionsThe data indicate that fasiglifam effectively reduced HbA1c from baseline for 24 weeks in participants with T2DM. The incidence of TEAEs was higher in the fasiglifam groups; however, the incidence of serious AEs was low overall and similar between groups. ALT elevations were observed only in the fasiglifam groups, which contributed to the decision to terminate the fasiglifam programme after completion of the present study.
      PubDate: 2017-07-11T05:56:36.005863-05:
      DOI: 10.1111/dom.13004
       
  • LAPSInsulin115: A novel ultra-long-acting basal insulin with a unique
           action profile
    • Authors: Nina Wronkowitz; Thorsten Hartmann, Sven Wolfgang Görgens, Daniela Dietze-Schroeder, Ira Indrakusuma, In Young Choi, Sung Hee Park, Young-Mi Lee, Se Chang Kwon, Yeonjoo Kang, Marcus Hompesch, Jürgen Eckel
      Pages: 1722 - 1731
      Abstract: AimsTo conduct a comprehensive pre-clinical study of the novel ultra-long acting insulin analogue LAPSInsulin115.MethodsPharmacokinetic/pharmacodynamic studies comparing LAPSInsulin115 with other basal insulins were conducted in genetically diabetic (db/db) mice. Insulin signalling in the major target organs was analysed using Western blot after single subcutaneous injection in wild-type male Wistar rats. Using in vitro assays we analysed transendothelial transport, insulin receptor (IR) interaction, and the mitogenic and metabolic properties of LAPSInsulin115. Furthermore, IR downregulation after long-term exposure to high concentrations of LAPSInsulin115 was analysed using an in vitro desensitization/resensitization model.ResultsThe novel Fc-conjugated insulin derivative LAPSInsulin115 showed an extensively prolonged pharmacokinetic and pharmacodynamic profile in rodents. Despite its size of 59 kDa, LAPSInsulin115 passes the vascular endothelial barrier and induces insulin signalling in all major target tissues in rats. In vitro, LAPSInsulin115 showed a very slow onset of action because of its reduced IR affinity; however, after long-term stimulation it was equipotent in respect to its metabolic potency and showed no increased mitogenic action when compared with regular insulin. Remarkably, under conditions of chronic exposure, LAPSInsulin115 does not induce irreversible desensitization of target cells, which is probably attributable to much less prominent IR downregulation.ConclusionThus, LAPSInsulin115 exhibits a unique in vivo and in vitro profile and thereby represents an excellent candidate for a once-weekly insulin analogue.
      PubDate: 2017-07-13T05:36:44.880022-05:
      DOI: 10.1111/dom.13006
       
  • Breaking up sedentary time with seated upper body activity can regulate
           metabolic health in obese high-risk adults: A randomized crossover trial
    • Authors: Matthew McCarthy; Charlotte L. Edwardson, Melanie J. Davies, Joseph Henson, Alex Rowlands, James A. King, Danielle H. Bodicoat, Kamlesh Khunti, Thomas Yates
      Pages: 1732 - 1739
      Abstract: AimsTo investigate the impact of performing short bouts of seated upper body activity on postprandial blood glucose and insulin levels during prolonged sitting.MethodsParticipants undertook two 7.5-hour experimental conditions in randomized order: (1) prolonged sitting only and (2) sitting, interspersed with 5 minutes of seated arm ergometry every 30 minutes. Blood samples were obtained while fasting and throughout the postprandial period after ingestion of two standardized meals. The incremental area under the curve (iAUC) was calculated for glucose and insulin throughout each experimental condition. A paired samples t-test was used to assess the difference in iAUC data between conditions for glucose (primary outcome) and insulin (secondary outcome).ResultsThirteen obese adults (7 women, 6 men; mean ± standard deviation [s.d.] age: 66 ± 6 years; body mass index 33.8 ± 3.8 kg/m2) completed this investigation. Compared with the prolonged sitting-only condition, the implementation of seated arm ergometry every 30 minutes significantly reduced mean blood glucose iAUC (from 7.4 mmol/L/h [95% confidence interval {CI} 5.2, 9.5] to 3.1 mmol/L/h [95% CI 1.3, 5.0]; P = .001). Significant reductions in mean insulin iAUC (from 696 mU/L/h [95% CI 359, 1032] to 554 mU/L/h [95% CI 298, 811]; P = .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.
      PubDate: 2017-07-20T09:00:28.647082-05:
      DOI: 10.1111/dom.13016
       
  • Ghrelin receptor inverse agonists as a novel therapeutic approach against
           obesity-related metabolic disease
    • Authors: Kathrin Abegg; Lara Bernasconi, Melanie Hutter, Lynda Whiting, Claudio Pietra, Claudio Giuliano, Thomas A. Lutz, Thomas Riediger
      Pages: 1740 - 1750
      Abstract: AimsGhrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand-independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested 2 novel synthetic compounds GHSR-IA1 and GHSR-IA2.Materials and MethodsIn functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids.ResultsBoth compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR-IA1 increased metabolic rate in chow-fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR-IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice.ConclusionsOur study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity-related metabolic disorders including diabetes mellitus.
      PubDate: 2017-07-13T05:45:59.707004-05:
      DOI: 10.1111/dom.13020
       
  • Effects of MetAP2 inhibition on hyperphagia and body weight in
           Prader–Willi syndrome: A randomized, double-blind, placebo-controlled
           trial
    • Authors: Shawn E. McCandless; Jack A. Yanovski, Jennifer Miller, Cary Fu, Lynne M. Bird, Parisa Salehi, Christine L. Chan, Diane Stafford, M. Jennifer Abuzzahab, David Viskochil, Sarah E. Barlow, Moris Angulo, Susan E. Myers, Barbara Y. Whitman, Dennis Styne, Elizabeth Roof, Elisabeth M. Dykens, Ann O. Scheimann, Jaret Malloy, Dongliang Zhuang, Kristin Taylor, Thomas E. Hughes, Dennis D. Kim, Merlin G. Butler
      Pages: 1751 - 1761
      Abstract: AimsThere are no treatments for the extreme hyperphagia and obesity in Prader–Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib.Materials and MethodsParticipants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151.ResultsOne-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference −6.3, 95% CI −9.6 to −3.0; P = .0003) and 2.4 mg beloranib groups (−7.0, 95% CI −10.5 to −3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference − 8.2%, 95% CI −10.8 to −5.6; P < .0001) and 2.4 mg beloranib (−9.5%, 95% CI −12.1 to −6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo.ConclusionsMetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.
      PubDate: 2017-07-13T05:35:48.144696-05:
      DOI: 10.1111/dom.13021
       
  • Once-weekly administration of a long-acting fibroblast growth factor 21
           analogue modulates lipids, bone turnover markers, blood pressure and body
           weight differently in obese people with hypertriglyceridaemia 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
      Pages: 1762 - 1772
      Abstract: AimsTo assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes.MethodsParticipants received PF-05231023 or placebo intravenously once weekly for 4 weeks. Safety (12-lead 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 (BP; mean, systolic and diastolic) and ECGs were monitored.ResultsA total of 107 people were randomized. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33%-43%) and increased HDL cholesterol (day 25, 15.7%-28.6%) and adiponectin (day 25, 1574 to 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 (P1NP) on day 25, although C-telopeptide cross-linking of type 1 collagen (CTX-1) increased minimally. Systolic, diastolic BP, and pulse rate increased in a dose- and time-related manner. There were 5 serious AEs (one treatment-related) and no deaths. Three participants discontinued because of AEs. The majority of AEs were gastrointestinal. PF-05231023 increased BP 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 showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long-acting FGF21 molecule.
      PubDate: 2017-07-21T06:50:53.033874-05:
      DOI: 10.1111/dom.13023
       
  • Projected long-term outcomes in patients with type 1 diabetes treated with
           fast-acting insulin aspart vs conventional insulin aspart in the UK
           setting
    • Authors: David Russell-Jones; Simon R. Heller, Sarah Buchs, Anna Sandberg, William J. Valentine, Barnaby Hunt
      Pages: 1773 - 1780
      Abstract: AimTo assess the impact of faster aspart vs insulin aspart on long-term clinical outcomes and costs for patients with type 1 diabetes mellitus (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 data on 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) vs 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 vs insulin aspart (cost savings of £1715), resulting from diabetes-related complications avoided and reduced treatment costs.ConclusionsFaster aspart was associated with improved clinical outcomes and cost savings vs insulin aspart for patients with T1DM in the UK setting.
      PubDate: 2017-07-25T06:41:29.633073-05:
      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
      Pages: 1793 - 1797
      Abstract: The range of glycated haemoglobin (HbA1c) responses and characteristics associated with above-average response to exenatide twice daily and once weekly were examined. Data were pooled from 8 exenatide-twice-daily and 5 exenatide-once-weekly 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 twice daily, n = 1414; exenatide once weekly, n = 941), baseline HbA1c correlated with change in HbA1c (P < .0001). Across baseline HbA1c levels, the 25th to 75th percentile of HbA1c change ranged from −0.3% to −3.2% with exenatide twice daily and from −0.5% to −3.6% with exenatide once weekly. Asian ethnicity and older age were significantly associated with high response to exenatide twice daily; no factors were significantly associated with response to exenatide once weekly. These data provide clinically useful information for estimating the likelihood that, depending on baseline HbA1c, an individual can achieve HbA1c goals. The association between Asian ethnicity, age and high response to exenatide twice daily may relate to the specific effects of exenatide twice daily on postprandial glucose.
      PubDate: 2017-07-25T06:40:57.126808-05:
      DOI: 10.1111/dom.13022
       
  • Impact of baseline glycated haemoglobin, diabetes duration and body mass
           index on clinical outcomes in the LixiLan-O trial testing a titratable
           fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) vs
           insulin glargine and lixisenatide monocomponents
    • Authors: Melanie J. Davies; Lawrence A. Leiter, Bruno Guerci, George Grunberger, F. Javier Ampudia-Blasco, Christine Yu, William Stager, Elisabeth Niemoeller, Elisabeth Souhami, Julio Rosenstock
      Pages: 1798 - 1804
      Abstract: To determine whether baseline characteristics had an impact on clinical outcomes in the LixiLan-O trial (N = 1170), we compared the efficacy and safety of iGlarLixi, a titratable fixed-ratio combination of insulin glargine 100 U (iGlar) and lixisenatide (Lixi) with iGlar or Lixi alone in patients with uncontrolled type 2 diabetes mellitus (T2DM) on oral therapy. Subgroups according to baseline glycated haemoglobin (HbA1c;
      PubDate: 2017-07-07T03:35:33.691884-05:
      DOI: 10.1111/dom.12980
       
  • Effects of combined low-dose spironolactone plus vitamin E vs vitamin E
           monotherapy on insulin resistance, non-invasive indices of steatosis and
           fibrosis, and adipokine levels in non-alcoholic fatty liver disease: a
           randomized controlled trial
    • Authors: Stergios A. Polyzos; Jannis Kountouras, Christos S. Mantzoros, Vaia Polymerou, Panagiotis Katsinelos
      Pages: 1805 - 1809
      Abstract: The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non-alcoholic fatty liver disease (NAFLD). The aim of the present 52-week randomized controlled trial was to compare the effects of low-dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non-invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA-IR) and non-invasive indices of steatosis and fibrosis were calculated. Analysis was intention-to-treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase-to-platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA-IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low-dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger-scale trials are needed to clarify the effect of low-dose spironolactone on hepatic histology.
      PubDate: 2017-07-10T05:20:21.306948-05:
      DOI: 10.1111/dom.12989
       
  • Pancreatic α-cell mass in obesity
    • Authors: Johanne H. Ellenbroek; Hendrica A. M. Töns, Maaike A. J. Hanegraaf, Ton J. Rabelink, Marten A. Engelse, Françoise Carlotti, Eelco J. P. de Koning
      Pages: 1810 - 1813
      Abstract: While it is well recognized that obesity is associated with an increased β-cell mass, the association with α-cell mass is less clear. Type 2 diabetes (T2DM) associated with obesity is a bihormonal disease characterized by inadequate insulin secretion and hyperglucagonaemia. We examined β- and α-cell mass throughout the pancreas in obese and lean subjects. Pancreatic tissue of the head, body and tail region of the pancreas was examined from 15 obese subjects (body mass index [BMI] ≥ 27 kg/m2) and 15 age-matched lean subjects (BMI ≤ 25 kg/m2) without diabetes. In obese subjects both β- and α-cell mass were proportionally higher compared with lean subjects, thereby maintaining the α- to β-cell ratio. The adaptation to obesity occurred preferentially in the head of the pancreas. As data so far have been derived from histological studies of β- and α-cell adaptation, in which the head region of the human pancreas was not included, the adaptive capacity of humans to obesity has previously been underestimated. Obesity is associated with an increased α-cell mass, which could contribute to the hyperglucagonaemia observed in people with T2DM.
      PubDate: 2017-07-13T05:36:02.170611-05:
      DOI: 10.1111/dom.12997
       
  • Comparative effects of liraglutide 3 mg vs 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
      Pages: 1814 - 1817
      Abstract: We compared the 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 (body mass index ≥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 magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate-intensity aerobic exercise (~200 min/wk; 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 < .01) and similar reductions in weight (−3.5 ± 3.3 vs −3.5 ± 2.1 kg, respectively, P = .72), LFF (−8.9 ± 13.4 vs −7.2% ± 7.1%, P = .70), serum alanine aminotransferase (−42 ± 46 vs −34 ± 27 U/L, P = .52) and aspartate aminotransferase (−23 ± 24 vs −18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight-loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.
      PubDate: 2017-07-14T03:30:27.089719-05:
      DOI: 10.1111/dom.13007
       
  • Effect of continuous exenatide infusion on cardiac function and
           peri-operative glucose control in patients undergoing cardiac surgery: 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
      Pages: 1818 - 1822
      Abstract: We performed a randomized controlled trial with the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide as add-on to standard peri-operative insulin therapy in patients undergoing elective cardiac surgery. The aims of the study were to intensify peri-operative glucose control while minimizing the risk of hypoglycaemia and to evaluate the suggested cardioprotective effects of GLP-1-based treatments. A total of 38 patients with decreased left ventricular systolic function (ejection fraction ≤50%) scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either exenatide or placebo in a continuous 72-hour intravenous (i.v.) infusion on top of standard peri-operative insulin therapy. While no significant difference in postoperative echocardiographic variables was found between the groups, participants receiving exenatide showed improved peri-operative glucose control as compared with the placebo group (average glycaemia 6.4 ± 0.5 vs 7.3 ± 0.8 mmol/L; P < .001; percentage of time in target range of 4.5–6.5 mmol/L 54.8% ± 14.5% vs 38.6% ± 14.4%; P = .001; percentage of time above target range 39.7% ± 13.9% vs 52.8% ± 15.2%; P = .009) without an increased risk of hypoglycaemia (glycaemia
      PubDate: 2017-07-31T01:35:25.592657-05:
      DOI: 10.1111/dom.13029
       
  • Comment on: Sodium-glucose co-transporter-2 inhibitors and risk of adverse
           renal outcomes among type 2 diabetes patients: A network and cumulative
           meta-analysis of randomized controlled trials
    • Authors: William Canovatchel; Jennifer Davidson, Norm Rosenthal
      Pages: 1823 - 1823
      PubDate: 2017-07-21T07:01:00.802827-05:
      DOI: 10.1111/dom.13035
       
 
 
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