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  [1589 journals]
  • Individual variability in response to renin-angiotensin-aldosterone system
           inhibition predicts cardiovascular outcome in patients with type 2
           diabetes: a primary care cohort study
    • Authors: Ellen M Apperloo; Michelle J Pena, Dick de Zeeuw, Petra Denig, Hiddo JL Heerspink
      Abstract: AimsVariability in response to Renin-Angiotensin-Aldosterone System (RAAS) inhibition has been shown in clinical trials but its occurrence and impact in clinical practice are unknown. We assessed variability in systolic blood pressure (SBP) and albuminuria (UACR) responses in patients with type 2 diabetes mellitus initiating RAAS inhibition, and assessed the association of response variability with cardiovascular outcomes.MethodsWe performed an observational cohort study in patients with type 2 diabetes who started RAAS inhibition between 2007 and 2013 (n=1600) were identified from general practices in the Netherlands. Individual response in SBP and UACR was assessed within 15 months follow-up. Patients were categorized as: good responders (∆SBP 0%). Multivariable Cox regression was performed to test the association between initial RAAS inhibition response and subsequent cardiovascular outcomes.ResultsAfter starting RAAS inhibition , mean SBP change was -13.2 mmHg and median UACR was -36.6%, with a large between individual variability, both in SBP [5th to 95th percentile: -48.5 to 20] and UACR [5th to 95th percentile: -87.6 to 171.4]. 812 patients (51%) were good responders, 353 (22%) had a good SBP but poor UACR response, 268 (17%) had a good UACR but poor SBP response, and 167 patients (10%) were poor responders. Good responders had a lower risk of cardiovascular events than poor responders (HR 0.51, 95% CI: 0.30 –0.86; p=0.012).ConclusionsSBP and UACR response after RAAS inhibition initiation varies between and within individual patients with type 2 diabetes treated in primary care. Poor responders have the highest risk of cardiovascular events, so more efforts are needed to develop personalized treatment plans for these patients.
      PubDate: 2018-01-18T06:10:23.095206-05:
      DOI: 10.1111/dom.13226
  • Intra- and Inter-Subject Variability for Increases in Serum Ketone Bodies
           in Patients With Type 2 Diabetes Treated With the Sodium Glucose
           Co-transporter 2 Inhibitor Canagliflozin
    • Authors: David Polidori; Hiroaki Iijima, Maki Goda, Nobuko Maruyama, Nobuya Inagaki, Peter A. Crawford
      Abstract: SGLT2 inhibitors have been associated with increased serum ketone bodies in patients with type 2 diabetes mellitus (T2DM). This analysis evaluated serum ketone body levels and variability in 1,278 Japanese patients with T2DM treated with canagliflozin 100 or 200 mg. Similar mean increases in ketone body concentrations of ~2-fold were seen with both canagliflozin doses. Median (interquartile range) percent change from baseline was 62% (0;180) for acetoacetate and 78% (2;236) for β-hydroxybutyrate. Approximately 2/3 of the variability in each ketone measure was attributed to intra-subject variability. Intra-subject variability was higher for serum ketones than other metabolites. Subjects in the lowest-response tertile exhibited no increase in ketones. Those in the highest-response tertile tended to be male and have higher fasting glucose, lower insulin, and longer T2DM duration at baseline. Moreover, changes in serum ketones were not fully explained by changes in plasma fatty acids, suggesting downstream effects of SGLT2 inhibition on hepatic metabolism that favour ketogenesis. In summary, increases in serum ketone bodies with canagliflozin were greater and more variable than changes in other metabolic measures in Japanese subjects with T2DM.
      PubDate: 2018-01-17T04:50:23.862334-05:
      DOI: 10.1111/dom.13224
  • Effect of immediate and prolonged GLP-1 receptor agonist administration on
           uric acid and its kidney clearance: post-hoc analyses of four clinical
    • Authors: Lennart Tonneijck; Marcel H.A. Muskiet, Mark M. Smits, Petter Bjornstad, Mark H.H. Kramer, Michaela Diamant, Ewout J. Hoorn, Jaap A. Joles, Daniël H. van Raalte
      Abstract: AimsTo determine effects of glucagon-like peptide (GLP)-1 receptor agonists (RA) on uric acid (UA)-levels and kidney UA-clearance.Material and methodsPost-hoc analyses of four controlled clinical trials, which assessed actions of GLP-1RA-administration on kidney physiology. Immediate effects of GLP-1RA exenatide-infusion versus placebo was determined in 9 healthy overweight males (Study-A) and in 52 overweight T2DM-patients (Study-B). Effects were also examined of 12-week long-acting GLP-1RA liraglutide versus placebo in 36 overweight T2DM-patients (Study-C) and of 8-week short-acting GLP-1RA lixisenatide versus once-daily titrated insulin-glulisine in 35 overweight T2DM-patients (Study-D). Plasma-UA, fractional (inulin-corrected) and absolute urinary-excretion of UA (UEUA) and sodium (UENa), and urine-pH was determined.ResultsMedian baseline plasma-UA levels was 5.39 to 6.33 mg/dL across all studies (17-22% of subjects were hyperuricemic). In study-A, exenatide-infusion slightly increased plasma-UA (+0.07±0.02mg/dL, P=0.04), and raised absolute-UEUA (+1.58±0.65mg/min/1.73m2, P=0.02), but did not affect fractional-UEUA compared to placebo. Fractional-UEUA and absolute-UEUA correlated with increases in urine-pH (r:0.86, P=0.003 and r:0.92, P
      PubDate: 2018-01-17T04:40:21.65258-05:0
      DOI: 10.1111/dom.13223
  • Cover Image, Volume 20, Issue 2
    • Authors: Yutaka Seino; Yasuo Terauchi, Takeshi Osonoi, Daisuke Yabe, Nobuyuki Abe, Tomoyuki Nishida, Jeppe Zacho, Shizuka Kaneko
      Abstract: The cover image, by Yutaka Seino et al., is based on the Original Article Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in Japanese people with type 2 diabetes,
      DOI : 10.1111/dom.13082.The cover image, by Yutaka Seino et al., is based on the Original Article Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in Japanese people with type 2 diabetes,
      DOI : 10.1111/dom.13082.
      PubDate: 2018-01-16T23:05:26.911353-05:
  • A Vitamin B12 Conjugate of Exendin-4 Improves Glucose Tolerance Without
           Associated Nausea or Hypophagia in Rodents
    • Authors: Elizabeth G. Mietlicki-Baase; Claudia G. Liberini, Jayme L. Workinger, Ron L. Bonaccorso, Tito Borner, David J. Reiner, Kieran Koch-Laskowski, Lauren E. McGrath, Rinzin Lhamo, Lauren M. Stein, Bart C. De Jonghe, George G. Holz, Christian L. Roth, Robert P. Doyle, Matthew R. Hayes
      Abstract: AimsWhile pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise.Materials and MethodsWe evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance, and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 versus unconjugated Ex4 are due to altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined.ResultsB12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting a lack of CNS penetrance in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycemic effects of B12-Ex4.ConclusionsThese novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.
      PubDate: 2018-01-12T01:40:56.644048-05:
      DOI: 10.1111/dom.13222
  • Short and medium-term efficacy of sodium glucose co-transporter-2 (SGLT-2)
           inhibitors: a meta-analysis of randomized clinical trials
    • Authors: Matteo Monami; Francesco Liistro, Alessia Scatena, Besmir Nreu, Edoardo Mannucci
      Abstract: AimsSodium glucose co-transport-2 (SGLT-2) inhibitors reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. Aim of this meta-analysis is the systematic collection of available data from randomized trials, in order to establish the durability of the efficacy of SGLT-2 inhibitors on glycemic control and body mass index.MethodsA meta-analysis was performed including all trials with a duration of at least 12 weeks, comparing SGLT-2 inhibitors with a non-SGLT-2 inhibitor agents in type 2 diabetes. The principal outcome was the effect of SGLT-2 inhibitors on HbA1c at 12, 24, 52, and 104 weeks. Data on body mass index at the same time points were also collected.ResultsAmong 66 randomized trials, hemoglobin A1c (HbA1c) reduction at 12, 24, 52, and 104 weeks was 0.63[0.57;0.68], 0.63[0.57;0.70], 0.66[0.57;0.74], and 0.60[0.40;0.81]%, respectively. SGLT-2 inhibitors showed a greater efficacy than Dipeptidyl-Peptidase-4 inhibitors (DPP-4i). Sulfonylureas appeared to be superior to SGLT-2 inhibitors at 12 weeks, but not at 24 and 52 weeks; SGLT-2 inhibitors produced a greater reduction of HbA1c than sulfonylureas at 104 weeks. SGLT-2 inhibitor-induced weight loss in placebo-controlled trials appeared to increase progressively with the duration of treatment.ConclusionsSGLT-2 inhibitors showed a good persistence of efficacy, at least up to two years, with a small but significant superiority over DPP-4i. Sulfonylureas are more effective in the very short term, but less effective in the longer term.
      PubDate: 2018-01-12T00:55:22.112201-05:
      DOI: 10.1111/dom.13221
  • Safety and efficacy of once-weekly semaglutide versus additional oral
           antidiabetic drugs, in Japanese subjects with inadequately controlled T2D:
           a randomised trial
    • Authors: Kohei Kaku; Yuichiro Yamada, Hirotaka Watada, Atsuko Abiko, Tomoyuki Nishida, Jeppe Zacho, Arihiro Kiyosue
      Abstract: AimsSemaglutide is a glucagon-like peptide 1 analogue in development for type 2 diabetes (T2D). Safety and efficacy of once-weekly subcutaneous semaglutide as monotherapy or combined with an oral antidiabetic drug (OAD) vs an additional OAD was evaluated in Japanese subjects with T2D inadequately controlled on diet/exercise or OAD monotherapy.MethodsIn this phase 3, open-label trial, adults with T2D were randomised 2:2:1 to semaglutide 0.5 mg or 1.0 mg, or one additional OAD (dipeptidyl peptidase-4 inhibitor, biguanide, sulphonylurea, glinide, α-glucosidase inhibitor or thiazolidinedione) with different modes of action. Primary endpoint was number of adverse events (AEs) after 56 weeks.ResultsBaseline characteristics were balanced between treatment arms (601 randomised). More AEs were reported with semaglutide 0.5 mg (86.2%) and 1.0 mg (88.0%) vs additional OAD (71.7%). These were typically mild/moderate. Gastrointestinal AEs were most frequent with semaglutide, which diminished over time. Mean HbA1c (baseline 8.1%) was significantly reduced with semaglutide 0.5 mg and 1.0 mg vs additional OAD (1.7% and 2.0% vs 0.7%, respectively; estimated treatment difference [ETD] vs additional OAD –1.08% and –1.37%, both p
      PubDate: 2018-01-11T01:36:21.304385-05:
      DOI: 10.1111/dom.13218
  • Declare-Timi 58: Participants’ Baseline Characteristics
    • Authors: Itamar Raz; Ofri Mosenzon, Marc P Bonaca, Avivit Cahn, Eri T Kato, Michael G Silverman, Deepak L Bhatt, Lawrence A. Leiter, Darren K. McGuire, John Wilding, Ingrid AM Gause-Nilsson, Anna Maria Langkilde, Peter A. Johansson, Marc S. Sabatine, Stephen D. Wiviott
      Abstract: BackgroundCardiovascular (CV) outcome trials with new glucose lowering agents (GLA) are designed to prove CV safety in high CV risk populations. However, the level of CV risk differs greatly among trials, which may influence comparability and generalizability of results.AimWe describe baseline characteristics of participants randomized in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58) trial, the pivotal study to assess CV outcomes with dapagliflozin.ResultsThe DECLARE-TIMI 58 trial randomized and will analyze 17,160 patients with type 2 diabetes (T2D) to treatment with dapagliflozin (10 mg/day) or matching placebo. The participants' mean age (SD): 63.8±6.8, 62.6%: male, mean diabetes duration: 11.8±7.8 years, HbA1c: 8.3%±1.2% and BMI: 32.1±6.0 kg/m2. Randomization included 6,971 (40.6%) patients with atherosclerotic cardiovascular disease (CVD), and 10,189 (59.4%) patients with multiple risk factors (MRF) for CV disease (defined as men: age ≥55 or women: ≥60; with at least one of: dyslipidemia, hypertension, or smoking). Patients with CVD compared with patients with MRF were younger (62.5±8.1 vs. 64.7±5.6 years), more frequently male (72.1% vs. 56.1%), less often used metformin (74.6% vs. 81.2%), more often used insulin (44.2% vs. 36.4%), and more frequently used statins, aspirin, clopidogrel and beta blockers (82.2% 71.1%, 24.7% and 66.6% vs. 63.7%, 39.1%, 1.5% and 32.3%), respectively.ConclusionThe DECLARE-TIMI 58 trial is expected to provide conclusive data on the effect of treatment with dapagliflozin versus placebo, each in addition to standard of care, on CV outcomes in a broad patient population with T2D and CVD or MRF for CVD.
      PubDate: 2018-01-11T01:15:29.271293-05:
      DOI: 10.1111/dom.13217
  • PREVIEW: Prevention of diabetes through lifestyle intervention in a
           multicentre study in Europe in children (10-17y). Design, methods, and
           baseline results
    • Authors: Elke Dorenbos; Mathijs Drummen, Jesse Rijks, Tanja Adam, Pauline Stouthart, J. Alfredo Martínez, Santiago Navas-Carretero, Gareth Stratton, Nils Swindell, Mikael Fogelholm, Anne Raben, Margriet Westerterp-Plantenga, Anita Vreugdenhil
      Abstract: Insulin resistance (IR) in adolescence is associated with T2DM. The PREVIEW study assesses the effectiveness of a high-protein, low-glycaemic index diet and moderate-protein, moderate-glycaemic index diet to decrease IR in insulin resistant children with overweight/obesity. Inclusion criteria were age 10-17y, HOMA-IR≥2.0 and overweight/obesity. In 126 children (13.6±2.2y, BMI z-score 3.04±0.66, HOMA-IR 3.48±2.28) anthropometrics, fat mass percentage (FM%), metabolic parameters, physical activity, food intake and sleep were measured. Baseline characteristics did not differ between the groups. IR was higher in pubertal children with morbid obesity than in prepubertal children with morbid obesity (5.41±1.86 vs. 3.23±1.86, p=0.007) and prepubertal and pubertal children with overweight/obesity (vs. 3.61±1.60, p=0.004 and vs. 3.40±1.50, p
      PubDate: 2018-01-11T01:00:36.297596-05:
      DOI: 10.1111/dom.13216
    • PubDate: 2018-01-10T02:10:22.947805-05:
      DOI: 10.1111/dom.13201
  • Basal Insulin Peglispro Increases Lipid Oxidation, Metabolic Flexibility,
           Thermogenesis And Ketone Bodies Compared To Insulin Glargine In Subjects
           With Type 1 Diabetes Mellitus
    • Authors: Niels K. Porksen; Helle Linnebjerg, Eric Chen Quin Lam, Parag Garhyan, Alok Pachori, Richard E. Pratley, Steven R. Smith
      Abstract: AIMSWhen treated with basal insulin peglispro (BIL), patients with type 1 diabetes mellitus (T1DM) exhibit weight loss and lower prandial insulin requirements versus insulin glargine (GL), while total insulin requirements remain similar. One possible explanation is enhanced lipid oxidation and improved ability to switch between glucose and lipid metabolism with BIL. This study compared the effects of BIL and GL on glucose and lipid metabolism in subjects with T1DM.MATERIALS AND METHODSFifteen subjects with T1DM were enrolled into this open-label, randomised, crossover study, and received once-daily stable, individualised, subcutaneous doses of BIL and GL for 4 weeks each. Respiratory quotient (RQ) was measured using whole-room calorimetry, and energy expenditure (EE) and concentrations of ketone bodies (3-hydroxybutyrate) and acylcarnitines were assessed.RESULTSMean sleep RQ was lower during the BIL (0.822) than the GL (0.846) treatment period, indicating greater lipid metabolism during the post-absorptive period with BIL. Increases in carbohydrate oxidation following breakfast were greater during BIL than GL treatment (mean change in RQ following breakfast = 0.111 for BIL, 0.063 for GL). Furthermore, BIL treatment increased total daily EE versus GL (2215.9 kcal/day for BIL, 2135.5 kcal/day for GL). Concentrations of ketone bodies and acylcarnitines appeared to be higher following BIL than GL treatment.CONCLUSIONSBIL increased sleeping fat oxidation, EE, ketone bodies, acylcarnitines and post-prandial glucose metabolism when switching from conventional insulin, thus, restoring metabolic flexibility and increasing thermogenesis. These changes may explain the previously observed weight loss with BIL versus GL.
      PubDate: 2018-01-08T04:55:24.478131-05:
      DOI: 10.1111/dom.13215
  • Effect of prandial treatment timing adjustment, based on continuous
           glucose monitoring, in patients with type 2 diabetes uncontrolled on once
           daily basal insulin: a randomized, phase IV study
    • Authors: Jacob Ilany; Hamad Bhandari, Dan Nabriski, Yoel Toledano, Noa Konvalina, Ohad Cohen,
      Abstract: OBJECTIVETo evaluate the glycemic control achieved by prandial once daily insulin glulisine injection timing adjustment based on continuous glucose monitoring sensor in comparison to once daily insulin glulisine injection before breakfast in type 2 diabetes patients uncontrolled on once daily basal insulin glargine.RESEARCH DESIGN AND METHODSThis was a 24-week open-label, randomized-controlled, multicenter trial. At the end of 8 weeks of basal insulin optimization period, patients with HbA1c ≥ 7.5% and FPG < 130 mg/dL were randomized (1:1) to either arm A (no sensor) or arm B (sensor) to receive 16-week intensified prandial glulisine treatment. Patients in arm A received pre-breakfast glulisine, and patients in arm B received glulisine before the meal with the highest glucose elevation based on the sensor data. The primary outcome was mean HbA1c at week 24 and secondary outcomes included rates of hypoglycemia events and insulin dosage.RESULTSA total of 121 patients were randomized to arm A (n = 61) or arm B (n = 60). There was no difference in the mean HbA1c at week 24 in arm A and arm B (8.5 ± 1.2% vs 8.4 ± 1.0%; P = 0.66). The prandial insulin glulisine dosage for arm A and arm B was 9.3 and 10.1 units, respectively (P = 0.39). The frequency of hypoglycemic events did not differ between study arms (36.1% vs. 51.7%; P = 0.08).CONCLUSIONUsing CGM sensor for identifying the meal with highest glucose excursion and adjusting the prandial insulin treatment timing does not show any advantage in terms of glycemic control or safety in our patients.
      PubDate: 2018-01-08T04:45:44.709032-05:
      DOI: 10.1111/dom.13214
  • Efficacy and safety of fast-acting insulin aspart in comparison with
           insulin aspart in type 1 diabetes (onset 1): a 52-week, randomized,
           treat-to-target, phase 3 trial
    • Authors: Chantal Mathieu; Bruce W. Bode, Edward Franek, Athena Philis-Tsimikas, Ludger Rose, Tina Graungaard, Anne Birk Østerskov, David Russell-Jones
      Abstract: AimsCompare safety and efficacy of fast-acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D).Materials and methodsonset 1 was a randomized, multicentre, treat-to-target, phase 3, 52-week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across nine countries. Adults with T1D were randomly allocated to double-blind mealtime faster aspart or IAsp, each with once- or twice-daily insulin detemir. The primary endpoint, change in HbA1c from baseline after the initial 26 weeks, has been reported previously; here, we report data from the full 52-week study period.ResultsBetween August 2013 and June 2015, 381 subjects were assigned to double-blind faster aspart and 380 subjects to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were −0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference (ETD) significantly favoured faster aspart (−0.10% [95% CI: [−0.19;−0.00]; P = 0.0424). Changes from baseline in 1-h postprandial plasma glucose (PPG) increment (meal test) (faster aspart, −1.05 mmol/l; IAsp, −0.14 mmol/l) also significantly favoured faster aspart (ETD: −0.91 mmol/l [−1.40;−0.43]; −16.48 mg/dl [−25.17;−7.80]; P = 0.0002). There was no difference in overall severe or blood glucose-confirmed hypoglycaemic episodes or treatment-emergent adverse events between treatments.ConclusionsAt 52 weeks, overall glycaemic control had significantly improved with faster aspart versus IAsp, consistent with the 26-week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels in subjects with T1D compared with IAsp.
      PubDate: 2018-01-08T04:30:51.473678-05:
      DOI: 10.1111/dom.13205
  • Long-term safety and efficacy of tofogliflozin add-on to insulin in
           patients with type 2 diabetes: results from a 52-week, multicenter,
           randomized, double-blind, open-label extension, Phase 4 study in Japan
    • Authors: Yasuo Terauchi; Masahiro Tamura, Masayuki Senda, Ryoji Gunji, Kohei Kaku
      Abstract: AimsTo evaluate the long-term safety and efficacy of tofogliflozin as an add-on treatment to insulin over 52 weeks.Materials and methodsThis 52-week, multicenter, Phase 4 study consisted of a 16-week, randomized, double-blind, placebo-controlled phase and a 36-week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus aged 20–75 years with suboptimal glycemic control (7.5%–10.5%) on insulin monotherapy (basal-bolus, bolus, premix [low and high], and basal) or on combination therapy of basal insulin and dipeptidyl peptidase-4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as “tofo-tofo group” and patients who received placebo and tofogliflozin (36 weeks) were referred to as “pla-tofo group”.ResultsA total of 210 patients received treatment as per randomization. Hypoglycemia was the most common treatment-emergent adverse event (AE) (42.9% in tofo-tofo group and 29.4% in pla-tofo group). Patients reported genital infection, urinary tract infection, excessive urination, and AEs related to volume depletion (2.1%, 2.1%, 7.1%, and 10.0% of patients in tofo-tofo group; and 0%, 1.5%, 2.9%, and 7.4% of patients in pla-tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo-tofo and pla-tofo groups were 8.53% (−0.76% ± 0.077) and 8.40% (−0.73% ± 0.102); 68.84 kg (−1.52 kg ± 0.207) and 72.24 kg (−2.13 kg ± 0.313), respectively.ConclusionsThis study demonstrates the safety and efficacy of tofogliflozin as add-on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management.
      PubDate: 2018-01-05T11:00:27.277903-05:
      DOI: 10.1111/dom.13213
  • Tofogliflozin decreases body fat mass and improves peripheral insulin
    • Authors: Ren Matsuba; Ikuro Matsuba, Mototsugu Shimokawa, Yoshio Nagai, Yasushi Tanaka
      Abstract: The impact of tofogliflozin, a sodium glucose transporter 2 inhibitor, on peripheral glucose uptake in patients with type 2 diabetes mellitus (T2DM) was investigated by the hyperinsulinemic-euglycemic clamp method in a single-arm, open-label study. The following parameters were compared between before and after tofogliflozin administration for 12 weeks in 16 T2DM patients using dipeptidyl peptidase 4 inhibitors: body weight, blood pressure, glucose metabolism, liver function, lipid profile, and body composition. Peripheral glucose uptake (M value and M/I ratio) was examined by the hyperinsulinemic-euglycemic clamp method. After 12 weeks, there was a significant decrease (P < .001) of hemoglobin A1c, body weight, body fat mass, and lean body mass. Peripheral glucose uptake, which indicates insulin sensitivity, increased significantly (M value by 0.90 and M/I ratio by 0.49; both P < .05). The change in the M value after 12 weeks of tofogliflozin therapy was correlated with the change in body fat mass (P < .05). Tofogliflozin significantly improved insulin sensitivity and peripheral glucose uptake in T2DM patients. These improvements were significantly correlated with reduction of body fat mass.
      PubDate: 2018-01-05T10:45:20.947074-05:
      DOI: 10.1111/dom.13211
  • Sustained high fat diet modulates inflammation, insulin signalling and
           cognition in mice and a modified xenin peptide ameliorates neuropathology
           in a chronic high fat model
    • Authors: Paul Denver; Victor A Gault, Paula L McClean
      Abstract: AimsMetabolic disease increases risk of Alzheimer's disease and cognitive dysfunction. Chronic high fat diet (HFD) feeding leads to cognitive impairment and neuroinflammation. This study demarcated pathological events in brain as a result of short-term to chronic HFD feeding. Efficacy of Xenin-25[Lys(13)PAL] was assessed in chronic HFD-fed mice.MethodsC57BL/6 mice were fed HFD or normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and Morris water maze. Markers of insulin signaling and inflammation were measured in brain and plasma using immunohistochemistry, qPCR and multi-array technology. Xenin-25[Lys(13)PAL] was also administered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathological stage.ResultsRecognition memory was consistently impaired in HFD-fed mice and spatial learning was impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616 were increased in the brain at day 18 in HFD-fed mice and were reduced by Xenin-25[Lys(13)PAL] in 21-week HFD-fed mice. In plasma, HFD feeding elevated IL-6 and CXCL1 at day 34 and IL-5 at week 10. In brain, HFD feeding reduced ERK2, mTOR, NF-κB1, PKCθ and TLR4 mRNA at week 10 and increased expression of GLP-1R, IKKβ, ERK2, mTOR, NF-κB1, PKCθ and TLR4 at week 21, elevations that were abrogated by Xenin-25[Lys(13)PAL].ConclusionsHFD feeding modulates cognitive function, synapse density, inflammation and insulin resistance in brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation and insulin signalling dysregulation and may have therapeutic potential in the treatment of diseases associated with neuroinflammation or perturbed insulin signalling in the brain.
      PubDate: 2018-01-05T10:40:22.440716-05:
      DOI: 10.1111/dom.13210
  • The association of hypoglycaemia severity and clinical, patient-reported
           and economic outcomes in US patients with type 2 diabetes using basal
    • Authors: Luigi F. Meneghini; Lulu Lee, Shaloo Gupta, Ron Preblick
      Abstract: AimsTo evaluate the clinical and patient-reported outcomes and healthcare utilization and costs associated with patient-reported hypoglycaemia in US adults with type 2 diabetes (T2D) treated with basal insulin.Materials and methodsThis was an observational, cross-sectional, survey-based study of adults with T2D on basal insulin ± oral antidiabetes drugs (OADs) or rapid-acting/premix insulin who had in the past ever experienced hypoglycaemia, using US data from the National Health and Wellness Survey. Eligible patients were categorized as having no hypoglycaemia (38.7%), non-severe hypoglycaemia (55.1%), or severe hypoglycaemia (6.2%) in the preceding 3 months. Outcomes included health-related quality of life (HRQoL), work productivity and activity impairment, healthcare-resource utilization, and estimated direct and indirect costs. Multivariable regression models were performed to control for patient characteristics.ResultsPatients who experienced severe hypoglycaemia had significantly (P < 0.05) lower HRQoL scores, greater overall impairment of work productivity and activity, greater healthcare-resource utilization, and higher costs compared with those who experienced non-severe or no hypoglycaemia. Patients with non-severe hypoglycaemia also reported an impact on the number of provider visits, indirect costs, and HRQoL.ConclusionsPatients with T2D using basal insulin ± rapid-acting/premix insulin in the US who experienced severe hypoglycaemia had greater impairment of activity and work productivity, utilized more healthcare resources, and incurred higher associated costs than those with non-severe or no hypoglycaemia. The study also demonstrated the impact that non-severe hypoglycaemia events have on economic and HRQoL outcomes. Reducing the incidence and severity of hypoglycaemia could lead to clinically meaningful improvements in HRQoL and may result in lower healthcare utilization and associated costs.
      PubDate: 2018-01-05T10:25:21.865934-05:
      DOI: 10.1111/dom.13208
  • Dapagliflozin for prednisone-induced hyperglycemia in acute exacerbation
           of chronic obstructive pulmonary disease
    • Authors: Maaike C. Gerards; Gerdien E. Venema, Kornelis W. Patberg, Martijn Kross, Bert Jan Potter van Loon, Ilse M. G. Hageman, Dominic Snijders, Dees P.M. Brandjes, Joost B. L. Hoekstra, Titia M. Vriesendorp, Victor E. A. Gerdes
      Abstract: This study aimed to compare the effectiveness and safety of add-on treatment with dapagliflozin to placebo in subjects with prednisone-induced hyperglycemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicenter double-blind randomized controlled study in which add-on treatment with dapagliflozin 10 mg was compared to placebo. Glycemic control and incidence of hypoglycemia were measured through a blinded subcutaneous continuous glucose measurement device. Subjects in the dapagliflozin group, spent 54 ± 27.7% of the time in target range (3.9-10 mmol/L) and this was 53.6 ± 23.4% in the placebo group (p = 0.96). Mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (p = 0.66). One patient using dapagliflozin and 2 patients using placebo experienced a symptomatic hypoglycemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycemia compared to placebo. Dapagliflozin did not result in better glycemic control compared to placebo in patients with prednisone-induced hyperglycemia during AECOPD.
      PubDate: 2018-01-05T10:15:20.050523-05:
      DOI: 10.1111/dom.13209
  • Have We Really Demonstrated the Cardiovascular Safety of Antihyperglycemic
           Drugs' Rethinking the Concepts of Macrovascular and Microvascular
           Disease in Type 2 Diabetes
    • Authors: Milton Packer
      Abstract: A primary goal of the treatment of type 2 mellitus is the prevention of morbidity and mortality due to cardiovascular disease. However, antihyperglycemic drugs have the capacity to cause deleterious effects on the circulation, a risk that is not adequately reflected by the endpoints selected for emphasis in large-scale clinical trials that are designed to evaluate cardiovascular safety. The primary endpoint of the large-scale studies mandated by regulatory authorities focuses only on 3-4 events that depict only a limited view of the circulatory system.One of the most serious adverse effects of many glucose-lowering drugs is new-onset or worsening heart failure. Most antidiabetic drugs can aggravate heart failure because they exert antinatriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain antihyperglycemic agents may worsen peripheral vascular disease and trigger cardiac arrhythmias that may lead to sudden death. Initiation of treatment with antidiabetic medications may also cause deterioration of the function of the kidneys, retina and peripheral nerves, which are typically regarded as reflecting microvascular disease.The current confusion about the cardiovascular effects of glucose-lowering drugs may be exacerbated by conceptual uncertainties about the classification of large and small vessel disease in determining the clinical course of diabetes. Physicians should not be falsely reassured by claims that a new treatment appears to have passed a narrowly-defined regulatory test. The management of diabetic patients often carries with it the risk of important cardiovascular consequences, even for drugs that do not overtly increase the risk of myocardial infarction or stroke.
      PubDate: 2018-01-05T09:25:24.614908-05:
      DOI: 10.1111/dom.13207
  • Effects of exenatide once weekly plus dapagliflozin, exenatide once
           weekly, or dapagliflozin added to metformin monotherapy on body weight,
           systolic blood pressure, and triglycerides in patients with type 2
           diabetes in the DURATION-8 study
    • Authors: Serge A. Jabbour; Juan P. Frías, Cristian Guja, Elise Hardy, Azazuddin Ahmed, Peter Öhman
      Abstract: This post hoc analysis assessed the effects on cardiovascular risk factors of body weight, systolic blood pressure (SBP), and triglycerides after 28 weeks’ treatment with exenatide once weekly (QW) plus dapagliflozin, as compared with exenatide QW or dapagliflozin, in patient subpopulations from the DURATION-8 trial of patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. Subgroups of patients were stratified according to their baseline body weight, SBP, and triglycerides. Body weight, SBP, and triglycerides were reduced across most respective subgroups, with no significant subgroup-by-treatment interactions. For each treatment, weight loss was numerically greater as baseline body mass index increased. SBP reductions were greater among patients with SBP ≥140 versus
      PubDate: 2018-01-05T08:40:55.19915-05:0
      DOI: 10.1111/dom.13206
  • Erratum to: Effect of GLP-1 receptor agonist treatment on body weight in
           obese antipsychotic-treated patients with schizophrenia: a randomized,
           placebo-controlled trial
    • Authors: Bjørn H. Ebdrup; Brian V. Broberg, Pelle L. Ishøy, Nikolaj Bak, Ulrik B. Andersen, Niklas R. Jørgensen, Jens J. Holst, Filip K. Knop, Birte Y. Glenthøj
      Abstract: “Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist (GLP-1RA): The TAO trial” is the first clinical investigation of GLP-1RA treatment (exenatide 2 mg once-weekly or placebo) in antipsychotic-treated schizophrenia patients with obesity.1 Recently, we published the main results from the TAO trial as an original article in Diabetes, Obesity and Metabolism.2We regret to report, that further analyses of the TAO dataset have revealed an error in our secondary analyses presented in the original publication.
      PubDate: 2018-01-05T08:25:20.088971-05:
      DOI: 10.1111/dom.13204
  • Diabetes, Obesity and Metabolism
    • Pages: 231 - 232
      PubDate: 2018-01-16T23:05:27.730701-05:
      DOI: 10.1111/dom.13090
    • PubDate: 2017-12-28T21:25:42.37377-05:0
      DOI: 10.1111/dom.13187
  • Effect of a Glucagon Receptor Antibody (REMD-477) in Type 1 Diabetes: A
           Randomized Controlled Trial
    • Authors: Jeremy Pettus; Dominic Reeds, Tricia Santos Cavaiola, Schafer Boeder, Michelle Levin, Gary Tobin, Edda Cava, Dung Thai, Jim Shi, Hai Yan, Edgar Bautista, John McMillan, Roger Unger, Robert R. Henry, Samuel Klein
      Abstract: The aim of the current study was to study the efficacy and safety of REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This was a randomized controlled trial in which 21 patients with type 1 diabetes were enrolled. Glycemic control and insulin use were evaluated during outpatient and inpatient settings, before and after, a single 70-mg dose of REMD-477 (half-life 7-10 days) or placebo. Inpatient insulin use was 26% (95% CI:47%,4%) lower 1 day after dosing with REMD-477 than placebo (p=0.02). Continuous glucose monitoring during post-treatment days 6-12 showed average daily glucose was 27 mg/dl lower (p180 mg/dl) was ~40% lower (~4 hours/day) (p=0.001) in the REMD-477 than the placebo group, without a difference in percent time-in-hypoglycemic-range (
      PubDate: 2017-12-28T09:21:32.854089-05:
      DOI: 10.1111/dom.13202
  • Injecting without pressing a button: an exploratory study of a
           shield-triggered injection mechanism
    • Authors: Eric Zijlstra; Hans-Veit Coester, Tim Heise, Leona Plum-Mörschel, Ole Rasmussen, Tord Rikte, Line Kynemund Pedersen, Marianne Qvist, Thomas Sparre
      Abstract: AimsTo evaluate injection success and user perception of a shield-triggered pen-injector mechanism.MethodsThe trial ( NCT02627287) was an exploratory, two-centre, one-visit, open-label, randomized controlled trial conducted in Germany in 150 injection-experienced subjects with type 1 or type 2 diabetes. Subjects self-administered subcutaneous injections of a placebo solution using a prototype shield-triggered pen-injector, DV3316 (Novo Nordisk, Bagsvaerd, Denmark), and FlexPen® (Novo Nordisk, Bagsvaerd, Denmark). Injection success was evaluated on a yes/no basis by the investigator. Subject confidence, leakage of fluid and pain were evaluated after each injection. Pain and device experience were assessed after completion of all injections with each pen-injector. Overall preference was assessed after completion of all injections with both pen-injectors.ResultsInjection success was high with both pen-injectors (97.0%, DV3316 vs. 99.7%, FlexPen). Subject confidence in dose delivery was similar between devices (88% of injections with DV3316 vs. 81% with FlexPen were scored as 'extremely confident'). Median injection pain score on a visual analogue scale (0–100), was 3 with DV3316 vs. 4 with FlexPen after each injection, and 4 with DV3316 vs. 5 with FlexPen after all injections with each device. After all injections were completed, 55% of subjects reported an overall preference for DV3316 vs. 21% for FlexPen.ConclusionThis study demonstrates that injection-experienced subjects can achieve a high injection success rate with a shield-triggered pen-injector, with similar subject confidence and injection pain compared with FlexPen.
      PubDate: 2017-12-27T07:19:15.120803-05:
      DOI: 10.1111/dom.13203
  • Relationship between treatment persistence and A1C trends among patients
           with type 2 diabetes newly initiated on basal insulin
    • Authors: Fang Liz Zhou; Lin Xie, Chunshen Pan, Yuexi Wang, Neel Vaidya, Fen Ye, Ronald Preblick, Luigi Meneghini
      Abstract: This study examines the relationship between glycated hemoglobin (A1C) levels and treatment persistence with, or time to discontinuation of, basal insulin in patients with type 2 diabetes (T2D) newly initiating insulin. Claims data were extracted from the Optum™ Clinformatics database from January 2010 to June 2015. Adult patients with T2D initiating insulin glargine 100 U/mL (Gla-100) or insulin detemir (DET) with ≥1 A1C measurement during 12-month baseline and 18-month follow-up periods were included. Patients with a refill gap of>90 days were considered non-persistent; otherwise patients were considered persistent with insulin. The main outcome was A1C, measured closest to the end of each quarter during the follow-up period. 3,993 of 109,934 patients met the inclusion criteria (43.0% persistent: 57.0% non-persistent). Persistent patients were older (54.7 vs 52.7 years; P < .001), male (59.4% vs 54.4%, P = .002), had significantly lower mean unadjusted A1C values at 18 months (8.26% vs 8.60%; P < .001) and quarterly. Only 43.0% of adults initiating basal insulin persisted with treatment for 18 months, with earlier discontinuation associated with higher A1C.
      PubDate: 2017-12-26T09:35:20.961401-05:
      DOI: 10.1111/dom.13200
  • The effect of low-volume high-intensity interval training versus endurance
           training on glycemic control in individuals with type 2 diabetes
    • Authors: Kamilla Munch Winding; Gregers Winding Munch, Ulrik Winning Iepsen, Gerrit Van Hall, Bente Klarlund Pedersen, Stefan Peter Mortensen
      Abstract: AbstractAIMTo evaluate if high-intensity interval training (HIIT) with a lower time commitment can be equally effective as endurance training (END) on glycemic control, physical fitness and body composition in individuals with type 2 diabetes.MATERIALS AND METHODSTwenty-nine individuals with type 2 diabetes were allocated to control (CON; no training), END, or HIIT. Training groups were prescribed three training sessions per week consisting of either 40 min cycling at 50% of peak workload (END) or ten 1 min intervals at 95% of peak workload interspersed by 1 min active recovery (HIIT). Glycemic control (HbA1c, oral glucose tolerance test, 3-hours mixed meal tolerance test with double tracer technique, and continuous glucose monitoring (CGM)), lipolysis, VO2peak and body composition were evaluated before and after 11 weeks of intervention.RESULTSExercise training increased VO2peak more in HIIT (20±20%) compared with END (8±9%) despite lower total energy expenditure and time usage during the training sessions. HIIT decreased whole body and android fat mass compared with CON. In addition, visceral fat mass, HbA1c, fasting glucose, postprandial glucose, glycemic variability and HOMA-IR decreased after HIIT. The reduced postprandial glucose in HIIT was primarily driven by a lower rate of exogenous glucose appearance. In CON, postprandial lipolysis was augmented over the 11 week control period.CONCLUSIONSDespite a ~45% lower training volume, HIIT resulted in similar or even better improvements in physical fitness, body composition and glycemic control compared to END. HIIT therefore appears to be an important time-efficient treatment for individuals with type 2 diabetes.
      PubDate: 2017-12-22T09:25:24.090598-05:
      DOI: 10.1111/dom.13198
  • Real-world evidence on clinical and economic outcomes of switching to
           insulin glargine 300 Units/mL vs other basal insulins in patients with
           type 2 diabetes on basal insulin
    • Authors: Fang Liz Zhou; Fen Ye, Paulos Berhanu, Vineet E. Gupta, Rishab A. Gupta, Jennifer Sung, Jukka Westerbacka, Timothy S. Bailey, Lawrence Blonde
      Abstract: This retrospective cohort study compared real-world clinical and healthcare-resource utilization (HCRU) data in patients with type 2 diabetes using basal insulin (BI) who switched to insulin glargine 300 units/mL (Gla-300) or another BI. Data from the Predictive Health Intelligence Environment database 12 months before (baseline) and 6 months after (follow-up) the switch date (index date, 1 March 2015 to 31 May 2016) included glycated haemoglobin A1c (HbA1c), hypoglycaemia, HCRU and associated costs. Baseline characteristics were balanced using propensity score matching. Change in HbA1c from baseline was similar in both matched cohorts (n = 1,819 in each); hypoglycaemia incidence and adjusted event rate were significantly lower with Gla-300. Patients switching to Gla-300 had a significantly lower incidence of HCRU related to hypoglycaemia. All-cause and diabetes-related hospitalization and emergency-department HCRU were also favourable for Gla-300. Lower HCRU translated to lower costs in patients using Gla-300. In this real-world study, switching to Gla-300 reduced risk of hypoglycaemia in patients with type 2 diabetes when compared with those switching to another BI, resulting in less HCRU and potential savings of the associated costs.
      PubDate: 2017-12-22T09:25:19.571598-05:
      DOI: 10.1111/dom.13199
  • Non-severe hypoglycemia is associated with weight gain in patients with
    • Authors: Anisoara Bumbu; Abdul Moutairou, Odette Matar, Frédéric Fumeron, Gilberto Velho, Jean-Pierre Riveline, Jean-François Gautier, Michel Marre, Ronan Roussel, Louis Potier
      Abstract: It is unclear whether the frequent non-severe episodes of hypoglycemia observed during intensive glucose control in people with type 1 diabetes (T1D) are associated with later weight gain. We analyzed the association between non-severe hypoglycemia and weight gain in 1441 DCCT participants. Non-severe hypoglycemia was assessed by a hypo-score (number of blood glucose values
      PubDate: 2017-12-22T09:20:19.466116-05:
      DOI: 10.1111/dom.13197
  • Long-term outcome on glycaemic control and β-cell preservation of early
           intensive treatment in patients with newly diagnosed Type 2 Diabetes: A
           Multicentre Randomised Trial
    • Authors: Suk Chon; Sang Youl Rhee, Kyu Jeung Ahn, Sei Hyun Baik, Yongsoo Park, Moon Suk Nam, Kwan Woo Lee, Soon Jib Yoo, Gwanpyo Koh, Dae Ho Lee, Young Seol Kim, Jeong-Taek Woo
      Abstract: AimTo determine the effects of early intensive glycaemic control with intensive insulin treatment (IIT) or initial combined oral anti-diabetic therapy (COAD) on long-term glycaemic control and the preservation of β-cell function in subjects with type 2 diabetes mellitus (T2DM).MethodsNewly diagnosed drug-naïve T2DM patients from eight outpatient diabetes centres were randomised to receive either IIT (n = 50; glargine/glulisine) or COAD (n = 47; glimepiride/metformin) as intensive treatment (IT) until the termination criteria to ensure euglycaemia were met. Following IT, the patients completed a follow-up (FU) period with either lifestyle modification (LSM) alone or rescue therapy to maintain target A1c levels < 7% up to Week 104. The primary outcomes were analysed after excluding anti-GAD Ab-positive patients.ResultsBoth IT methods were effective for short-term glycaemic control but improvements in the disposition index (DI) were significantly greater in the IIT group than the COAD group (p = 0.021). During the FU period after IT, the two groups significantly differed in rescue method regarding the maintenance of comparable levels of glycaemic control (p = 0.010) and more subjects that received IIT exhibited well-controlled T2DM with LSM alone. Additionally, the IIT group maintained a higher DI than the COAD group during the FU period. A Cox regression analysis revealed that the IIT method was associated with a 52.5% lower risk of failing to maintain drug-free glycaemic remission compared to the COAD method (p = 0.015).ConclusionsThe present findings indicate that outpatient clinic-based IIT to ensure euglycaemia in newly diagnosed T2DM patients might be an effective initial therapeutic option for improvements in β-cell function and glycaemic control over the long-term without serious adverse events.
      PubDate: 2017-12-22T09:15:26.56473-05:0
      DOI: 10.1111/dom.13196
  • Ertugliflozin Plus Sitagliptin Versus Either Individual Agent Over 52
           Weeks in Patients with Type 2 Diabetes Mellitus Inadequately Controlled
           With Metformin: The VERTIS FACTORIAL Randomized Trial
    • Authors: Richard E. Pratley; Roy Eldor, Annaswamy Raji, Gregory Golm, Susan B. Huyck, Yanping Qiu, Sheila Sunga, Jeremy Johnson, Steven G. Terra, James P. Mancuso, Samuel S. Engel, Brett Lauring
      Abstract: AIMSTo evaluate the efficacy and safety of ertugliflozin and sitagliptin co-administration vs the individual agents in patients with type 2 diabetes inadequately controlled on metformin.METHODSPatients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) on metformin ≥1500 mg/day (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/day, sitagliptin 100 mg/day (S100), or co-administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26.RESULTSAt Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (–1.5%) and E15/S100 (–1.5%) than with individual agents (–1.0%, –1.1%, and –1.1% for E5, E15, and S100, respectively; P < 0.001 for all comparisons). HbA1c
      PubDate: 2017-12-21T09:25:36.922272-05:
      DOI: 10.1111/dom.13194
  • Visit-to-visit HbA1c variability and systolic blood pressure (SBP)
           variability are significantly and additively associated with mortality in
           people with type 1 diabetes: an observational study
    • Authors: Stuart S. Wightman; Christopher A.R. Sainsbury, Gregory C. Jones
      Abstract: TitleVisit-to-visit HbA1c variability and systolic blood pressure (SBP) variability are significantly and additively associated with mortality in people with type 1 diabetes: an observational study.AimTo investigate relationship between variability in both visit-to-visit HbA1c and SBP, and mortality in people with Type 1 diabetes.MethodsThe Scottish Care Information (SCI) Diabetes dataset was used to identify 5,952 people with type 1 diabetes for inclusion in this observational study. The SCI-Diabetes dataset allowed access to blood pressure values, HbA1c readings, demographic information and mortality rates for all study participants. Participants were dichotomised to above and below median values for both HbA1c coefficient of variation (CV) and SBP CV, thus dividing participants into four cohorts for survival analysis. Survival analysis was carried out over 1,430 days. A Cox proportional hazard model was used to allow comparison of mortality between the four cohorts.ResultsOf the 5,952 patients, death occurred in 416. CV for both HbA1c and SBP were significantly associated with mortality. The median value for HbA1c CV and SBP CV was 8.0 and 8.1 respectively. Hazard ratio for high HbA1c CV only (p=0.0015) was 1.78±0.36. Hazard ratio for high SBP CV only (p=0.0018) was 1.69±0.33. Hazard ratio for both high HbA1c CV and high SBP CV (p
      PubDate: 2017-12-21T08:55:21.571506-05:
      DOI: 10.1111/dom.13193
    • PubDate: 2017-12-19T04:30:37.372665-05:
      DOI: 10.1111/dom.13188
  • Effect of a single dose of the DPP-4 inhibitor sitagliptin on β-cell
           function and incretin hormone secretion after meal ingestion in healthy
           volunteers and drug-naïve, well-controlled type 2 diabetes subjects
    • Authors: Wathik Alsalim; Olga Göransson, Richard D. Carr, Roberto Bizzotto, Andrea Tura, Giovanni Pacini, Andrea Mari, Bo Ahrén
      Abstract: To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and β-cell glucose sensitivity after meal ingestion, twelve healthy- and twelve drug naïve well-controlled type 2 diabetes subjects (T2D; mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100mg) or placebo before a meal (525 kcal). β-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β-cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion both in healthy and T2D subjects compared to placebo but without increasing β-cell glucose sensitivity. Sitagliptin also increased active glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and reduced total (reflecting the secretion) GIP but not total GLP-1 levels. We conclude that a single dose of DPP-4 inhibition induces dissociated effects on different aspects of β-cell function and incretin hormones after meal ingestion in healthy subjects and in well-controlled T2D.
      PubDate: 2017-12-11T11:05:47.020767-05:
      DOI: 10.1111/dom.13192
  • Comparative effectiveness of metformin monotherapy in extended release and
           immediate release formulations for the treatment of type 2 diabetes in
           treatment-naïve Chinese patients: analysis of results from the CONSENT
    • Authors: Linong Ji; Jing Liu, Jing Yang, Yufeng Li, Li Liang, Dalong Zhu, Quanmin Li, Tianrong Ma, Haiyan Xu, Yanlan Yang, Jiaoe Zeng, Bo Feng, Shen Qu, Yiming Li, Lizhen Ma, Shanshan Lin, Jianping Wang, Wei Li, Weihong Song, Xiaoxing Li, Yong Luo, Shugang Xi, Mei Lin, Yu Liu, Zerong Liang
      Abstract: AimsMetformin treatment for type 2 diabetes (T2DM) can be limited by gastrointestinal (GI) adverse events (AEs), resulting in treatment discontinuation. We investigated whether once-daily metformin extended release (XR) is superior in terms of GI tolerability, with non-inferior efficacy, compared with thrice-daily metformin immediate release (IR) in treatment-naïve Chinese patients with T2DM.Materials and MethodsThis prospective, open-label, randomized, multicenter, phase IV interventional study enrolled Chinese T2DM patients to receive either metformin XR or metformin IR with a 2-week screening period, 16-week treatment period, and 2-week follow-up period without treatment. Co-primary endpoints were a non-inferiority assessment of XR metformin versus IR metformin in glycated hemoglobin (HBA1c) least squares mean (LSM) change from baseline to week 16 and the superiority of GI tolerability for metformin XR versus metformin IR.ResultsOverall, 532 patients were randomized to metformin IR (n=267) or metformin XR (n=265). The HbA1c LSM change was −1.61% and −1.58% in each group, respectively (LSM difference, 0.03; 95% confidence interval [CI], −0.10, 0.17). Incidences of drug-related AEs were 26.5% (n=66) in the metformin IR-only group and 32.2% (n=85) in the metformin XR-only group, and GI AEs were 23.8% and 22.3% in each group, respectively (difference, −1.52; 95% CI, −8.60, 5.56). The treatment difference met the predefined non-inferiority upper CI margin of 0.4% in HbA1c.ConclusionsMetformin XR was non-inferior to metformin IR for the LSM change in HbA1c from baseline to week 16 and not superior to metformin IR for overall GI AE incidence during treatment of Chinese T2DM patients.
      PubDate: 2017-12-11T10:55:20.218568-05:
      DOI: 10.1111/dom.13190
  • Role of the Sodium-Hydrogen Exchanger in Mediating the Renal Effects of
           Drugs Commonly Used in the Treatment of Type 2 Diabetes
    • Authors: Milton Packer
      Abstract: Diabetes is characterized by an increased activity of the sodium-hydrogen exchanger (NHE) in the glomerulus and renal tubules, which contributes importantly to the development of nephropathy. Despite the established role played by the exchanger in experimental studies, it has not been specifically targeted by those seeking to develop novel pharmacological treatments for diabetes. This review demonstrates that many existing drugs that are commonly prescribed to patients with diabetes act on the NHE1 and NHE3 isoforms in the kidney. This action may explain their effects on sodium excretion, albuminuria and the progressive decline of glomerular function in clinical trials; these responses cannot be readily explained by the influence of these drugs on blood glucose. Agents that may affect the kidney in diabetes by virtue of an action on NHE include: (1) insulin and insulin sensitizers; (2) incretin-based agents; (3) sodium-glucose cotransporter 2 inhibitors; (4) antagonists of the renin-angiotensin system (angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, and angiotensin receptor neprilysin inhibitors); and (5) inhibitors of aldosterone action and cholesterol synthesis (spironolactone, amiloride and statins). The renal effects of each of these drug classes in patients with type 2 diabetes may be related to a single shared biological mechanism.
      PubDate: 2017-12-11T10:35:29.910248-05:
      DOI: 10.1111/dom.13191
  • Insulin Secretion Predicts the Response to Therapy with Exenatide Plus
           Pioglitazone but not to Basal/Bolus Insulin in Poorly Controlled T2DM
           Patients: Results from the Qatar Study
    • Authors: Muhammad Abdul-Ghani; Osama Migahid, Ayman Megahed, Rajvir Singh, Dalia Kamal, Ralph A. DeFronzo, Amin Jayyousi
      Abstract: The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide versus basal/bolus insulin therapy in T2DM patients who are poorly controlled on maximum/near-maximum doses metformin plus a sulfonylurea. Participants in the Qatar study received a 75-gram OGTT with measurement of plasma glucose, insulin, and C-peptide concentration at baseline and then were randomized to receive treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤7.0%) with pioglitazone plus exenatide. A 54% increase in 2-h plasma C-peptide concentration above the fasting level identified subjects who achieved the glycemic goal (HbA1c
      PubDate: 2017-12-11T10:30:56.09849-05:0
      DOI: 10.1111/dom.13189
  • Claims-based studies of oral glucose-lowering medications can achieve
           balance in critical clinical parameters only observed in electronic health
    • Authors: E Patorno; C Gopalakrishnan, JM Franklin, KG Brodovicz, E Masso-Gonzalez, DB Bartels, J Liu, S Schneeweiss
      Abstract: BackgroundHealthcare claims databases can provide information on the effects of type 2 diabetes (T2DM) medications as used in routine care, but often do not contain data on important clinical characteristics, which may be captured in electronic health records (EHR).ObjectivesTo evaluate the extent to which balance in unmeasured patient characteristics was achieved in claims data, by comparing against more detailed information from linked EHR data.MethodsWithin a large US commercial insurance database and using a cohort design, we identified T2DM patients initiating linagliptin or a comparator agent within class (i.e., other DPP-4 inhibitors) or outside class (i.e., (pioglitazone or sulfonylureas) between 05/2011-12/2012. We focused on comparators used at a similar stage of diabetes as linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance over 100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHRs was available for a subset of patients. We assessed representativeness of the claims-EHR linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SD), and quantified the potential bias associated with observed imbalances.ResultsFrom a claims-based study population of 166,613 T2DM patients, 7,219 (4.3%) patients were linked to their EHR data. Claims-based characteristics between the EHR-linked and EHR-unlinked patients were comparable (SD
      PubDate: 2017-12-05T08:55:26.033525-05:
      DOI: 10.1111/dom.13184
  • Reversibility of Myocardial Metabolism and Remodeling in Morbidly Obese
           Patients Six Months after Bariatric Surgery
    • Authors: Jarna C. Hannukainen; Riikka Lautamäki, Jussi Pärkkä, Marjatta Strandberg, Virva Saunavaara, Saija Hurme, Minna Soinio, Prince Dadson, Kirsi A. Virtanen, Tove Grönroos, Sarita Forsback, Paulina Salminen, Patricia Iozzo, Pirjo Nuutila
      Abstract: Aims/hypothesisTo study myocardial substrate uptake, structure and function before and after bariatric surgery to clarify the interaction between myocardial metabolism and cardiac remodeling in morbid obesity.MethodsWe studied 46 subjects (age 44±10 yrs, BMI 42±4 kg/m2), including 18 with type 2 diabetes before and six months after bariatric surgery and 25 healthy age-matched controls. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated glucose uptake (MGU) were measured using PET. Myocardial structure, function, triglyceride content (MTGC) and intrathoracic fat were measured with MRI and MRS.ResultsMorbidly obese subjects, with or without type 2 diabetes, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared to controls. Surgery led to marked weight reduction and remission of type 2 diabetes in most of the subjects. Post-operatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with LV hypertrophy and BMI, age and intrathoracic fat mass were the main parameters associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU.Conclusions/interpretationIn the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodeling in morbidly obese subjects with or without type 2 diabetes. Cardiac remodeling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of type 2 diabetes.
      PubDate: 2017-12-05T08:41:11.823177-05:
      DOI: 10.1111/dom.13183
  • Plasma PCSK9 and Cardiovascular Events in Type 2 Diabetes
    • Authors: Petra El Khoury; Ronan Roussel, Frederic Fumeron, Yara Abou-Khalil, Gilberto Velho, Kamel Mohammedi, Marie-Paule Jacob, P. Gabriel Steg, Louis Potier, Youmna Ghaleb, S El Bitar, S Ragot, Francesco Andreata, Giusepinna Caligiuri, Samy Hadjadj, Catherine Boileau, Michel Marre, Marianne Abifadel, Mathilde Varret, Boris Hansel
      Abstract: AimsThe prognostic value of proprotein-convertase-subtilisin/kexin type 9 (PCSK9) specifically in type 2 diabetes mellitus (T2DM) is unknown. Our aim was to investigate whether plasma concentrations of PCSK9 was associated with cardiovascular (CV) events in two cohorts of patients with T2DM.MethodsWe considered patients from the DIABHYCAR (n=3,137) and the SURDIAGENE (n=1,468) studies. Baseline plasma PCSK9 was measured by an immunofluorescence assay. In a post-hoc but preplanned analyses, we assessed the relationship between PCSK9 and the following endpoints: (1) a combined endpoint of major CV events: CV death, non-fatal myocardial infarction (MI), stroke and heart failure-related hospital admission; (2) a composite of all CV events: MI, stroke, heart failure-related hospital admission, coronary/peripheral angioplasty or bypass, CV death; (3) MI, (4) stroke/transient ischemic attack (TIA), and (5) CV death.ResultsIn DIABHYCAR, plasma PCSK9 tertiles were associated with the incidence of MI, all CV events and stroke/TIA (p for trend
      PubDate: 2017-12-05T08:21:27.245643-05:
      DOI: 10.1111/dom.13181
  • LH-21 and Abn-CBD improve β-cell function in isolated human and mouse
           islets through GPR55-dependent and -independent signalling
    • Authors: Inmaculada Ruz-Maldonado; Attilio Pingitore, Bo Liu, Patricio Atanes, Guo Cai Huang, David Baker, Francisco José Alonso, Francisco Javier Bermúdez-Silva, Shanta J. Persaud
      Abstract: AimsCB1 and GPR55 are GPCRs expressed by islet β-cells. Pharmacological compounds have been used to investigate their function, but off-target effects of ligands have been reported. This study examined the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and islets from GPR55-/- mice were used to determine signalling via GPR55.Materials and methodsIslets isolated from human organ donors and mice were incubated in the absence or presence of Abn-CBD or LH-21 and insulin secretion, [Ca2+]i, cAMP, apoptosis, β-cell proliferation and CREB and AKT phosphorylation were examined by standard techniques.ResultsAbn-CBD potentiated glucose-stimulated insulin secretion and elevated [Ca2+]i in human islets and islets from both GPR55+/+ and GPR55-/- mice. LH-21 also increased insulin secretion and [Ca2+]i in human islets and GPR55+/+ mouse islets, but concentrations of LH-21 up to 0.1 μM were ineffective in islets from GPR55-/- mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn-CBD and LH-21 reduced cytokine-induced apoptosis in human islets and GPR55+/+ mouse islets, and these effects were suppressed following GPR55 deletion. They also increased β-cell proliferation: the effects of Abn-CBD were preserved in islets from GPR55-/- mice, while those of LH-21 were abolished. Abn-CBD and LH-21 increased AKT phosphorylation in mouse and human islets.ConclusionsThis study demonstrated that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55-/- mice suggests that designation of Abn-CBD and LH-21 as GPR55 agonist and CB1 antagonist, should be revised.
      PubDate: 2017-12-05T07:40:30.595225-05:
      DOI: 10.1111/dom.13180
  • Clinical correlates of hypoglycaemia over 4 years in people with type 2
           diabetes starting insulin: An analysis from the CREDIT study
    • Authors: Philip Home; Francoise Calvi-Gries, Lawrence Blonde, Valerie Pilorget, Joseph Berlingieri, Nick Freemantle
      Abstract: AimTo identify factors associated with documented symptomatic and severe hypoglycaemia over 4 years in people with type 2 diabetes starting insulin therapy.Materials and methodsCREDIT, a prospective international observational study, collected data over 4 years on people starting any insulin in 314 centers; 2729 and 2271 people had hypoglycaemia data during the last 6 months of years 1 and 4. Multivariable logistic regression was used to select characteristics associated with documented symptomatic hypoglycaemia, and the model tested against severe hypoglycaemia.ResultsParticipants reporting ≥1 non-severe event were 18.5% and 16.6% in years 1 and 4, 24.6% and 18.3% in those achieving an HbA1c
      PubDate: 2017-12-05T07:25:20.684045-05:
      DOI: 10.1111/dom.13179
  • Pharmacokinetics and tolerability of semaglutide in subjects with hepatic
    • Authors: Lene Jensen; Viera Kupcova, Gerhard Arold, Jonas Pettersson, Julie B. Hjerpsted
      Abstract: AimsTo investigate whether the pharmacokinetic characteristics of semaglutide were altered in subjects with hepatic impairment, assessed using Child-Pugh criteria, versus those with normal hepatic function.MethodsIn this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ID NCT02210871), four groups of subjects with normal hepatic function (n = 19) or mild (n = 8), moderate (n = 10) or severe (n =7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35 days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-∞). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-groups ratio (hepatic impairment/normal) was within the interval 0.70–1.43.ResultsSemaglutide exposure was similar across all groups, with AUC0-∞ treatment ratios for mild impairment/normal of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal 1.02 (0.93, 1.12), and severe impairment/normal 0.97 (0.84, 1.12). The maximum plasma semaglutide concentration (Cmax) did not appear to be influenced by hepatic function, with mild impairment/normal treatment ratios of 0.99 (0.80, 1.23), moderate impairment/normal 1.02 (0.88, 1.18) and severe impairment/normal 1.15 (0.89, 1.48) (sensitivity analysis excluding one extreme semaglutide concentration: 1.05 (0.88, 1.25)). Ten subjects reported twelve mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed.ConclusionsSemaglutide exposure did not appear to be affected by hepatic impairment, suggesting that no dose adjustment may be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.
      PubDate: 2017-12-05T02:00:47.645429-05:
      DOI: 10.1111/dom.13186
  • Comparison of glucose-lowering agents following dual therapy failure in
           type 2 diabetes Systematic review and network meta–analysis of
           randomised controlled trials
    • Authors: Francesco Zaccardi; Nafeesa N. Dhalwani, Jolyon Dales, Hamid Mani, Kamlesh Khunti, Melanie J. Davies, David R. Webb
      Abstract: AimsTo assess the evidence supporting the choice of third–line agents in adults with inadequately controlled type 2 diabetes.Materials and MethodsWe searched RCTs published between Jan 2000 and July 2017 reporting data on cardiometabolic outcomes and hypoglycaemia for glucose–lowering agents added to metformin–based dual treatments. Data were stratified by background therapy and RCT duration and synthesised, when possible, with network meta–analyses.Results43 RCTs (16590 participants) were included, with metformin combined to sulphonylurea (SU) in 20 RCTs; thiazolidinedione (TZD) in 10; basal or rapid acting insulin in 6; DPP–4i in 3; GLP–1RA in 2; and SGLT–2i in 2. When added to metformin and SU, after 24–36 weeks rapid acting insulin resulted in the largest reduction of HbA1c (1.6% vs placebo) followed by GLP–1RA (1.0%), basal insulin (0.8%), and SGLT–2i (0.7%), with no difference between GLP–1RA and SGLT–2i; body weight increased with insulin treatment (about 3 kg vs placebo) while the greatest reduction was observed for SGLT–2i compared to all other therapies. Limited data for hypoglycaemia indicated a similar risk for SGLT–2i and GLP–1RA. Results for third–line agents added to metformin and TZD were comparable, showing similar HbA1c reduction and risk of hypoglycaemia between SGLT–2i and GLP–1RA and a slightly greater reduction of body weight with SGLT–2i vs GLP–1RA. Data for 52–54 weeks were more limited: added to metformin and SU, a TZD, GLP–1RA, or SGLT–2i reduced HbA1c to a similar extent but had different effects on body weight (7 kg and 5 kg more with TZD vs SGLT–2i and GLP–1RA, respectively; 2 kg less comparing SGLT–2i vs GLP–1RA). Formal analyses could not be performed for any other dual failure combinations due to the small number of available RCTs.ConclusionsModerate–quality evidence supports the choice of a third–line agent only in patients on metformin combined with SU or TZD, with SGLT–2i performing generally better than other drugs. In suggesting third–line agents, future guidelines should recognise the widely different evidence across possible dual failures.
      PubDate: 2017-12-05T01:50:26.929454-05:
      DOI: 10.1111/dom.13185
  • Use and effectiveness of a fixed-ratio combination of insulin
           degludec/liraglutide (IDegLira) in a real-world population with type 2
           diabetes: Results from a European, multicentre, retrospective chart review
    • Authors: Hermione Price; Matthias Blüher, Rudolf Prager, Tra-Mi Phan, Brian Larsen Thorsted, Bernd Schultes,
      Abstract: AimsEXTRA aimed to describe real-world use and effectiveness of IDegLira, a fixed-ratio combination of the basal insulin degludec, and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide.Materials and methodsThis European, multicentre, retrospective chart review comprised adults (n=611) with type 2 diabetes, who started IDegLira ≥6 months before data collection. Clinical characteristics were assessed at baseline (defined as the most recent recording during the 6 months before the first IDegLira prescription) and 3, 6, 9 and 12 months (± 45 days for each time point) after commencing IDegLira, where data available.ResultsBaseline regimens included non-injectables (19%), basal insulin (19%), GLP-1RA (10%), free combination (insulin/GLP-1RA, 24%) and multiple daily-dose insulin injections (MDI, 28%), all ± oral antidiabetic drugs. After 6 months, significant HbA1c reductions were observed in patients overall and in all subgroups (–0.9% [–10 mmol/mol] overall, p
      PubDate: 2017-12-05T01:20:31.389683-05:
      DOI: 10.1111/dom.13182
  • Treatment of clozapine-associated obesity and diabetes with exenatide
           (CODEX) in adults with schizophrenia: a randomised controlled trial
    • Authors: Dan Siskind; Anthony W Russell, Clare Gamble, Karl Winckel, Karla Mayfield, Sam Hollingworth, Ingrid Hickman, Victor Siskind, Steve Kisely
      Abstract: Clozapine causes obesity and type-2 diabetes (T2DM). Glucagon-like-peptide-1 (GLP-1) agonists (e.g. exenatide) can counter clozapine-associated GLP-1 dysregulation in animals, and may be beneficial in people on clozapine. This randomised, controlled, open-label, pilot trial evaluated weekly exenatide for weight loss among clozapine-treated obese adults with schizophrenia, with or without T2DM. Twenty-eight outpatients were randomised to once-weekly extended-release sub-cutaneous exenatide or usual care for 24 weeks. The primary outcome was proportion with>5% weight loss. All 28 participants completed the study: 3/14 in the exenatide group and 2/14 in the usual care had T2DM. Six people on exenatide achieved>5% weight loss versus one usual care (p=0.029). Compared to usual care, participants on exenatide had greater mean weight loss (-5.29kg vs -1.12kg, p=0.015), BMI reduction (-1.78 vs -0.39 p=0.019), and reduced fasting glucose (-0.34 vs 0.39, p=0.036) and HbA1c (-0.21 vs 0.03, p=0.004). There were no significant differences in other metabolic syndrome components. Exenatide may be a promising therapeutic agent for glycaemic control and weight loss in clozapine-treated people with obesity, and could assist in reducing clozapine-associated cardio-metabolic morbidity and mortality.
      PubDate: 2017-11-30T08:00:41.62568-05:0
      DOI: 10.1111/dom.13167
  • Incretin-based therapies and risk of pancreatic cancer in patients with
           type 2 diabetes: a meta-analysis of randomised controlled trials
    • Authors: Haining Wang; Ye Liu, Qing Tian, Jin Yang, Ran Lu, Siyan Zhan, Jari Haukka, Tianpei Hong
      Abstract: AimsConflicting evidence exists regarding the potential risk of pancreatic cancer with use of incretin drugs in patients with type 2 diabetes (T2DM). We performed a meta-analysis of randomised controlled trials (RCTs), including six recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with T2DM.Materials and methodsThe PubMed, Embase, Cochrane Central Register and databases were searched for RCTs in T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of no less than 52 weeks, from January 1, 2007 to May 1, 2017. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate.ResultsThirty-three studies (n=79,971), including the six CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered with incretin drugs compared to controls (Peto OR 0.67 [95%CI 0.44 to 1.02]). In the six CVOTs, 79 pancreatic cancer events were identified in 55,248 subjects. Pooled estimates of the six CVOTs displayed the identical tendency (Peto OR 0.65 [95%CI 0.42 to 1.01]). Notably, in the subgroup of patients who received treatment and follow-up for 104 weeks or more, 84 pancreatic cancer events were identified in 59,919 subjects, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62 [95%CI 0.41 to 0.95]).ConclusionsTreatment with incretin drugs is not associated with an increased risk of pancreatic cancer in patients with T2DM. Instead, it might protect against the pancreatic malignancy in patients treated for 104 weeks or more. The major limitations of this study are that pancreatic safety was not the primary outcome of these enrolled trials, and the event number and follow-up time are limited.
      PubDate: 2017-11-30T02:15:21.556222-05:
      DOI: 10.1111/dom.13177
  • Initiation of dapagliflozin and treatment-emergent fractures
    • Authors: Konstantinos A. Toulis; John P. Bilezikian, G. Neil Thomas, Wasim Hanif, Kalliopi Kotsa, Rasiah Thayakaran, Deepiksana Keerthy, Abd Tahrani, Krishnarajah Nirantharakumar
      Abstract: An increase in the fracture risk was reported in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin, possibly mediated by effects induced by all members of the sodium-glucose co-transporter 2 inhibitors (SGLT2i) class. It is unclear whether initiation of dapagliflozin is followed by an increase in the risk of fracture. Therefore, we performed a population-based, open cohort study was performed (January 2013-January 2016) using The Health Improvement Network (THIN). 22,618 patients with T2DM (4,548 exposed to dapagliflozin and 18,070 under standard antidiabetic treatment, matched for age and sex) with no history of fractures at baseline. The primary outcome was the occurrence of any fragility fracture during the observation period. Risk of any fracture served as a secondary outcome. Adjusted Hazard Rate Ratios (aHR) with 95% confidence intervals (CI) were calculated using Cox regression. A total of 289 fractures (132 fragility fractures) were recorded during the observation period. No difference in the risk of fragility fracture was detected between patients prescribed dapagliflozin and matched controls (Crude HR: 0.90, 95% CI: 0.59-1.39, p-value = 0.645 and adjusted HR: 0.87, 95% CI: 0.56-1.35, p-value = 0.531). Similarly, no difference in the risk of any fracture was detected (aHR: 0.89, 95% CI: 0.66-1.20, p-value =0.427). Sensitivity analyses limited to the subset of the population at high risk of fracture produced similar results. Thus, there was no evidence to suggest an increase in the risk of treatment-emergent fractures in patients with T2DM being initiated treatment with dapagliflozin.
      PubDate: 2017-11-30T02:05:25.821658-05:
      DOI: 10.1111/dom.13176
  • Effectiveness and tolerability of therapy with exenatide once-weekly
           versus basal insulin among injectable-naïve elderly or renal impaired
           patients with type 2 diabetes in the United States
    • Authors: Anita M Loughlin; Qing Qiao, Anthony Philip Nunes, Peter Öhman, Stephen Ezzy, Laura Yochum, C. Robin Clifford, Robert Gately, David D Dore, John Seeger
      Abstract: AimTo evaluate the effectiveness and tolerability of exenatide once-weekly (EQW) compared to basal insulin (BI) among injectable-naïve T2DM patients who are elderly or have renal impairment (RI).Methods and MaterialsInitiators of EQW and BI with T2DM were identified from 2012-2015 within a United States electronic health record database and matched by propensity score. Matched EQW and BI initiators aged 65+ years or who have RI were compared. Weight, HbA1c, eGFR, blood pressure, and lipids were obtained at baseline and quarterly (Q1-Q4) or semi-annually for one year following drug initiation. Hypoglycemia and gastrointestinal symptoms were identified using diagnosis codes and data abstracted from clinical notes.ResultsAmong patients aged 65+ years, HbA1c changed by -0.50 and -0.31 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by -1.6 kg among EQW initiators compared to 0.2 kg among BI initiators. Compared to BI initiators, EQW initiators had a 1.45-fold increased risk of nausea and vomiting. Among RI patients, HbA1c changed by -0.58 and -0.33 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by -1.9 kg for EQW initiators while BI initiators had no change in weight. EQW initiators had a 1.28-fold increased risk of constipation and diarrhea compared to BI initiators.ConclusionRegardless of age or renal function, the benefits of EQW relative to BI treatment are improved glycemic control and increased weight loss, which should be weighed against the increased risk of gastrointestinal symptoms.
      PubDate: 2017-11-30T01:35:22.804786-05:
      DOI: 10.1111/dom.13175
  • Overtreatment of older patients with type 2 diabetes mellitus in primary
    • Authors: E Hart Huberta; E Rutten Guy, N Bontje Kyra, C Vos Rimke
      Abstract: There are indications of overtreatment in older type 2 diabetes patients in both the US and Europe. We assessed the level of personalized diabetes treatment for older patients in primary care, focusing on overtreatment.Based on Dutch guidelines individuals ≥ 70 years were classified into three HbA1c treatment target groups: 7% (53 mmol/mol), 7.5% (58 mmol/mol) and 8% (64 mmol/mol).In our cohort of 1.002 patients (n=319 ≥ 70 yrs), the 165 patients with target above 7% had more micro- and macrovascular complications, used more often ≥ 5 medicines and were more often frail compared to those with an HbA1c target ≤ 7%. Of these 165 patients 64 (38.8%) were overtreated, i.e. 20% of all people ≥ 70 years. The majority of overtreated people were frail and used ≥ 5 medicines. Hypoglycemia occurred in 20.3% of these patients and almost 30% reported fall accidents.Personalized treatment in older people with type 2 diabetes is no common practice. A substantial number of older people are overtreated, with likely harmful consequences. To prevent overtreatment, definition of lower HbA1C limits might be helpful.
      PubDate: 2017-11-30T01:25:29.469813-05:
      DOI: 10.1111/dom.13174
  • Semaglutide, reduction in HbA1c and the risk of diabetic retinopathy
    • Authors: Tina Vilsbøll; Stephen C. Bain, Lawrence A. Leiter, Ildiko Lingvay, David Matthews, Rafael Simó, Ida Carøe Helmark, Nelun Wijayasinghe, Michael Larsen
      Abstract: AimsTo evaluate diabetic retinopathy data from across the SUSTAIN clinical trial programme.Materials and methodsThe SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon-like peptide-1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6 − a 2-year, preapproval cardiovascular outcomes trial − semaglutide was associated with a significant increase in the risk of diabetic retinopathy complications (DRC) versus placebo. Diabetic retinopathy (DR) data from across the SUSTAIN trials were evaluated and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at-risk patients and a mediation analysis with initial change in HbA1c (percentage-points at Week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor on risk of DRC.ResultsThere was no imbalance in DR adverse events across the SUSTAIN 1−5 and Japanese trials. The majority of the effect with semaglutide versus placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients with pre-existing DR, poor glycaemic control at baseline, and treated with insulin.ConclusionsEarly worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin; similar recommendations may be appropriate for semaglutide.
      PubDate: 2017-11-27T05:16:15.135424-05:
      DOI: 10.1111/dom.13172
  • The effect of non-surgical weight management on weight and glycaemic
           control in people with type 2 diabetes: a comparison of interventional and
           non-interventional outcomes at three years
    • Authors: Shani Botha; Lorna Forde, Sheila MacNaughton, Ross Shearer, Robert Lindsay, Naveed Sattar, David Morrison, Paul Welsh, Jennifer Logue
      Abstract: AbstractBackgroundLifestyle weight management interventions are recommended in clinical guidelines for patients with type 2 diabetes and obesity, but lack evidence regarding their long term effectiveness.Materials and MethodsElectronic health records were used to follow 23,208 patients with type 2 diabetes and obesity in Glasgow, Scotland, for up to 3 years between 2005 and 2014. Patients were stratified by referral to and attendance at a lifestyle weight management intervention, and by attainment of a target weight loss of ≥5kg over 7-9 sessions (“successful completers”). Outcomes were change in weight, HbA1c, and diabetes medications.Results3471 potentially eligible patients were referred to the service, and less than half of those attended (n=1537). Of those who attended 7-9 sessions,>40% successfully completed with a 5kg weight loss (334/808). Successful completers maintained greater weight loss (change at 3 years -8.03kg; 95%CI -9.44;-6.62) than the non-completers (-3.26kg; 95%CI; -4.01;-2.51; p
      PubDate: 2017-11-27T05:16:11.251826-05:
      DOI: 10.1111/dom.13171
  • Effects of an energy-restricted low-carbohydrate, high unsaturated fat/low
           saturated fat diet versus a high carbohydrate, low fat diet in type 2
           diabetes: a 2 year randomized clinical trial
    • Authors: Jeannie Tay; Campbell H. Thompson, Natalie D. Luscombe-Marsh, Thomas P. Wycherley, Manny Noakes, Jonathan D. Buckley, Gary A. Wittert, William S. Yancy, Grant D. Brinkworth
      Abstract: AimTo examine whether a low-carbohydrate, high unsaturated/low saturated fat diet (LC) improves glycemic control and cardiovascular disease (CVD) risk factors in overweight and obese patients with type 2 diabetes (T2D).Methods115 adults with T2D (mean[SD]; BMI:34.6[4.3]kg/m2, age:58[7]yrs, HbA1c:7.3[1.1]%) were randomized to one of two planned energy-matched, hypocaloric diets combined with aerobic/resistance exercise (1hr,3d/wk) for 2 years:(1) LC:14% energy as carbohydrate, 28% protein, 58% fat [
      PubDate: 2017-11-27T04:20:37.556829-05:
      DOI: 10.1111/dom.13164
  • “Risk of a first ever acute myocardial infarction and all-cause
           mortality with sulphonylurea treatment: a population-based cohort study”
    • Authors: Judith van Dalem; Martijn CGJ Brouwers, Coen DA Stehouwer, André Krings, Olaf H Klungel, Johanna HM Driessen, Frank de Vries, Andrea M Burden
      Abstract: We investigated the association between the current use of individual sulphonylureas and the risk of a first ever acute myocardial infarction (AMI) and all-cause mortality, in a population-based cohort study using primary care data from the Clinical Practice Research Datalink (CPRD) database (2004–2012). New users (N=121,869) with at least one prescription for a non-insulin antidiabetic agent, and aged ≥18 years were included. The first prescription defined start of follow-up. Time-dependent Cox proportional hazards models were used to estimate the risk of a first ever AMI and all-cause mortality associated with the use of individual sulphonylureas, and other non-insulin glucose-lowering drugs. No differences in risk of a first ever AMI (adjusted hazard ratio [HRadj]: 1.02, 95% Confidence Interval [CI]: 0.70-1.50) or all-cause mortality (HRadj: 0.97, 95% CI: 0.80-1.17) were observed comparing gliclazide use with non-gliclazide sulphonylurea use. Similar results were found for each individual sulphonylurea. As evidence is accumulating that gliclazide is no safer than other sulphonylureas, current guidelines suggesting superiority should be carefully evaluated.
      PubDate: 2017-11-24T08:45:24.689142-05:
      DOI: 10.1111/dom.13168
  • Uric Acid lowering in relation to HbA1c reductions with the SGLT2
           inhibitor Tofogliflozin
    • Authors: Motoshi Ouchi; Kenzo Oba, Kohei Kaku, Hideki Suganami, Akihiro Yoshida, Yasunori Fukunaka, Promsuk Jutabha, Asuka Morita, Naoyuki Otani, Keitaro Hayashi, Tomoe Fujita, Tatsuya Suzuki, Masahiro Yasutake, Naohiko Anzai
      Abstract: An integrated analysis was performed with data from four phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10-transformed urinary N-acetyl-β-D-glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 weeks and 24 weeks in multivariate analysis (respectively, P < 0.0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c> 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decrease in those with moderate HbA1c levels.
      PubDate: 2017-11-24T08:35:19.926357-05:
      DOI: 10.1111/dom.13170
  • Practical Strategies for Improving Outcomes in T2DM: the potential role of
           pioglitazone and DPP4 inhibitors
    • Authors: Stefano Del Prato; Robert Chilton
      Abstract: T2DM is a complex disease recognizing multiple pathogenic defects responsible for the development and progression of hyperglycemia. Each of these factors can now be tackled in a more targeted manner thanks to glucose-lowering drugs made available in the past two to three decades. Recognition of the multiplicity of the mechanisms underlying hyperglycemia calls for treatments addressing more than one these mechanisms with more emphasis placed on the earlier use of combination therapies. Although chronic hyperglycemia contributes to and amplifies cardiovascular risk, several trials have failed to show a marked effect from intensive glycemic control. During the past ten years, the effect of specific glucose-lowering agents on cardiovascular risk has been explored with dedicated trials. Overall, the cardiovascular safety of the new glucose-lowering agents has been proven with some of the trials summarized in this review, showing significant reduction of cardiovascular risk. Against this background, pioglitazone, in addition to exerting a sustained glucose-lowering effect, also has ancillary metabolic actions of potential interest in addressing the cardiovascular risk of T2DM, such as preservation of beta-cell mass and function. As such it seems a logical agent to combine with other oral anti-hyperglycemic agents, including dipeptidyl peptidase-4 inhibitors (DPP4i). DPP4i, which may also have a potential to preserve beta-cell function, is available as a fixed-dose combination with pioglitazone, and could, potentially, attenuate some of the side effects of pioglitazone, particularly if a lower dose of the thiazolidinedione is used. This review critically discusses the potential for early combination of pioglitazone and DPP4i.
      PubDate: 2017-11-24T08:15:21.835799-05:
      DOI: 10.1111/dom.13169
  • In response to: Metformin for the Management of Peri-operative
    • Authors: A.H. Hulst; J. Hermanides, J.H. DeVries, B. Preckel
      Abstract: We thank Dr Brown and Dr Paul for their insightful commentary on our study1 and the subject of perioperative continuation of metformin, stressing again the importance of perioperative hyperglycaemia and treatment of diabetes mellitus (DM).
      PubDate: 2017-11-20T03:10:38.863614-05:
      DOI: 10.1111/dom.13166
  • Beta-cell sensitivity to glucose is impaired after gastric bypass surgery
    • Authors: Marzieh Salehi; Amalia Gastaldelli, David A. D'Alessio
      Abstract: AimsPatients with Roux-en-Y gastric bypass surgery (GB) have exaggerated postprandial insulin secretion, which has been attributed to increased meal glucose appearance and enhanced incretin effect. Here we sought to determine β-cell glucose sensitivity in the absence of meal stimulation and insulinotropic gut factors.Materials and methodsTwelve non-diabetic subjects with prior GB, and 7 matched non-surgical controls with normal glucose tolerance were studied. Blood glucose and insulin secretion rates were measured during a graded glucose infusion at increasing and then decreasing rates. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by the minimal model.ResultsThe GB subjects had comparable SI to the controls. The GB subjects had relative hyperglycemia during highest dose of glucose infusion associated with significantly reduced β-cell glucose sensitivity throughout both step-up (GB: 34±6, CN: 82±9 pmol.min-1.mM-1.L, p
      PubDate: 2017-11-20T03:00:19.588816-05:
      DOI: 10.1111/dom.13165
  • Systemic Use of Antibiotics and Risk of Diabetes in Adults: A Nested
           Case-control Study of Alberta's Tomorrow Project
    • Authors: Ming Ye; Paula J. Robson, Dean T. Eurich, Jennifer E. Vena, Jian-Yi Xu, Jeffrey A. Johnson
      Abstract: AimsPrevious observational studies using administrative health records have suggested an increased risk of diabetes with use of antibiotics. However, unmeasured confounding factors may explain these results. This study characterized the association between systemic use of antibiotics and risk of diabetes in a cohort of adults in Canada, accounting for both clinical and self-reported disease risk factors.Materials and methodsIn this nested case-control study, we used data from Alberta's Tomorrow Project (ATP), a longitudinal cohort study in Canada, and the linked administrative health records (2000-2015). Incident cases of diabetes were matched with up to eight age-, sex- controls per case. Conditional logistic regression was used to examine the association between antibiotic exposures and incident diabetes after sequentially adjusting for important clinical and lifestyle factors.ResultsThis study included 1,676 diabetes cases and 13,401 controls. Although 17.9% of cases received more than 5 courses of antibiotics compared to 13.8% of controls (p=5 courses].ConclusionsAfter adjustment for clinical and difficult-to-capture lifestyle data, we found no association between systemic use of antibiotics and risk of diabetes. Our results suggest that those positive associations observed by previous studies using only administrative records might have been confounded.
      PubDate: 2017-11-20T02:50:23.280628-05:
      DOI: 10.1111/dom.13163
  • 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
    • 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
  • 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
    • 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
    • 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
    • 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
  • 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
  • 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
  • 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
      Pages: 233 - 237
      PubDate: 2017-09-28T00:35:25.029406-05:
      DOI: 10.1111/dom.13102
  • Prevention of cardiovascular disease through reduction of glycaemic
           exposure in type 2 diabetes: A perspective on glucose-lowering
    • Authors: Ronan Roussel; Philippe Gabriel Steg, Kamel Mohammedi, Michel Marre, Louis Potier
      Pages: 238 - 244
      Abstract: Type 2 diabetes is a leading cause of cardiovascular disease (CVD). Observational studies have consistently shown an association between glycaemic level and risk of major adverse cardiovascular events (MACE); however, intervention studies have provided limited evidence supporting a reduction in the cardiovascular burden of diabetes through intensive glucose control. In the present review, we aimed to examine the concept of cumulative glycaemic exposure with regard to protection against CVD in diabetes. We address how we can move from a binary approach in trials, to a more quantitative approach based on differences in cumulative glycaemic exposure. We plotted the association between differing glycaemic exposures between study arms and the hazard ratio for MACE in randomized controls trials comparing intensive with conventional glycaemic control in type 2 diabetes. We found a strikingly strong correlation between differential exposure and cardiovascular risk reduction. Similar results were obtained for trials comparing antidiabetes drugs with placebo. The results suggest that a minimum study duration and a minimum gain in glycated haemoglobin (HbA1c) reduction are necessary to drive a relevant risk reduction in CVD risk, and we provide a quantitative perspective in that respect. The present analysis underlines that the duration of the intensification of glycemic control, and the amplitude of the resulting reduction in HbA1c, are important notions for clinical decision-making.
      PubDate: 2017-07-25T06:42:13.36557-05:0
      DOI: 10.1111/dom.13033
  • The challenges of achieving postprandial glucose control using closed-loop
           systems in patients with type 1 diabetes
    • Authors: Véronique Gingras; Nadine Taleb, Amélie Roy-Fleming, Laurent Legault, Rémi Rabasa-Lhoret
      Pages: 245 - 256
      Abstract: For patients with type 1 diabetes, closed-loop delivery systems (CLS) combining an insulin pump, a glucose sensor and a dosing algorithm allowing a dynamic hormonal infusion have been shown to improve glucose control when compared with conventional therapy. Yet, reducing glucose excursion and simplification of prandial insulin doses remain a challenge. The objective of this literature review is to examine current meal-time strategies in the context of automated delivery systems in adults and children with type 1 diabetes. Current challenges and considerations for post-meal glucose control will also be discussed. Despite promising results with meal detection, the fully automated CLS has yet failed to provide comparable glucose control to CLS with carbohydrate-matched bolus in the post-meal period. The latter strategy has been efficient in controlling post-meal glucose using different algorithms and in various settings, but at the cost of a meal carbohydrate counting burden for patients. Further improvements in meal detection algorithms or simplified meal-priming boluses may represent interesting avenues. The greatest challenges remain in regards to the pharmacokinetic and dynamic profiles of available rapid insulins as well as sensor accuracy and lag-time. New and upcoming faster acting insulins could provide important benefits. Multi-hormone CLS (eg, dual-hormone combining insulin with glucagon or pramlintide) and adjunctive therapy (eg, GLP-1 and SGLT2 inhibitors) also represent promising options. Meal glucose control with the artificial pancreas remains an important challenge for which the optimal strategy is still to be determined.
      PubDate: 2017-08-10T02:25:21.04811-05:0
      DOI: 10.1111/dom.13052
  • Therapeutic application of GPR119 ligands in metabolic disorders
    • Authors: Jin Won Yang; Hyo Seon Kim, Yong-Won Choi, Young-Mi Kim, Keon Wook Kang
      Pages: 257 - 269
      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 hypoglycaemia. 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 any passed beyond phase II clinical studies. Herein, we summarize recent advances in research concerning the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and we speculate on future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease.
      PubDate: 2017-08-22T21:25:56.630463-05:
      DOI: 10.1111/dom.13062
  • 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
      Pages: 270 - 282
      Abstract: The identification of the critical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) 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% to 70%, and appear to be safe and acceptable to patients over at least 2 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 remain to be demonstrated if they are to be used widely in coronary prevention.
      PubDate: 2017-08-30T01:55:38.868386-05:
      DOI: 10.1111/dom.13070
  • A first-in-human pharmacodynamic and pharmacokinetic study of a fully
           human anti-glucagon receptor monoclonal antibody in normal healthy
    • Authors: Ana Kostic; Thomas Alexander King, Feng Yang, Kuo-Chen Chan, George D. Yancopoulos, Jesper Gromada, Joyce B. Harp
      Pages: 283 - 291
      Abstract: AimsGlucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 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-blinded trial.MethodsHealthy men and women received single ascending doses of REGN1193 ranging from 0.05 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 hyperglycaemia by serial glucagon challenges.ResultsREGN1193 was generally well tolerated. There were small (50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC0-90 minutes) by 80% to 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.ConclusionREGN1193, 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 suggests an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown.
      PubDate: 2017-09-14T07:15:39.537577-05:
      DOI: 10.1111/dom.13075
  • 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
      Pages: 292 - 300
      Abstract: AimsThe long-term safety and efficacy of gemigliptin was evaluated in the present extension study after a 12-week study during a 40-week follow-up period.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) and moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7% to 11% and an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas 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 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: 2017-09-06T03:01:49.317116-05:
      DOI: 10.1111/dom.13059
  • Insights into optimal basal insulin titration in type 2 diabetes: Results
           of a quantitative survey
    • Authors: Lori Berard; Mireille Bonnemaire, Marie Mical, Steve Edelman
      Pages: 301 - 308
      Abstract: AimsBasal insulin (BI) treatment initiation and dose titration in type 2 diabetes (T2DM) are often delayed. Such “clinical inertia” results in poor glycaemic 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 to 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% to 28% of patients remembered such discussions, many (32%–42%) were unaware of the need to titrate BI, and only 28% to 39% recalled mention of the time needed to reach glycaemic 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 hypoglycaemia, 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 hypoglycaemia 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: 2017-09-12T02:10:36.84155-05:0
      DOI: 10.1111/dom.13064
  • 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
      Pages: 309 - 318
      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.MethodsA retrospective cohort study was conducted with 137 935 Chinese patients aged 18 to 79 years with T2DM and without prior history of CVD, who had received public primary care services between January 1, 2010 and December 31, 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.ResultsFor 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, a 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.ConclusionThe developed models, translated into a web calculator and color-coded chart, served as evidence-based visual aids that facilitate clinicians to estimate quickly the 5-year CVD risk for Chinese T2DM patients and to guide intervention.
      PubDate: 2017-08-25T06:16:51.429746-05:
      DOI: 10.1111/dom.13066
  • Beneficial long-term antidiabetic actions of N- and C-terminally modified
           analogues of apelin-13 in diet-induced obese diabetic mice
    • Authors: Vadivel Parthsarathy; Christopher Hogg, Peter R. Flatt, Finbarr P. M. O'Harte
      Pages: 319 - 327
      Abstract: AimsTo investigate the chronic effects of twice-daily administration of stable apelin analogues, apelin-13 amide and pyroglutamyl (pGlu) apelin-13 amide, on metabolic variables in glucose-intolerant and insulin-resistant diet-induced obese mice fed a high-fat diet for 150 days.MethodsGroups of mice received twice-daily (9 am and 5 pm) 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 variables such as lipids and total GLP-1 were monitored. Dual-energy X-ray absorptiometry analysis and indirect calorimetry were also performed.ResultsAdministration of apelin-13 amide, (pGlu)apelin-13 amide or exendin-4 significantly decreased body weight, food intake and blood glucose and increased plasma insulin compared with high-fat-fed saline-treated controls (P 
      PubDate: 2017-08-22T21:31:02.975732-05:
      DOI: 10.1111/dom.13068
  • Evaluation of the specific effects of intranasal glucagon on glucose
           production and lipid concentration in healthy men during a pancreatic
    • Authors: Satya Dash; Changting Xiao, Priska Stahel, Khajag Koulajian, Adria Giacca, Gary F. Lewis
      Pages: 328 - 334
      Abstract: AimTo investigate the specific effects of intranasal glucagon (ING) on plasma glucose, endogenous glucose production (EGP) and lipid concentration.MethodsWe conducted a single-blind, randomized, crossover study at our academic investigation unit. Under pancreatic clamp conditions with tracer infusion, 1 mg ING or intranasal placebo (INP) was administered to 10 healthy men. As pilot studies showed that ING transiently increased plasma glucagon, we infused intravenous glucagon for 30 minutes along with INP to ensure similar plasma glucagon concentrations between interventions. The main outcome measures were plasma glucose, EGP, free fatty acid (FFA) and triglyceride (TG) concentrations.ResultsIn the presence of similar plasma glucagon concentrations, the increase in plasma glucose under these experimental conditions was attenuated with ING (mean plasma glucose analysis of variance P 
      PubDate: 2017-09-14T07:10:39.624746-05:
      DOI: 10.1111/dom.13069
  • 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: Wenying Yang; Kyungwan Min, Zhiguang Zhou, Ling Li, XiangJin Xu, Dalong Zhu, A. Venkateshwar Rao, Laxminarayanappa Sreenivasa Murthy, Nianxian Zhang, Ivy Li, Elisabeth Niemoeller, Shuhua Shang
      Pages: 335 - 343
      Abstract: AimsTo assess the effects on glycaemic control of lixisenatide vs placebo as add-on treatment to basal insulin (BI) ± metformin and effects 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 (BW); total daily BI dose; fasting plasma glucose; and safety assessments.ResultsBaseline demographics were similar in the two treatment groups. After insulin optimization during run-in, lixisenatide was superior to placebo in mean change from baseline (7.9% [standard deviation {s.d.}, 0.66] and 7.9% [0.70], respectively) to week 24 in HbA1c (least squares mean [standard error {s.e.}] change −0.62% [0.09] vs −0.11% [0.09]; P 
      PubDate: 2017-10-05T01:55:34.596619-05:
      DOI: 10.1111/dom.13072
  • Dapagliflozin is associated with lower risk of cardiovascular events and
           all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when
           compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational
           observational study
    • Authors: Frederik Persson; Thomas Nyström, Marit E. Jørgensen, Bendix Carstensen, Hanne L. Gulseth, Marcus Thuresson, Peter Fenici, David Nathanson, Jan W. Eriksson, Anna Norhammar, Johan Bodegard, Kåre I. Birkeland
      Pages: 344 - 351
      Abstract: AimsTo compare the sodium-glucose-cotransporter-2 (SGLT-2) inhibitor dapagliflozin with dipeptidyl peptidase-4 (DPP-4) inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non-fatal myocardial infarction, non-fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world setting.MethodsAll patients with T2D prescribed glucose-lowering drugs (GLDs) during 2012 to 2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided into two groups: new users of dapagliflozin and new users of DPP-4 inhibitors, matched 1:3 by propensity score, calculated by patient characteristics, comorbidities and drug treatment. Cox survival models were used to estimate hazard ratio (HR) per country separately, and a weighted average was calculated.ResultsAfter matching, a total of 40 908 patients with T2D were identified as new users of dapagliflozin (n = 10 227) or a DPP-4 inhibitor (n = 30 681). The groups were well balanced at baseline; their mean age was 61 years and 23% had CV disease. The mean follow-up time was 0.95 years, with a total of 38 760 patient-years. Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors: HRs 0.79 (95% confidence interval [CI] 0.67-0.94), 0.62 (95% CI 0.50-0.77), and 0.59 (95% CI 0.49-0.72), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [95% CI 0.72-1.16]), stroke (0.79 [95% CI 0.61-1.03]) and CV mortality (0.76 [95% CI 0.53-1.08]) Neutral associations with atrial fibrillation and severe hypoglycaemia were observed.ConclusionsDapagliflozin was associated with lower risks of CV events and all-cause mortality compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D population.
      PubDate: 2017-09-08T03:55:30.662073-05:
      DOI: 10.1111/dom.13077
  • Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients
           with post-bariatric hypoglycaemia
    • Authors: Colleen M. Craig; Li-fen Liu, Thi Nguyen, Candice Price, Justus Bingham, Tracey L. McLaughlin
      Pages: 352 - 361
      Abstract: AimTo evaluate the efficacy, pharmacokinetic (PK) profile and tolerability of subcutaneous (s.c.). exendin 9-39 (Ex-9) injection in patients with post-bariatric hypoglycaemia (PBH).MethodsNine women who had recurrent symptomatic hypoglycaemia after undergoing Roux-en-Y gastric bypass were enrolled in this 2-part, single-blind, single-ascending-dose study. In Part 1, a single participant underwent equimolar low-dose intravenous (i.v.) vs s.c. Ex-9 administration; in Part 2, 8 participants were administered single ascending doses of s.c. Ex-9 during an oral glucose tolerance test (OGTT). Glycaemic, hormonal, PK and symptomatic responses were compared with those obtained during the baseline OGTT.ResultsAlthough an exposure–response relationship was observed, all doses effectively prevented hyperinsulinaemic hypoglycaemia 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.ConclusionsInjection s.c. of 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: 2017-09-24T21:25:52.790803-05:
      DOI: 10.1111/dom.13078
  • 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
      Pages: 362 - 369
      Abstract: AimsDiscovery 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, double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. During 4 experimental study days, either sevelamer 3200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min) or saline was administered in randomized order. 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: 2017-09-24T21:25:28.425879-05:
      DOI: 10.1111/dom.13080
  • Sodium-glucose cotransporter-2 inhibition improves incretin sensitivity of
           pancreatic β-cells in people with type 2 diabetes
    • Authors: Chang Ho Ahn; Tae Jung Oh, Soo Heon Kwak, Young Min Cho
      Pages: 370 - 377
      Abstract: AimTo test the hypothesis that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, improves β-cell responses to incretin hormones (or β-cell incretin sensitivity) by alleviating glucose toxicity in people with type 2 diabetes mellitus (T2DM).MethodsA total of 19 people with T2DM underwent a 3-hour hyperglycaemic clamp study with incretin infusion before and after 8-week treatment with dapagliflozin added to the background treatment. In addition, 10 people with normal glucose tolerance (NGT) underwent a single hyperglycaemic clamp study. The hyperglycaemic clamp was targeted at 15.5 mmol/L for 3 hours, with synthetic glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) infusion over a 60- to 180-minute and a 120- to 180-minute period, respectively.ResultsCompared with baseline, the C-peptide response to GLP-1 (incremental area under the curve [iAUC] of C-peptide60-120 minutes) significantly increased (83.6 ± 42.1 to 106.6 ± 45.7 nmol/L × min; P = .011), and the C-peptide response to GIP/GLP-1 (iAUC of C-peptide120-180 minutes) tended to increase after dapagliflozin treatment (82.5 ± 58.4 to 101.9 ± 50.3 nmol/L × min; P = .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 participants with T2DM were far lower than those in the participants with NGT. In addition, the improvement in insulin responses to hyperglycaemia was correlated with the improvement in insulin responses to incretin infusion.ConclusionsDapagliflozin improved β-cell responses to incretin hormones as well as glucose during the hyperglycaemic clamp in patients with inadequately controlled T2DM.
      PubDate: 2017-10-02T03:05:13.053665-05:
      DOI: 10.1111/dom.13081
  • Safety and efficacy of semaglutide once weekly vs sitagliptin once daily,
           both as monotherapy in Japanese people with type 2 diabetes
    • Authors: Yutaka Seino; Yasuo Terauchi, Takeshi Osonoi, Daisuke Yabe, Nobuyuki Abe, Tomoyuki Nishida, Jeppe Zacho, Shizuka Kaneko
      Pages: 378 - 388
      Abstract: AimsTo assess the safety and efficacy of monotherapy with once-weekly subcutaneous (s.c.) semaglutide vs sitagliptin in Japanese people with type 2 diabetes (T2D).MethodsIn this phase IIIa randomized, open-label, parallel-group, active-controlled, multicentre trial, Japanese adults with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed out during the 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 participants were randomized and exposed to treatment, with similar baseline characteristics across the groups. In total, 2.9% of participants 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 attributable to adverse events (AEs). More TEAEs were reported in semaglutide- vs sitagliptin-treated participants (74.8%, 71.6% and 66.0% in the semaglutide 0.5 mg, semaglutide 1.0 mg and sitagliptin groups, respectively). AEs were mainly mild to moderate. Gastrointestinal AEs, most frequently reported with semaglutide, diminished in frequency over time. The mean glycated haemoglobin (HbA1c [baseline 8.1%]) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, vs 0.7% with sitagliptin (estimated treatment difference [ETD] vs sitagliptin −1.13%, 95% confidence interval [CI] −1.32; −0.94, and −1.44%, 95% CI −1.63; −1.24; both P 
      PubDate: 2017-10-05T01:51:13.137255-05:
      DOI: 10.1111/dom.13082
  • 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
      Pages: 389 - 399
      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 and 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: 2017-09-28T00:55:25.203666-05:
      DOI: 10.1111/dom.13083
  • Single-dose euglycaemic clamp studies demonstrating pharmacokinetic and
           pharmacodynamic similarity between MK-1293 insulin glargine and originator
           insulin glargine (Lantus) in subjects with type 1 diabetes and healthy
    • Authors: Michael F. Crutchlow; John S. Palcza, Kate M. Mostoller, Chantal D. Mahon, April M. Barbour, Michael C. Marcos, Yang Xu, Elaine Watkins, Linda Morrow, Marcus Hompesch
      Pages: 400 - 408
      Abstract: AimsMK-1293 is an insulin glargine that has an amino acid sequence identical to that of Lantus, the originator insulin glargine. Two euglycaemic clamp studies, 1 in subjects with type 1 diabetes (T1D) and 1 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 the USA (US-Lantus).Materials and MethodsBoth studies were single-dose, randomized, double-blind, single-centre, 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 euglycaemic clamp platform.ResultsIn both studies, pre-specified similarity criteria were met between MK-1293 and Lantus for comparison of PK (AUC0-24 and Cmax of M1) and PD (GIR-AUC0-24, GIR-AUC0-12, GIR-AUC12-24, and GIRmax) primary endpoints. All treatments were well tolerated.ConclusionBased on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK-1293 are highly similar to those of Lantus. ( NCT02059174).
      PubDate: 2017-09-26T22:55:28.168547-05:
      DOI: 10.1111/dom.13084
  • Effect of once-weekly dulaglutide on glycated haemoglobin (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
      Pages: 409 - 418
      Abstract: AimsTo evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD-1 to -6 and -8 clinical trials).MethodsChange in HbA1c was analysed by gender, duration of diabetes (
      PubDate: 2017-10-05T01:55:22.236476-05:
      DOI: 10.1111/dom.13086
  • Attenuated suppression of lipolysis explains the increases in triglyceride
           secretion and concentration associated with basal insulin peglispro
           relative to insulin glargine treatment in patients with type 1 diabetes
    • Authors: Rakel F. Johansen; Esben Søndergaard, Helle Linnebjerg, Parag Garhyan, Eric C. Q. Lam, Niels Porksen, Scott J. Jacober, Søren Nielsen
      Pages: 419 - 426
      Abstract: AimsTo test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very-low-density lipoprotein (VLDL)-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition.MethodsIn this open-label, randomized, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualized, 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.ResultsThe VLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL-TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL-TG storage rate was −0.36 (95% CI −0.83, 0.12).ConclusionsBIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration compared with GL-treated patients, 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: 2017-10-10T23:00:36.965051-05:
      DOI: 10.1111/dom.13087
  • 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
      Pages: 427 - 437
      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 January 1, 2004 to August 1, 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: 2017-10-01T22:40:38.733126-05:
      DOI: 10.1111/dom.13088
  • 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
      Pages: 438 - 442
      Abstract: This study aimed to assess the effect of luseogliflozin on liver fat deposition and compare luseogliflozin to metformin in type 2 diabetes (T2D) patients with non-alcoholic fatty liver disease (NAFLD). Thirty-two T2D patients with NAFLD diagnosed by computed tomography or abdominal sonography were recruited. Participants were randomly assigned to receive either luseogliflozin (2.5 mg, newly administered) or metformin (1500 mg, newly or additionally administrated). Data on the liver-to-spleen attenuation ratio (L/S), visceral fat area, body mass index, glycated hemoglobin (HbA1c), alanine aminotransferase (ALT), fasting plasma glucose, C-peptide immunoreactivity (CPR), and CPR index were collected at baseline and after 6 months. The change in L/S was significantly greater in the luseogliflozin group than in the metformin group. Similarly, the changes in the visceral fat area, HbA1c, and body mass index were significantly greater in the luseogliflozin group than in the metformin group. The changes in ALT, fasting glucose, CPR, and CPR index were not significant in both groups. In conclusion, luseogliflozin significantly reduced liver fat deposition as compared to metformin, which may indicate clinical relevant benefits for NAFLD.
      PubDate: 2017-08-22T21:40:22.218591-05:
      DOI: 10.1111/dom.13061
  • The effect 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
      Pages: 443 - 447
      Abstract: The aim of this pilot study was to investigate the effect of exercise on sleep and nocturnal hypoglycaemia 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 2 separate 45-minutes 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 = .0015) on nights following aerobic exercise and 27 (±78) minutes (P = .3) following resistance exercise relative to control nights. The odds ratio with confidence intervals of nocturnal hypoglycaemia 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 hypoglycaemia.
      PubDate: 2017-09-14T07:10:50.321198-05:
      DOI: 10.1111/dom.13065
  • Glycaemic control and hypoglycaemia in people with type 2 diabetes
           switching from twice-daily basal insulin to once-daily insulin glargine
           300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup
    • Authors: Ronan Roussel; Michael C. d'Emden, Miles Fisher, F. Javier Ampudia-Blasco, Peter Stella, Florence Bizet, Anna M. G. Cali, Carol H. Wysham
      Pages: 448 - 452
      Abstract: In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla-300) and glargine 100 U/mL (Gla-100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice-daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice-daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla-300 or Gla-100 (least squares mean difference −0.01%; 95% confidence interval [CI] −0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI −0.25 to 0.57, in EDITION 2). Participants previously receiving twice-daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 vs Gla-100 at night (00:00–05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla-300 provided similar glycaemic control with less hypoglycaemia compared with Gla-100 in people with T2DM switching from twice-daily to once-daily basal insulin.
      PubDate: 2017-09-14T01:51:09.427328-05:
      DOI: 10.1111/dom.13071
  • Efficacy and safety of teneligliptin added to canagliflozin monotherapy in
           Japanese patients with type 2 diabetes mellitus: A multicentre,
           randomized, double-blind, placebo-controlled, parallel-group comparative
    • Authors: Takashi Kadowaki; Nobuya Inagaki, Kazuoki Kondo, Kenichi Nishimura, Genki Kaneko, Nobuko Maruyama, Nobuhiro Nakanishi, Maki Gouda, Hiroaki Iijima, Yumi Watanabe
      Pages: 453 - 457
      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 to 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 randomized to receive add-on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was 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 < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM.
      PubDate: 2017-09-15T06:00:30.917123-05:
      DOI: 10.1111/dom.13079
  • 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
      Pages: 458 - 462
      Abstract: The aim of this study was to describe the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). PubMed, CENTRAL, EMBASE and were searched for randomized controlled trials of SGLT2 inhibitors in patients with T2DM up to May 20, 2017. A total of 62 studies, comprising 34 941 patients, were included. Any of the SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, tofogliflozin, luseogliflozin or ipragliflozin) significantly decreased SUA levels compared with control (total weighted mean difference [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 during long-term treatment. Dapagliflozin decreased SUA in a dose-dependent manner (from 5 to 50 mg, P = .014). In subgroup analyses, greater reductions could be observed during the course of early diabetes and the SUA-lowering effect was abolished in patients with chronic kidney disease (estimated glomerular filtration rate
      PubDate: 2017-09-27T01:45:33.370049-05:
      DOI: 10.1111/dom.13101
  • 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
      Pages: 463 - 467
      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) at 7.0% to 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: 2017-10-02T03:10:07.881088-05:
      DOI: 10.1111/dom.13104
  • Comparative effectiveness of once-weekly glucagon-like peptide-1 receptor
           agonists with regard to 6-month glycaemic 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
      Pages: 468 - 473
      Abstract: A retrospective cohort study was conducted in patients with type 2 diabetes in an electronic medical record database to compare real-world, 6-month glycated haemoglobin (HbA1c) and weight outcomes for exenatide once weekly with those for dulaglutide and albiglutide. The study included 2465 patients: exenatide once weekly, n = 2133; dulaglutide, n = 201; and albiglutide, n = 131. The overall mean (standard deviation [s.d.]) age was 60 (11) years and 54% were men; neither differed among the comparison groups. The mean (s.d.) baseline HbA1c was similar in the exenatide once-weekly (8.3 [1.7]%) and dulaglutide groups (8.5 [1.5]%; P = .165), but higher in the albiglutide group (8.7 [1.7]%; P 
      PubDate: 2017-10-08T23:20:19.635143-05:
      DOI: 10.1111/dom.13107
  • Primary sulphonylurea therapy in a newborn with transient neonatal
           diabetes attributable to a paternal uniparental disomy 6q24 (UPD6)
    • Authors: Uta Neumann; Christoph Bührer, Oliver Blankenstein, Peter Kühnen, Klemens Raile
      Pages: 474 - 475
      PubDate: 2017-10-05T02:00:23.530857-05:
      DOI: 10.1111/dom.13085
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