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      Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes

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          Abstract

          Aims

          To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready‐to‐use autoinjector with a Miglyol diluent (exenatide QWS‐AI). This study compared the efficacy and safety of exenatide QWS‐AI with the first‐in‐class glucagon‐like peptide‐1 receptor agonist exenatide twice daily ( BID).

          Materials and Methods

          This randomized, open‐label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose‐lowering medication randomized patients 3:2 to either exenatide QWS‐AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28‐week change in glycated haemoglobin ( HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments.

          Results

          A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m 2; diabetes duration, 8.5 years) received either exenatide QWS‐AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by −1.4% and −1.0%, respectively (least‐squares mean difference, −0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS‐AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups ( P = .37 for difference). Gastrointestinal adverse events ( AEs) were reported in 22.7% (exenatide QWS‐AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS‐AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use.

          Conclusions

          Exenatide QWS‐AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

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          Most cited references10

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          GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.

          In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of β-cell apoptosis. Native GLP-1 is degraded within ~2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient.
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            Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes

            OBJECTIVE To evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy. RESEARCH DESIGN AND METHODS In this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m2, A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16. RESULTS Dose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P < 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide. CONCLUSIONS Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.
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              The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis

              Aims To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus. Methods Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo) in adults with type 2 diabetes and a mean body mass index ≥ 25kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator. Results In the mixed treatment comparison (27 trials), the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2mg/week: -1.62kg (95% CrI: -2.95kg, -0.30kg), exenatide 20μg: -1.37kg (95% CI: -222kg, -0.52kg), liraglutide 1.2mg: -1.01kg (95%CrI: -2.41kg, 0.38kg) and liraglutide 1.8mg: -1.51 kg (95% CI: -2.67kg, -0.37kg) compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss. Conclusions This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.
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                Author and article information

                Contributors
                cwysham@rockwoodclinic.com
                Journal
                Diabetes Obes Metab
                Diabetes Obes Metab
                10.1111/(ISSN)1463-1326
                DOM
                Diabetes, Obesity & Metabolism
                Blackwell Publishing Ltd (Oxford, UK )
                1462-8902
                1463-1326
                22 August 2017
                January 2018
                : 20
                : 1 ( doiID: 10.1111/dom.2018.20.issue-1 )
                : 165-172
                Affiliations
                [ 1 ] Rockwood Clinic Spokane Washington
                [ 2 ] Dallas Diabetes Research Center at Medical City Dallas Texas
                [ 3 ] Bristol‐Myers Squibb Princeton New Jersey
                [ 4 ] AstraZeneca Gaithersburg Maryland
                Author notes
                [*] [* ] Correspondence

                Carol H. Wysham MD, Rockwood Center for Diabetes and Endocrinology, 400 East Fifth Avenue, Spokane, Washington 99202. Email: cwysham@ 123456rockwoodclinic.com

                Author information
                http://orcid.org/0000-0002-3056-0047
                Article
                DOM13056
                10.1111/dom.13056
                5724491
                28685973
                01d34531-e6c9-41d7-8aaa-7f87f42c9910
                © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 14 February 2017
                : 28 June 2017
                : 03 July 2017
                Page count
                Figures: 2, Tables: 2, Pages: 8, Words: 5429
                Funding
                Funded by: Bristol‐Myers Squibb
                Funded by: AstraZeneca
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                dom13056
                January 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:11.12.2017

                Endocrinology & Diabetes
                autoinjector,exenatide,glucagon‐like peptide‐1 receptor agonist,type 2 diabetes

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