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      Comparison of Power, Prognosis, and Extrapolation Properties of Four Population Pharmacodynamic Models of HbA1c for Type 2 Diabetes

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          Abstract

          Reusing published models saves time; time to be used for informing decisions in drug development. In antihyperglycemic drug development, several published HbA1c models are available but selecting the appropriate model for a particular purpose is challenging. This study aims at helping selection by investigating four HbA1c models, specifically the ability to identify drug effects (shape, site of action, and power) and simulation properties. All models could identify glucose effect nonlinearities, although for detecting the site of action, a mechanistic glucose model was needed. Power was highest for models using mean plasma glucose to drive HbA1c formation. Insulin contribution to power varied greatly depending on the drug target; it was beneficial only if the drug target was insulin secretion. All investigated models showed good simulation properties. However, extrapolation with the mechanistic model beyond 12 weeks resulted in drug effect overprediction. This investigation aids drug development in decisions regarding model choice if reusing published HbA1c models.

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          Most cited references26

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          Factors affecting blood glucose monitoring: sources of errors in measurement.

          B Ginsberg (2009)
          Glucose monitoring has become an integral part of diabetes care but has some limitations in accuracy. Accuracy may be limited due to strip manufacturing variances, strip storage, and aging. They may also be due to limitations on the environment such as temperature or altitude or to patient factors such as improper coding, incorrect hand washing, altered hematocrit, or naturally occurring interfering substances. Finally, exogenous interfering substances may contribute errors to the system evaluation of blood glucose. In this review, I discuss the measurement of error in blood glucose, the sources of error, and their mechanism and potential solutions to improve accuracy in the hands of the patient. I also discuss the clinical measurement of system accuracy and methods of judging the suitability of clinical trials and finally some methods of overcoming the inaccuracies. I have included comments about additional information or education that could be done today by manufacturers in the appropriate sections. Areas that require additional work are discussed in the final section. Copyright 2009 Diabetes Technology Society.
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            Double-Blind, Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY2189102, a Neutralizing IL-1β Antibody, in Patients With Type 2 Diabetes

            OBJECTIVE Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1β antibody, in T2DM patients. RESEARCH DESIGN AND METHODS Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications. RESULTS LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: −0.27, −0.38 and −0.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated. CONCLUSIONS Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM.
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              A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes.

              This Phase IIb, randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, tolerability and pharmacokinetics of empagliflozin in patients with type 2 diabetes. Four hundred and eight patients (treatment-naïve or after a 4-week wash-out period) were randomized to receive empagliflozin 5, 10 or 25 mg once daily, placebo or open-label metformin for 12 weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) after 12 weeks. After 12 weeks' treatment, empagliflozin showed dose-dependent reductions in HbA1c from baseline [5 mg: -0.4%, 10 mg: -0.5%, 25 mg: -0.6%; all doses p < 0.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased with empagliflozin [5 mg: -1.29 mmol/l, 10 mg: -1.61 mmol/l, 25 mg: -1.72 mmol/l; all doses p < 0.0001 vs. placebo (+0.04 mmol/l)]. Body weight decreased in all empagliflozin groups (all doses p < 0.001 vs. placebo). The incidence of adverse events (AEs) was similar in the placebo (32.9%) and empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one (1.2%) on placebo. Genital infections were reported in five (2%) patients on empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature discontinuation. In patients with type 2 diabetes, empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile. © 2013 Blackwell Publishing Ltd.
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                Author and article information

                Contributors
                maria.kjellsson@farmbio.uu.se
                Journal
                CPT Pharmacometrics Syst Pharmacol
                CPT Pharmacometrics Syst Pharmacol
                10.1002/(ISSN)2163-8306
                PSP4
                CPT: Pharmacometrics & Systems Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                2163-8306
                25 March 2018
                May 2018
                : 7
                : 5 ( doiID: 10.1002/psp4.v7.5 )
                : 331-341
                Affiliations
                [ 1 ] Department of Pharmaceutical Biosciences Uppsala University Uppsala Sweden
                Author notes
                [*] [* ]Correspondence: M Kjellsson ( maria.kjellsson@ 123456farmbio.uu.se )
                Article
                PSP412290
                10.1002/psp4.12290
                5980569
                29575656
                edfde34b-6afd-45bd-b3c6-4fc1eae8dda6
                © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ 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
                : 27 October 2017
                : 22 January 2018
                : 05 February 2018
                Page count
                Figures: 6, Tables: 1, Pages: 11, Words: 6823
                Funding
                Funded by: Innovative Medicines Initiative Joint Undertaking
                Award ID: 115156
                Funded by: European Union's Seventh Framework Programme
                Award ID: FP7/2007‐2013
                Funded by: European Federation of Pharmaceutical Industries and Associations (EFPIA)
                Funded by: IDeAl Project
                Award ID: FP7 HEALTH 2013‐602552
                Categories
                Research
                Research
                Custom metadata
                2.0
                psp412290
                May 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.0 mode:remove_FC converted:31.05.2018

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