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      Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes

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          Abstract

          Aims

          To determine the effects of empagliflozin on blood pressure ( BP) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus ( T2DM).

          Methods

          We conducted a post hoc analysis of data from a phase III trial in patients with T2DM and hypertension receiving 12 weeks' empagliflozin and four phase III trials in patients with T2DM receiving 24 weeks' empagliflozin (cohort 1, n = 823; cohort 2, n = 2477). BP was measured using 24‐h BP monitoring (cohort 1) or seated office measurements (cohort 2).

          Results

          Empagliflozin reduced systolic BP ( SBP) and diastolic BP in both cohorts (p < 0.001 vs placebo), without increasing heart rate. Empagliflozin reduced pulse pressure ( PP; adjusted mean difference vs placebo cohort 1: −2.3 mmHg; cohort 2: −2.3 mmHg), mean arterial pressure ( MAP; cohort 1, −2.3 mmHg; cohort 2, −2.1 mmHg) and double product (cohort 1, −385 mmHg × bpm; cohort 2, −369 mmHg × bpm) all p < 0.001 vs placebo. There was a trend towards a reduction in the ambulatory arterial stiffness index ( AASI) with empagliflozin in cohort 1 (p = 0.059 vs placebo). AASI was not measured in cohort 2. Subgroup analyses showed that there were greater reductions in PP with increasing baseline SBP in cohort 1 (p = 0.092). In cohort 2, greater reductions in MAP were achieved in patients with higher baseline SBP (p = 0.027) and greater reductions in PP were observed in older patients (p = 0.011).

          Conclusions

          Empagliflozin reduced BP and had favourable effects on markers of arterial stiffness and vascular resistance.

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          Most cited references23

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          Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I.

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            Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors.

            Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. [(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [(3)H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes. © 2011 Blackwell Publishing Ltd.
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              Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial.

              We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0·74% (95% CI -0·88 to -0·59; p<0·0001) for empagliflozin 10 mg, -0·85% (-0·99 to -0·71; p<0·0001) for empagliflozin 25 mg, and -0·73% (-0·88 to -0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. Boehringer Ingelheim and Eli Lilly. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                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
                09 October 2015
                December 2015
                : 17
                : 12 ( doiID: 10.1111/dom.2015.17.issue-12 )
                : 1180-1193
                Affiliations
                [ 1 ] Department of MedicineUniversity of Texas Health Science Center San Antonio TXUSA
                [ 2 ]Helsinki University Hospital and Minerva Institute for Medical Research, University of Helsinki HelsinkiFinland
                [ 3 ] Department of CardiologyHarvard Clinical Research Institute Boston MAUSA
                [ 4 ]Boehringer Ingelheim Pharma GmbH & Co. KG IngelheimGermany
                [ 5 ]Boehringer Ingelheim Norway KS AskerNorway
                Author notes
                [*] [* ] Correspondence to: Odd Erik Johansen, Boehringer Ingelheim Norway KS, Asker, Norway.

                E‐mail: odd_erik.johansen@ 123456boehringer-ingelheim.com

                Article
                DOM12572
                10.1111/dom.12572
                5057299
                26343814
                42763393-4416-4c3c-b93d-296e9e2a576c
                © 2015 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
                : 29 July 2015
                : 29 August 2015
                : 01 September 2015
                Page count
                Pages: 14
                Funding
                Funded by: Boehringer Ingelheim
                Funded by: Eli Lilly and Company
                Funded by: Accumetrics
                Funded by: Arisaph
                Funded by: Astra Zeneca
                Funded by: GlaxoSmithKline
                Funded by: Janssen
                Funded by: Merck
                Funded by: Takeda
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                dom12572
                December 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:12.10.2016

                Endocrinology & Diabetes
                cardiovascular disease,phase iii study,sglt2 inhibitor,type 2 diabetes

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