Rationale and design of the genotype-blinded trial of torasemide for the treatment of hypertension (BHF UMOD)

McCallum, L., Brooksbank, K., McConnachie, A. , Aman, A., Lip, S., Dawson, J. , MacIntyre, I. M., MacDonald, T. M., Webb, D. J. and Padmanabhan, S. (2021) Rationale and design of the genotype-blinded trial of torasemide for the treatment of hypertension (BHF UMOD). American Journal of Hypertension, 34(1), pp. 92-99. (doi: 10.1093/ajh/hpaa166) (PMID:33084880) (PMCID:PMC7891239)

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Abstract

Background: There is evidence from genome wide association study that single-nucleotide polymorphisms (SNPs) in the 5' end of the uromodulin gene (UMOD) affect uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb of the loop of Henle (TAL) and its effect on BP appear to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. As volume overload is considered as one of the primary drivers for uncontrolled hypertension, targeting loop-diuretics to individuals who are more likely to respond to this drug class, using UMOD genotype, could be an efficient precision medicine strategy. Methods: A genotype-blinded, multi-centre trial comparing the BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants with uncontrolled BP aged ≥18 years, on ≥1 antihypertensive agent for ≥3 months, will be included. Uncontrolled BP is average systolic BP (SBP) >135mmHg and/or diastolic BP >85mmHg on home monitoring. Torasemide, 5mg daily, is taken for 16 weeks. The primary outcome is the change in 24h ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160). Registration at https://clinicaltrials.gov/ct2/show/NCT03354897. Results: The study should conclude August 2021. Conclusions: If hypothesis confirmed, a targeted strategy will improve BP control and could reduce the burden of uncontrolled hypertension.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lip, Dr Stefanie and McConnachie, Professor Alex and Padmanabhan, Professor Sandosh and Brooksbank, Dr Katriona and Dawson, Professor Jesse and Aman, Alisha and McCallum, Dr Linsay
Authors: McCallum, L., Brooksbank, K., McConnachie, A., Aman, A., Lip, S., Dawson, J., MacIntyre, I. M., MacDonald, T. M., Webb, D. J., and Padmanabhan, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:American Journal of Hypertension
Publisher:Oxford University Press
ISSN:0895-7061
ISSN (Online):1941-7225
Published Online:21 October 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in American Journal of Hypertension 34(1): 92-99
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173522Clinical study of UMOD NKCC2 interaction on salt-sensitivity in hypertensionSandosh PadmanabhanBritish Heart Foundation (BHF)CS/16/1/31878Institute of Cardiovascular & Medical Sciences