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

L. McCallum, K. Brooksbank, A. McConnachie, A. Aman, S. Lip, J. Dawson, I. M. MacIntyre, T. M. MacDonald, D. J. Webb, S. Padmanabhan (Lead / Corresponding author)

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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.

Original languageEnglish
JournalAmerican Journal of Hypertension
Early online date21 Oct 2020
DOIs
Publication statusE-pub ahead of print - 21 Oct 2020

Keywords

  • Uromodulin
  • loop diuretic
  • furosemide
  • NKCC2

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