title: Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3): protocol for a randomised double-blind trial in patients with essential hypertension.
abstract: BACKGROUND
  Thiazide diuretics are associated with increased risk of diabetes mellitus. This risk may arise from K(+)-depletion. We hypothesised that a K(+)-sparing diuretic will improve glucose tolerance, and that combination of low-dose thiazide with K(+)-sparing diuretic will improve both blood pressure reduction and glucose tolerance, compared to a high-dose thiazide.
  
  
  METHODS
  This is a parallel-group, randomised, double-blind, multicentre trial, comparing hydrochlorothiazide 25-50 mg, amiloride 10-20 mg and combination of both diuretics at half these doses. A single-blind placebo run-in of 1 month is followed by 24 weeks of blinded active treatment. There is forced dose-doubling after 3 months. The Primary end point is the blood glucose 2 h after oral ingestion of a 75 g glucose drink (OGTT), following overnight fasting. The primary outcome is the difference between 2 h glucose at weeks 0, 12 and 24. Secondary outcomes include the changes in home systolic blood pressure (BP) and glycated haemoglobin and prediction of response by baseline plasma renin. Eligibility criteria are: age 18-79, systolic BP on permitted background treatment ≥ 140 mm Hg and home BP ≥ 130 mm Hg and one component of the metabolic syndrome additional to hypertension. Principal exclusions are diabetes, estimated-glomerular filtration rate <45 mL/min, abnormal plasma K(+), clinic SBP >200 mm Hg or DBP >120 mm Hg (box 2). The sample size calculation indicates that 486 patients will give 80% power at α=0.01 to detect a difference in means of 1 mmol/L (SD=2.2) between 2 h glucose on hydrochlorothiazide and comparators.
  
  
  BACKGROUND
  PATHWAY-3 was approved by Cambridge South Ethics Committee, number 09/H035/19. The trial results will be published in a peer-reviewed scientific journal.
  
  
  BACKGROUND
  Eudract number 2009-010068-41 and clinical trials registration number: NCT02351973.
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK Trial Executive for the British Hypertension Society's PATHWAY Programme of Trials Steering Committee for the British Hypertension Society's PATHWAY Programme of Trials.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
authors.affiliation: Trial Executive for the British Hypertension Society's PATHWAY Programme of Trials Steering Committee for the British Hypertension Society's PATHWAY Programme of Trials Institute of Cardiovascular Sciences, University College London, London, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Williams
authors.affiliation: Trial Executive for the British Hypertension Society's PATHWAY Programme of Trials Steering Committee for the British Hypertension Society's PATHWAY Programme of Trials Medicines Monitoring Unit, Medical Research Institute, University of Dundee, Dundee, Tayside, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: MacDonald
authors.affiliation: Steering Committee for the British Hypertension Society's PATHWAY Programme of Trials William Harvey Institute, QMUL, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.affiliation: Cardiovascular Medicine & Diabetes, King's College London, London, UK.
authors.forename: J Kennedy
authors.initials: JK
authors.lastname: Cruickshank
authors.affiliation: Institute of Cardiovascular Medical Sciences, Western Infirmary, London, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: McInnes
authors.affiliation: Steering Committee for the British Hypertension Society's PATHWAY Programme of Trials Centre of Circulatory Health, Imperial College, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Sever
authors.affiliation: Steering Committee for the British Hypertension Society's PATHWAY Programme of Trials Clinical Pharmacology Unit, University of Edinburgh, Edinburgh, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Jackie
authors.initials: J
authors.lastname: Salsbury
authors.affiliation: Medicines Monitoring Unit, Medical Research Institute, University of Dundee, Dundee, Tayside, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Morant
authors.affiliation: Trial Executive for the British Hypertension Society's PATHWAY Programme of Trials Steering Committee for the British Hypertension Society's PATHWAY Programme of Trials Robertson Centre, University of Glasgow, Glasgow, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000584:Amiloride / Q000008:administration & dosage* / Q000009:adverse effects; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002985:Clinical Protocols; D004232:Diuretics / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000075222:Essential Hypertension; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage* / Q000009:adverse effects; D006973:Hypertension / Q000188:drug therapy*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D004232:Diuretics; D006852:Hydrochlorothiazide; D000584:Amiloride
keywords: CLINICAL PHARMACOLOGY