Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3)

protocol for a randomised double-blind trial in patients with essential hypertension

Morris J. Brown (Lead / Corresponding author), Bryan Williams, Thomas M. MacDonald, Mark Caulfield, J. Kennedy Cruickshank, Gordon McInnes, Peter Sever, David J. Webb, Jackie Salsbury, Steve Morant, Ian Ford

    Research output: Contribution to journalArticle

    4 Citations (Scopus)
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    Abstract

    INTRODUCTION: 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 AND ANALYSIS: 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.

    ETHICS AND DISSEMINATION: 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.

    TRIAL REGISTRATION NUMBERS: Eudract number 2009-010068-41 and clinical trials registration number: NCT02351973.

    Original languageEnglish
    Article numbere008086
    Number of pages8
    JournalBMJ Open
    Volume5
    Issue number8
    DOIs
    Publication statusPublished - 7 Aug 2015

    Fingerprint

    Diuretics
    Blood Pressure
    Glucose
    Thiazides
    Hydrochlorothiazide
    Blood Glucose
    Sodium Chloride Symporter Inhibitors
    Ethics Committees
    Amiloride
    Glycosylated Hemoglobin A
    Glucose Tolerance Test
    Glomerular Filtration Rate
    Renin
    Ethics
    Sample Size
    Multicenter Studies
    Essential Hypertension
    Fasting
    Diabetes Mellitus
    Eating

    Cite this

    Brown, Morris J. ; Williams, Bryan ; MacDonald, Thomas M. ; Caulfield, Mark ; Cruickshank, J. Kennedy ; McInnes, Gordon ; Sever, Peter ; Webb, David J. ; Salsbury, Jackie ; Morant, Steve ; Ford, Ian. / Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3) : protocol for a randomised double-blind trial in patients with essential hypertension. In: BMJ Open. 2015 ; Vol. 5, No. 8.
    @article{ca286d0479974c54a78feb4bf2784b34,
    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 = "INTRODUCTION: 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 AND ANALYSIS: 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.ETHICS AND DISSEMINATION: 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.TRIAL REGISTRATION NUMBERS: Eudract number 2009-010068-41 and clinical trials registration number: NCT02351973.",
    author = "Brown, {Morris J.} and Bryan Williams and MacDonald, {Thomas M.} and Mark Caulfield and Cruickshank, {J. Kennedy} and Gordon McInnes and Peter Sever and Webb, {David J.} and Jackie Salsbury and Steve Morant and Ian Ford",
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    Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3) : protocol for a randomised double-blind trial in patients with essential hypertension. / Brown, Morris J. (Lead / Corresponding author); Williams, Bryan; MacDonald, Thomas M.; Caulfield, Mark; Cruickshank, J. Kennedy; McInnes, Gordon; Sever, Peter; Webb, David J.; Salsbury, Jackie; Morant, Steve; Ford, Ian.

    In: BMJ Open, Vol. 5, No. 8, e008086, 07.08.2015.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3)

    T2 - protocol for a randomised double-blind trial in patients with essential hypertension

    AU - Brown, Morris J.

    AU - Williams, Bryan

    AU - MacDonald, Thomas M.

    AU - Caulfield, Mark

    AU - Cruickshank, J. Kennedy

    AU - McInnes, Gordon

    AU - Sever, Peter

    AU - Webb, David J.

    AU - Salsbury, Jackie

    AU - Morant, Steve

    AU - Ford, Ian

    N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

    PY - 2015/8/7

    Y1 - 2015/8/7

    N2 - INTRODUCTION: 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 AND ANALYSIS: 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.ETHICS AND DISSEMINATION: 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.TRIAL REGISTRATION NUMBERS: Eudract number 2009-010068-41 and clinical trials registration number: NCT02351973.

    AB - INTRODUCTION: 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 AND ANALYSIS: 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.ETHICS AND DISSEMINATION: 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.TRIAL REGISTRATION NUMBERS: Eudract number 2009-010068-41 and clinical trials registration number: NCT02351973.

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