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.