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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 MJ, Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P, Webb DJ, Salsbury J, Morant S, Ford I - BMJ Open (2015)

Bottom Line: 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.The primary outcome is the difference between 2 h glucose at weeks 0, 12 and 24.PATHWAY-3 was approved by Cambridge South Ethics Committee, number 09/H035/19.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Evidence for dose–response to thiazide diuretics (A). Comparison of blood pressure response to dose-doubling of a calcium-channel blocker, nifedipine and diuretic combination, hydrochlorothiazide and amiloride, in the INSIGHT study. The figure shows the response in patients achieving target blood pressure, 140/90 mm Hg, on low-dose (left panel) or high-dose (right panel) monotherapy. (Unpublished data from reference 6) (B). Comparison of blood pressure response to dose-doubling of three types of diuretic-bendroflumethiazide, amiloride, spironolactone. (Data redrawn from ref. 8).
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BMJOPEN2015008086F1: Evidence for dose–response to thiazide diuretics (A). Comparison of blood pressure response to dose-doubling of a calcium-channel blocker, nifedipine and diuretic combination, hydrochlorothiazide and amiloride, in the INSIGHT study. The figure shows the response in patients achieving target blood pressure, 140/90 mm Hg, on low-dose (left panel) or high-dose (right panel) monotherapy. (Unpublished data from reference 6) (B). Comparison of blood pressure response to dose-doubling of three types of diuretic-bendroflumethiazide, amiloride, spironolactone. (Data redrawn from ref. 8).

Mentions: Diuretics are no longer used at doses achieving maximum reduction in BP. This is because of the evidence that higher doses are associated with increased risk of diabetes mellitus (DM), and an extrapolation from small studies in the 1980's and 90's that maximal blood pressure reductions were achieved by low-dose thiazides.2–5 However, unpublished dose-titration data from INSIGHT (figure 1A), where the average age was 60, shows as steep a dose–response for hydrochlorothiazide as for nifedipine in patients (right panel) whose dose was doubled after 2 weeks.6 Amiloride has never been fully investigated at doses equi-effective with thiazides, and is used mainly in an ancillary K+-sparing role.7 A diuretic crossover study (‘SALT’) confirmed that in low-renin patients bendroflumethiazide 2.5 mg is not maximal, and showed either spironolactone or amiloride to be effective alternatives to the higher dose (figure 1B).8 Several indices in SALT indicated that even 5 mg of bendroflumethiazide was a less effective natriuretic than the K+-sparing diuretics, perhaps because it lowers blood pressure (BP) partly through vasodilation.9 The difference in mechanisms raised the possibility, to be explored by PATHWAY-3, that the diuretics will be found to have an additive effect on BP.


Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3): protocol for a randomised double-blind trial in patients with essential hypertension.

Brown MJ, Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P, Webb DJ, Salsbury J, Morant S, Ford I - BMJ Open (2015)

Evidence for dose–response to thiazide diuretics (A). Comparison of blood pressure response to dose-doubling of a calcium-channel blocker, nifedipine and diuretic combination, hydrochlorothiazide and amiloride, in the INSIGHT study. The figure shows the response in patients achieving target blood pressure, 140/90 mm Hg, on low-dose (left panel) or high-dose (right panel) monotherapy. (Unpublished data from reference 6) (B). Comparison of blood pressure response to dose-doubling of three types of diuretic-bendroflumethiazide, amiloride, spironolactone. (Data redrawn from ref. 8).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539390&req=5

BMJOPEN2015008086F1: Evidence for dose–response to thiazide diuretics (A). Comparison of blood pressure response to dose-doubling of a calcium-channel blocker, nifedipine and diuretic combination, hydrochlorothiazide and amiloride, in the INSIGHT study. The figure shows the response in patients achieving target blood pressure, 140/90 mm Hg, on low-dose (left panel) or high-dose (right panel) monotherapy. (Unpublished data from reference 6) (B). Comparison of blood pressure response to dose-doubling of three types of diuretic-bendroflumethiazide, amiloride, spironolactone. (Data redrawn from ref. 8).
Mentions: Diuretics are no longer used at doses achieving maximum reduction in BP. This is because of the evidence that higher doses are associated with increased risk of diabetes mellitus (DM), and an extrapolation from small studies in the 1980's and 90's that maximal blood pressure reductions were achieved by low-dose thiazides.2–5 However, unpublished dose-titration data from INSIGHT (figure 1A), where the average age was 60, shows as steep a dose–response for hydrochlorothiazide as for nifedipine in patients (right panel) whose dose was doubled after 2 weeks.6 Amiloride has never been fully investigated at doses equi-effective with thiazides, and is used mainly in an ancillary K+-sparing role.7 A diuretic crossover study (‘SALT’) confirmed that in low-renin patients bendroflumethiazide 2.5 mg is not maximal, and showed either spironolactone or amiloride to be effective alternatives to the higher dose (figure 1B).8 Several indices in SALT indicated that even 5 mg of bendroflumethiazide was a less effective natriuretic than the K+-sparing diuretics, perhaps because it lowers blood pressure (BP) partly through vasodilation.9 The difference in mechanisms raised the possibility, to be explored by PATHWAY-3, that the diuretics will be found to have an additive effect on BP.

Bottom Line: 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.The primary outcome is the difference between 2 h glucose at weeks 0, 12 and 24.PATHWAY-3 was approved by Cambridge South Ethics Committee, number 09/H035/19.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus