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Uncontrolled hypertension: combination of Amiloride and Hydrochlorothiazide, each at half dose, reduces blood pressure without the side-effects caused by full doses of either alone


Researchers from the PATHWAY 3 study have found that the combination of two commonly used diuretics, each at half dose, can significantly reduce blood pressure without the side-effects caused by full doses of either alone.

The combination of two commonly used diuretics, each at half dose, can significantly reduce blood pressure without the side-effects caused by full doses of either alone, researchers from the PATHWAY 3 study have found.
The findings support first-line use of this combination in patients requiring diuretic therapy for hypertension.

That matched doses of the two classes of diuretics could neutralize undesirable effects while potentiating the desirable is an important discovery.

Thiazide diuretics such as Hydrochlorothiazide ( HCTZ ) have been first-line treatment for hypertension for many decades, but their usage has declined because of concerns that they increase the risk of diabetes.

A leading hypothesis has been that this risk is due to depletion of potassium by thiazides. Potassium-sparing diuretics such as Amiloride offer a potential solution, but theoretical risk of high potassium levels requires increased monitoring.

The combination of both diuretics at lower than normal doses can neutralize these potassium changes while at the same enhancing sodium excretion at two different targets in the kidneys ( natriuretic synergism ), thus reducing blood pressure more than either diuretic can do alone.

It is probable therefore that it is the prevention of potassium depletion, combined with effective blood pressure reduction, which underpins the success of Amiloride - Hydrochlorothiazide in the present study.

PATHWAY-3 investigated this in 399 obese, hypertensive patients ( mean age 61-63 years ) who had an indication for diuretic treatment, and at least one additional component of the metabolic syndrome.

Patients were randomized to receive either Amiloride 10 mg alone ( n=132 ), Hydrochlorothiazide alone 25 mg ( n=134 ) or a combination of both at half dose ( n=133 ) for 12 weeks, followed by another 12 weeks at double the dose for all groups.

For the primary endpoint, which was the change from baseline in an oral glucose tolerance test ( OGTT ), there was a significant difference between the Amiloride and Hydrochlorothiazide groups, with glucose levels rising in the latter, and dropping in the former.
The average difference in blood glucose levels between the two groups was 0.55 mmol/L ( P=0.009 ) over the study period.

In contrast, blood glucose levels remained unchanged in patients on the combination regimen, with a significant difference from levels in the HCTZ group ( 0.42 mmol/L; P=0.048 ).

The secondary endpoint of blood pressure control was acceptable and similar in both single drug arms, with a drop of 14.7 mmHg in the Amiloride group and 14.0 mmHg in the Hydrochlorothiazide group.

However, the anti-hypertensive impact was greatest in the combination group, with an additional drop of 3.4 mmHg compared to the HCTZ group ( P=0.007 ).

The study showed that Amiloride itself is a very good drug, at least as effective as Hydrochlorothiazide; and better blood pressure, lower glucose and no change in potassium can be obtained combining a half-dose of it with half-dose of Hydrochlorothiazide. ( Xagena )

Source: European Society of Cardiology ( ESC ), 2015

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