Physicians' Academy for Cardiovascular Education

Combination of two well-known diuretics at half dose effective without undesired side effects

ESC - London 2015

News - Sep. 1, 2015

Principal results from Prevention And Treatment of Hypertension With Algorithm based therapY (PATHWAY): comparison of single and combination diuretics in essential hypertension - PATHWAY-3

Presented at the ESC Congress 2015 by: Morris Brown (Cambridge, UK)


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. This risk is thought to be 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, thus reducing blood pressure more than either diuretic can do alone.
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), HCTZ 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.

Main results

  • 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 HCTZ 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.
  • 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 HCTZ group.
  • 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 combination was neutral for glucose and K+.
  • Amiloride was well tolerated, with no instances of K+ >5.8 mmol/L despite background ACEi/ARB


The combination of amiloride and HCTZ at equipotent doses amplifies the desirable effects of each drug on BP, and neutralises the undesirable changes in blood glucose and potassium.
Dr. Brown commented that amiloride itself is a very good drug – at least as effective as HCTZ; and that combining a half-dose of it with half-dose of HCTZ is a ‘win-win’ - producing better blood pressure, lower glucose and no change in potassium.
During the discussion at the press conference the question was raised why these older drugs have fallen out of use. Adverse metabolic effects will have contributed to an attention shift towards newer agents. Also, older medication is often used in suboptimal doses, which will lower confidence in their effectiveness. And with regard to potassium sparing diuretics, doctors are generally very worried about hyperkalaemia.
PATHWAY-2 and PATHWAY-3 show that K+-sparing diuretics are effective and safe, and can be preferred choices for the treatment of hypertension.

- Our reports are based on information made available at the ESC congress -

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