PATHWAY3: Amiloride-HCTZ Lowers BP With Neutral Effect on Glucose, Potassium

September 02, 2015

LONDON, UK — Combining two diuretics, amiloride and hydrochlorothiazide (HCTZ), results in a significant reduction in blood pressure, more so than when each drug is used alone, and has the beneficial effect of neutralizing undesirable changes in blood glucose and potassium, according to the results of a new study.

In presenting the results of PATHWAY3 at the European Society of Cardiology (ESC) 2015 Congress, lead investigator Dr Morris Brown (University of Cambridge, UK) told heartwire from Medscape that the study is a win-win for patients, as the combination of amiloride/HCTZ resulted in significantly better blood-pressure control and blunted or neutralized adverse side effects such as hyperglycemia or electrolyte imbalances.

Dr Morris Brown

"It's a big issue," said Brown, referring to concerns about the adverse metabolic effects with diuretic medications. "Because of the risk of diabetes, which has been constant around 25% to 30% in numerous outcomes trials, this has led to diuretics being used at lower doses." The doses used, he noted, are significantly lower than those used in clinical-outcomes studies performed in the past.

Speaking during the late-breaking clinical-trials session, Dr Antonio Coca (University of Barcelona, Spain) said the results provide strong support that changes in glucose metabolism are related to the changes in potassium, given that amiloride is a potassium-sparing agent, and appeared to offset the adverse metabolic effects. Coca, who was scheduled discussant and not involved in the trial, suggested the amiloride/HCTZ combination might be particularly beneficial in patients with insulin resistance or the metabolic syndrome.

Offsetting Metabolic Changes While Decreasing BP

Dr Antonio Coca

In the PATHWAY3 study, investigators enrolled patients with uncontrolled hypertension (systolic blood pressure >140 mm Hg) eligible for diuretic therapy. Patients in the trial also had at least one additional component of the metabolic syndrome. In total, 440 patients were randomized to amiloride 10 to 20 mg or amiloride 5 to 10 mg and HCTZ 12.5 to 25 mg or HCTZ 25 to 50 mg.

Regarding the primary outcome, which was the change from baseline in 2-hour oral glucose tolerance test (OGTT), treatment with HCTZ resulted in an increase in the 2-hour OGTT when measured at 12 and 24 weeks, while amiloride went the other direction, with patients having a reduction in 2-hour glucose after 12 and 24 weeks on treatment. Compared with HCTZ alone, amiloride significantly reduced the 2-hour OGTT (0.71-mmol/L difference vs HCTZ at 24 weeks), while the combination of amiloride/HCTZ was neutral on 2-hour glucose (0.58-mmol/L difference vs HCTZ at 24 weeks).

As for systolic blood pressure, the two full-dose agents both decreased blood pressure approximately 14 mm Hg, but there was a an additional 3.4-mm-Hg reduction in patients treated with the amiloride/HCTZ combination. Importantly, investigators say the combination was safe, with a neutral effect on potassium levels. No patient had a potassium level increase beyond 5.8 mmol/L, despite background ACE-inhibitor or angiotensin-receptor–blocker therapy.

To heartwire , Brown said that over the years, especially given the concerns about possible adverse metabolic risks, a mantra developed—"low-dose thiazides are maximal"—which he likened to "having our cake and eating it, too." The view was that physicians could use lower doses of the thiazides to avoid the risks of diabetes but also achieve blood-pressure control. This, however, is simply not the case, said Brown.

"Bit by bit, eventually, we showed that this wasn't true, but the damage was done as people began to realize that the doses of diuretics used in clinical practice are much lower than were used in the clinical-outcomes trials," said Brown. "The consequence of that is that they became less popular in some of the guidelines, particularly the UK guidelines, and they have come to be seen as less cost-effective. Although people still debate how important the diabetes risk is, the fact is that once a patient becomes diabetic, it's an added healthcare cost."

The study was funded by the British Heart Foundation and National Institute for Health Research.


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