The results of the phase 2 BrigHTN study demonstrate that baxdrostat significantly lowers blood pressure in patients with resistant hypertension. Unlike other molecules previously tested, baxdrostat inhibits aldosterone synthesis without inhibiting cortisol synthesis. If efficacy and safety are confirmed in phase 3, it could become the prototype of the first new class of antihypertensive drugs to be introduced into the clinic since 2007.
Aldosterone in resistant hypertension
10-20% of hypertensive patients have resistant hypertension, i.e. an outpatient pressure greater than 130/80 mm Hg despite treatment with at least three antihypertensives with different mechanisms of action (a diuretic plus a drug acting on the renin-angiotensin system and a calcium channel blocker) at the maximum tolerated dose.Obviously, we can speak of resistant hypertension only if the patient adheres to the therapy completely.
Since resistance to treatments has been associated with excessive secretion of aldosterone, this hormone is the logical one on which to act. A first possible strategy is to use a mineralocorticoid receptor antagonist. Spironolactone is effective, but its use is limited by side effects (gynecomastia in men and menstrual irregularities and postmenopausal bleeding in women); In addition, by not being selective, spironolactone increases the risk of hyperkalemia.
The alternative is to block aldosterone synthesis, a strategy complicated by the fact that the amino acid sequence of aldosterone synthase is 93% identical to that of 11β-hydrolase, necessary for cortisol synthesis. In preclinical and phase 1 studies, the inhibitor baxdrostat demonstrated high selectivity (100:1) for aldosterone synthase.
The BrigHTN study
The randomized placebo-controlled trial enrolled 248 patients with resistant hypertension.Three doses of baxdrostat (2.1 or 0.5 mg/day) were tested. The primary endpoint was the change in systolic blood pressure at the end of the twelfth week of treatment.
Relative to baseline, blood pressure was reduced by 20.3, 17.5, 12.1 and 9.4 mm Hg in patients assigned to baxdrostat 2 mg, 1 mg, 0.5 mg, and placebo, respectively. The changes observed with baxdrostat 2 mg (-11.0 mm Hg [95%CI -16.4 to -5.5] compared to placebo were statistically significant; P<0.001) and baxdrostat 1 mg (-8.1 mm Hg [95%CI -13.5 to -2.8]; P=0.003), but not that observed with baxdrostat at the lowest dose. From a safety point of view, no deaths occurred and no serious adverse events attributed to baxdrostat were recorded. No problems of adrenocortical insufficiency emerged.
Beware of potassium
Two of the patients treated with the inhibitor had potassium elevations above 6.0 mmol/L, however the hyperkalemia resolved after stopping treatment and did not recur when the patient returned to baxdrostat.
In the editorial accompanying the article in the New England Journal of Medicine, Michael Azizi, head of the Hypertension Unit at the Georges Pompidou European Hospital in Paris, points out that the fact that one of the exclusion criteria was an eGFR <45 ml/min/1.73 m2 reduced the likelihood of observing hyperkalemia, a problem that may therefore have been underestimated."If baxdrostat were to enter the market," he writes, "monitoring of serum potassium and creatinine levels would be necessary, as is necessary for mineralocorticoid receptor antagonists."
«New perspectives are opening up for the care of patients with resistant hypertension and also those with primary aldosteronism – comments Azizi – However, larger and longer studies are needed that include 24-hour ambulatory pressure monitoring and steroid profile analysis, in which there is an active control group treated with a mineralocorticoid receptor antagonist».
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Source — https://www.univadis.it/viewarticle/una-nuova-chance-l%25E2%2580%2599ipertensione-resistente-2023a10002xg