Efficacy of the Selective Aldosterone Synthase Inhibitor Baxdrostat for the Treatment of Resistant Hypertension

Apr 03, 2023   |  Leili Behrooz, MD, MPH; Christopher Jennings Regan, MD, FACC

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  • Use of selective aldosterone synthase inhibitor baxdrostat led to a dose-dependent reduction in systolic blood pressure in patients with treatment-resistant hypertension.
  • Baxdrostat was well tolerated among patients with treatment-resistant hypertension.

Hypertension is the leading modifiable risk factor for cardiovascular disease worldwide. Resistant hypertension refers to elevated blood pressure (BP) that does not respond adequately to at least three antihypertensive medications of different classes including a diuretic.1 It is estimated that resistant hypertension affects about 10% of all patients with hypertension.2

Aldosterone synthase, the enzyme involved in the biosynthesis of aldosterone, has a fundamental role in regulating BP and has been a target for treating hypertension. Selective inhibition of aldosterone synthase is challenging because of its similarity to the enzyme involved in cortisol synthesis.3 The BrigHTN trial studied the use of baxdrostat, a selective inhibitor of aldosterone synthase, for the treatment of resistant hypertension.4

In this multicenter, placebo-controlled phase 2 trial, 275 patients with resistant hypertension with a mean BP ≥130/80 mm Hg were randomized to either receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily or placebo for 12 weeks. The primary outcome was the change in systolic BP (SBP) from baseline to 12 weeks. The SBP change was -20.3 mm Hg, -17.5 mm Hg, and -12.1 mm Hg in the baxdrostat 2 mg, 1 mg, and 0.5 mg group, respectively, and -9.4 mm Hg in the placebo group. The difference in SBP change between the baxdrostat 2 mg group and placebo was -11 mm Hg (95% CI, -16.4 to -5.5; P<0.001) and -8.1 mm Hg (95% CI, -13.5 to -2.8; P=0.003) between the 1 mg and placebo group. There were no adverse events or occurrences of adrenocortical insufficiency.

The BrigHTN trial provides evidence that selective inhibition of aldosterone synthase leads to a substantial dose-dependent reduction in BP among patients with resistant hypertension and that baxdrostat may be a new tool for the treatment of resistant hypertension. The benefits and safety of baxdrostat need to be confirmed in a phase 3 trial over a longer period.

References

  1. Carey RM, Calhoun DA, Bakris GL, et al; American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension 2018;72:e53-e90.
  2. Noubiap JJ, Nansseu JR, Nyaga UF, Sime PS, Francis I, Bigna JJ. Global prevalence of resistant hypertension: a meta-analysis of data from 3.2 million patients. Heart 2019;105:98-105.
  3. Lenzini L, Zanotti G, Bonchio M, Rossi GP. Aldosterone synthase inhibitors for cardiovascular diseases: a comprehensive review of preclinical, clinical and in silico data. Pharmacol Res 2021;163:105332.
  4. Freeman MW, Halvorsen Y-D, Marshall W, et al; BrigHTN Investigators. Phase 2 trial of baxdrostat for treatment-resistant hypertension. N Engl J Med 2023;388:395–405.

Clinical Topics: Prevention, Hypertension, Vascular Medicine

Keywords: AHA Annual Scientific Sessions, AHA22, Antihypertensive Agents, Cytochrome P-450 CYP11B2, Aldosterone, Diuretics, Hydrocortisone, Cardiovascular Diseases, Hypertension, Hypoaldosteronism, Risk Factors


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