Aldosterone Synthase Inhibition for Resistant Hypertension

Several effective BP-lowering agents are available for the management of hypertension. However, a satisfactory BP control is often not achieved, exposing patients to a higher cardiovascular risk. In particular, a condition characterized by office BP values persistently exceeding 140/90 mmHg, in spite of three drugs including a diuretic, is defined resistant hypertension.^[2–4]

Several attempts have been made to develop new drugs or non-pharmacological tools to achieve better BP control, particularly in resistant hypertension.^[5] Among these, a novel atrial natriuretic peptide (ANP)-based compound mutant ANP^[6,7] and endothelin receptor antagonists, such as aprocitentan,^[8] appear to provide additional BP reduction through different mechanisms and beyond the effects of recommended drug classes. Renal denervation, as an adjunctive strategy to pharmacological treatment for reducing BP in patients with resistant hypertension, has also been investigated.^[9] Current guidelines recommend MRAs as the first additional step in patients with resistant hypertension, in view of the proposed role of aldosterone in maintaining high BP levels in this setting, and on the basis of promising results of several trials.^[10,11] However, the frequent adverse effects of steroidal MRAs, such as gynecomastia, hyperkalaemia and worsening renal function, have limited the use of these compounds on top of other antihypertensive agents.

The Phase 2 BrigHTN study^[1] provides evidence in support of an alternative strategy based on the inhibition of aldosterone biosynthesis, by showing a dose-dependent BP-lowering efficacy of baxdrostat, a selective aldosterone synthase inhibitor, in patients with treatment-resistant hypertension. The dose-related and sustained reductions of aldosterone levels without significant changes in cortisol levels support the high selectivity of baxdrostat, with respect to previously developed aldosterone synthase inhibitors, such as osilodrostat.

Some limitations of the present study deserve to be outlined. First, the BP thresholds used to define resistant hypertension were >130 and >80 mmHg for office SBP and DBP, respectively, despite stable treatment with at least three drugs including a diuretic. These criteria are not consistent with current European Guidelines, in which office BP levels >140/90 mmHg are necessary to confirm a diagnosis of resistant hypertension.^[2–4] Moreover, out-of-office BP measurements and in particular ambulatory BP monitoring, that are required to confirm resistant hypertension, were not performed. Second, although the medications used at randomization are listed by the authors, no information is available about which pharmacological therapies were received by the patients, thus the use of adequate doses or combinations of BP-lowering drugs cannot be assessed. Third, although the authors suggest that the selection of patients with an eGFR >45 mL/min/1.73 m² reduced the likelihood of hyperkalaemia, this criterion introduces a significant limitation to a safe use of baxdrostat in patients with moderate renal insufficiency, which is frequent among those with resistant hypertension. Fourth, the enrolled population included an unusually high proportion of diabetic (about 40%) and obese (mean body mass index, 32 kg/m2) subjects and this may have influenced the achieved results. In fact, these metabolic disorders may independently contribute to the development and maintenance of difficult-to-treat or resistant forms of hypertension. Fifth, information about the proportion of patients who achieved a normalization of BP levels or, on the other hand, did not respond to the experimental treatment is lacking. Finally, as acknowledged by the authors, the follow-up period was limited to 12 weeks.

We conclude that selective aldosterone synthase inhibition represents a promising approach to the management of resistant hypertension. However, the clinical efficacy and safety of baxdrostat need to be confirmed in Phase 3 trials involving more patients treated for a longer term, in order to assess the influence of improved BP control on hypertension-mediated cardiovascular and renal damage.