Key Points:
- Hypertension (HTN), a major risk factor for cardiovascular disease, remains uncontrolled in many groups
- Lorundostat is an aldosterone synthase inhibitor, a novel anti-hypertensive agent that has shown some efficacy and safety in HTN treatment
- The ADVANCE-HTN trial was a multicenter randomized controlled trial evaluating the blood pressure lowering effect of lorundostat in uncontrolled and resistant HTN, finding an additional 8 mmHg decrease in 24-hour SBP compared to placebo
- This trial suggests that novel anti-hypertensive agents, particularly targeting aldosterone production, may be beneficial in HTN treatment and possibly cardiovascular risk reduction
Hypertension is the most prevalent modifiable risk factor for cardiovascular disease. However, many patients have resistant and refractory HTN cases on standard medical therapy. Lorundrostat is an aldosterone synthase inhibitor, a novel class of blood pressure lowering medication. Rather than traditional mineralocorticoid receptor antagonists, lorundrostat works by inhibition of aldosterone biosynthesis. A small dose-finding trial suggested that lorundrostat was safe and effective for blood pressure control. Here in the ADVANCE-HTN trial, the investigators conducted a randomized controlled trial to evaluate safety and efficacy of this medication in uncontrolled HTN.
The ADVANCE-HTN trial aimed to assess the 24-hour blood pressure lowering effect of lorundrostat dosed daily in patients with uncontrolled and treatment-resistant hypertension currently treated with standard anti-hypertensive therapy. This was a multicenter (103 US-based sites), prospective, randomized, double-blind, placebo-controlled, parallel group phase 2b trial enrolling 926 patients and ultimately randomizing 285 patients. Patients on two to five medications with SBP 140-180 or DBP 90-110 were screened for two weeks, followed by a 3-week single-blind run-in period of switching to guideline-based anti-hypertensive therapy with a thiazide diuretic, olmesartan, and/or amlodipine versus placebo. After BP confirmation with 24-hour ABPM, enrollees underwent randomized double-blind treatment with placebo, lorundostat 50mg daily, or 50 to 100mg daily (if office SBP remained greater than or equal to 130 mmHg with stable sodium, potassium, and renal function).
Regarding primary endpoint, the study found a significant decrease in average 24-hour SBP from baseline to week 12 among lorundrostat compared to placebo, with an average additional decrease in SBP by 7.9 mmHg (p = 0.001) with 50mg and by 6.5 mg (p = 0.006) with 50-100mg. Additional key secondary endpoints, including change in 24-hour average SBP at week 4, proportion of 24-hour SBP < 125mg at week 4, and change in office SBP over 12 weeks were all significantly improved with lorundrostat 50mg compared to placebo. In addition, there was no significant difference in adverse outcomes, including hypotension, hyponatremia, or hyperkalemia, compared to placebo.
In summary, the study investigators conclude that lorundrostat effectively lowered 24-hour blood pressure among patients with uncontrolled and resistant HTN but noted that escalation of dose from 50mg to 100mg was not associated with additional blood pressure reduction. Although this trial was not a head-to-head trial with other anti-hypertensives and did not look at major adverse cardiovascular or kidney outcomes, the ADVANCE-HTN trial shows that novel therapies, particularly aldosterone production targets, have great potential for blood pressure reduction, and therefore, may have benefit in cardiovascular risk reduction.