ClinicReview Article | DOI: https://doi.org/10.31579/2834-8761/047
Aldosterone Synthase Inhibitors for Treatment of Hypertension and Chronic Kidney Disease
- Nasser Mikhail *
Endocrinology Division1, Endocrinology Division, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA
*Corresponding Author: Nasser Mikhail, Endocrinology Division1, Endocrinology Division, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA
Citation: Aldosterone Synthase Inhibitors for Treatment of Hypertension and Chronic Kidney Disease, Clinical Endocrinology and Metabolism, 3(1) DOI:10.31579/2834-8761/047
Copyright: © 2024, Nasser Mikhail. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 18 January 2024 | Accepted: 29 January 2024 | Published: 02 February 2024
Keywords: aldosterone synthase; hyperkalemia; hypertension; chronic kidney disease; albuminuria
Abstract
Aldosterone excess is known to worsen hypertension and kidney function. Three selective aldosterone synthase inhibitors (ASIs) were evaluated in 3 phase 2 trials. In the first study, the ASI baxdrostat 2 mg orally once daily decreased systolic blood pressure (SBP) by 11.0 mmHg compared with placebo after 12 weeks in patients with treatment-resistant hypertension. In the second study including patients with uncontrolled hypertension, placebo-corrected reduction in SBP with lorundrostat 50 mg once daily was 9.6 mmHg after 8 weeks. Patients receiving thiazides and those with body mass index (BMI) > 30 kg/m2 had the optimum blood pressure (BP) response to lorundrostat, whereas plasma renin activity (PRA) did not affect the its antihypertensive potency. In the third trial including patients with chronic kidney disease (CKD), the ASI BI 690517 (10 mg once daily) decreased urinary albumin creatinine ratio (UACR) by 39% after 14 weeks compared with 3% reduction with placebo. Reduction in UACR was generally similar in presence or absence of concomitant treatment with empagliflozin. The 3 ASIs mildly decreased (by <15%) estimated glomerular filtration rate (eGFR) compared with placebo. The most common adverse effects of ASIs were hyperkalemia occurring in 2.9% and 7.9% among patients randomized to baxdrostat and lorundrostat, respectively versus none in the placebo groups. In patients with CKD, frequency of hyperkalemia was higher: 14.2% and 6.0% with BI 690517 and placebo, respectively. Adrenal insufficiency was reported in 1.3% of patients randomized to BI 690517 versus 1.0% with placebo. Preliminary data suggest that selective ASIs are effective in lowering BP in patients with resistant and uncontrolled hypertension and decreasing albuminuria in CKD. Phase 3 clinical trials should be conducted to assess long-term efficacy and safety of ASIs in a wide spectrum of patients with uncontrolled BP and CKD.
Introduction
Aldosterone excess causes hypertension through it salt-retaining effect [1]. In addition, accumulating evidence suggests that aldosterone has deleterious effects on the cardiorenal system by promoting inflammation, vascular stiffness, and thrombosis resulting in coronary artery disease, heart failure, and progression of kidney disease [1]. Furthermore, aldosterone may compromise renal function by causing tubulointerstitial inflammation and fibrosis and damage of podocytes [1]. Verma et al [2] have shown that higher circulating aldosterone levels among patients with CKD were independently associated with increased risk for kidney disease progression (defined as the composite of 50
Conclusions and future directions
Preliminary results suggest that the 3 ASIs bedrest, lorundrostat and BI 690517 are effective in lowering BP. Furthermore, BI 690517 decreases albuminuria in patients with CKD. Hyperkalemia represents their major limitation. Well-designed long-term trials should examine the effects of ASIs for treatment of hypertension and CKD in patients with different races and with a broad spectrum of BP, kidney function, and BMI. These trials should have CV events and mortality as primary outcome. In addition, head-to-head trials comparing safety and efficacy of ASIs with the non-steroidal aldosterone receptor blocker finerenone should be performed. This comparison will clarify whether inhibition of aldosterone synthesis or blocking its receptors is the ideal approach to target aldosterone. Trials designed to evaluate baxdrostat as treatment for patients with primary hyperaldosteronism and those with uncontrolled hypertension and CKD are underway [9]. Standardization of the proper methodology of BP measurement is crucial in future trials to validate comparison between different ASIs [10].
Conflict of interest
The author does not have any conflict of interest to declare.
| Baxdrostat [6] | Lorundrostat [7] | BI 690517 [8] |
Design | Randomized, double-blind, placebo-controlled, multicenter, phase 2 trial | Randomized, placebo-controlled, dose-ranging, multicenter in the USA, phase 2 trial | Randomized, placebo-controlled, multinational, phase 2 trial |
Disease | Treatment-resistant hypertension defined as seated BP ≥130/80 mmHg on ≥3 medications including a diuretic | Uncontrolled hypertension defined as automated office SBP ≥130 mmHg | CKD with eGFR 30 to < 90> |
Patients’ characteristics | N=275, mean age 62 years, 55% men, 70% Whites, 28% Blacks, 38% with type 2 diabetes | Cohort 1 with PRA ≤1.0 ng/ml/h (n= 163), cohort 2 PRA > 1.0 ng/ml/h (n=37). Mean age 65.7 years, 40% men, 36% Blacks, 48% Hispanics, 40% with type 2 diabetes | n= 586, mean age 63.8 years, 67% men, 58% Whites, mean eGFR 51.9 ml/min/1.73 m2, median UACR 426 mg/g, 71% with type 2 diabetes |
Mean SBP at baseline | 148 mmHg | 142 mmHg (cohort 1), 139.1 mmHg (cohort 2) | 134 mmHg |
Intervention | Baxdrostat 0.5 mg (n=69), 1 mg (n=70), 2 mg (n=67) and placebo (n=69) | Lorundrostat 12.5 mg, 50 mg, or 100 mg once daily, 12.5 mg or 25 mg bid | Empagliflozin vs placebo in the run-in phase followed by another randomization to BI 690517 at doses of 3, 10, 20 mg vs placebo |
Primary outcome | Change in SBP from baseline to week 12 | Change in office SBP from baseline to week 8 | Change in UACR from second randomization (start of BI 690517) to week 14 |
Follow-up | 12 weeks | 8 weeks | Run-in phase: randomization to empagliflozin for 8 weeks, phase 2: randomization to BI 690517 in doses 3,10,20 mg/d or placebo for 14 weeks, then 4 weeks wash-out |
Effect of ASI on primary outcome | Difference between baxdrostat 2 mg and placebo -11.0 mmHg (95% CI, -16.4 to -5.5; P <0 P=0.003)> | Difference from placebo in SBP with 100 mg: -7.8 mmHg (90% CI, -14.1 to -1.5; P=0.04), with 50 mg: -9.6 mmHg (90% CI, -15.8 to -3.4; P=0.01). Reductions in SBP with other doses vs placebo were not significant. | Placebo-corrected reductions in UACR were -20% (95% CI, -39 to 3), -37% (95% CI, -52 to -18), and -35% (95% CI, -51 to -14) with BI 690517 3mg, 10 mg., and 20 mg, respectively. |
Proportions of subjects with any adverse effects | 48-52% versus 41% with placebo | 43-57% versus 40% with placebo | 61-62% versus 54% with placebo |
Frequency of hyperkalemia (K 5.6-5.9 mmol/L) | 6/205 (2.9%) with baxdrostat vs none with placebo | 13/164 (7.9%) vs none with placebo | 62/436 (14.2%) vs 9/147 (6%) with placebo |
Frequency of serum K ≥ 6.0 mmol/L | 5/205 (2.4%) with baxdrostat vs none with placebo | 6/164 (3.6%) vs none with placebo | 6/436 (1.3%) vs 1/147 (0.6%) with placebo |
Incidence of adrenal insufficiency | None | None | 7/436 (1.3%) vs 1/147 (0.6%) with placebo |
Hypotension | 1 severe case at day 64 who discontinued baxdrostat | 2/110 (1.8%) vs none with placebo | 7/436 (1.6%) vs 1/147 (0.6%) with placebo |
Comments | Baxdrostat 2 mg decreased DBP by -5.2 mmHg versus placebo | Better SBP response in patients taking thiazides and with BMI > 30 kg/m2, and less SBP response in African Americans | Placebo-corrected decrease in SBP was -7 to -8 mmHg with BI 690517 + empagliflozin vs -4 to -6 mmHg with BI 690517 without empagliflozin |
Table 1. Overview of trials of aldosterone synthase inhibitors
Abbreviations: SBP: systolic blood pressure, CKD: chronic kidney disease, eGFR: estimated glomerular filtration rate, UACR; urine albumin to creatinine ratio, ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin receptor blocker, PRA: plasma renin activity. DBP: diastolic blood pressure, SBP: systolic blood pressure. BMI: body mass index.
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