Tulane University School of Medicine, New Orleans, LA (K.C.F.).
Quantum Genomics, Paris, France (F.B., B.B., S.D.).
Circulation. 2019 Jul 9;140(2):138-146. doi: 10.1161/CIRCULATIONAHA.119.040070. Epub 2019 Apr 24.
Despite existing therapy, successful control of hypertension in the United States is estimated at less than 50%. In blacks, hypertension occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure (BP) control, especially in blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population.
Two hundred fifty-six overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg BID orally for 2 weeks, then 500 mg BID if automated office blood pressure (AOBP) >140/90 mm Hg; hydrochlorothiazide 25 mg QD was added after 1 month if AOBP ≥160/110 mm Hg). The primary end point was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary end points include diastolic AOBP, 24-hour mean ambulatory BP and safety.
Firibastat lowered systolic AOBP by 9.5 mm Hg ( P<0.0001) and diastolic AOBP by 4.2 mm Hg ( P<0.0001). 85% of the subjects did not receive hydrochlorothiazide and were treated with firibastat alone. Significant BP reduction was found across all subgroups regardless age, sex, body mass index, or race. Systolic AOBP decreased by 10.2 mm Hg ( P<0.0001) in obese patients, by 10.5 mm Hg ( P<0.0001) in blacks, and 8.9 mm Hg ( P<0.0001) in nonblacks. Most frequent adverse events were headaches (4%) and skin reactions (3%). No angioedema was reported. No change in potassium, sodium, and creatinine blood level were observed.
Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant hypertension.
URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03198793.
尽管有现有的治疗方法，但美国高血压的控制成功率估计不足 50%。在黑人中，高血压发病更早、更严重、控制率更低，且发病率和死亡率均高于白人。黑人对血管紧张素转换酶抑制剂或血管紧张素 II 受体 1 型阻滞剂的单药治疗反应也较差。肥胖、较高的盐敏感性和较低的血浆肾素活性可能是导致血压控制不佳的原因，尤其是在黑人中。本研究的目的是评估 firibastat（一种新型的氨基肽酶 A 抑制剂，可阻止脑内血管紧张素 II 转化为血管紧张素 III）在降低高危、多样化高血压人群血压方面的疗效和安全性。
256 名超重或肥胖的高血压患者，包括 54%的黑人和西班牙裔个体，入组了一项多中心、开放性、二期研究。经过 2 周的洗脱期后，受试者接受 firibastat 治疗 8 周（前 2 周每天口服 250mg，bid；如果自动诊室血压（AOBP）>140/90mmHg，则增加至 500mg，bid；如果 AOBP≥160/110mmHg，则在 1 个月后加用氢氯噻嗪 25mg，qd）。主要终点是治疗 8 周后收缩压 AOBP 的变化，次要终点包括舒张压 AOBP、24 小时平均动态血压和安全性。
Firibastat 使收缩压 AOBP 降低 9.5mmHg（P<0.0001），舒张压 AOBP 降低 4.2mmHg（P<0.0001）。85%的患者未接受氢氯噻嗪治疗，仅接受了 firibastat 治疗。无论年龄、性别、体重指数或种族如何，所有亚组均观察到显著的血压降低。肥胖患者的收缩压 AOBP 降低了 10.2mmHg（P<0.0001），黑人患者降低了 10.5mmHg（P<0.0001），非黑人患者降低了 8.9mmHg（P<0.0001）。最常见的不良事件是头痛（4%）和皮肤反应（3%）。未报告血管性水肿。钾、钠和肌酐的血液水平无变化。
我们的结果表明，在高危、多样化的人群中，firibastat 降低血压的疗效显著，而血管紧张素转换酶抑制剂或血管紧张素 II 受体 1 型阻滞剂的单药治疗可能效果较差，支持进一步研究 firibastat 在治疗难治性或潜在耐药性高血压患者中的策略。
