Abstract Body (Do not enter title and authors here): Background: In patients with resistant hypertension (RHT), diabetes is a frequent comorbidity that increases the risk of cardiovascular events. The phase-3 PRECISION study demonstrated the efficacy of aprocitentan (APRO), a dual endothelin ET_A/ET_B receptor antagonist, to lower blood pressure (BP) in patients with RHT. In this pre-planned PRECISION post hoc analysis, we evaluated the BP lowering effect of APRO in diabetic patients.
Methods: Eligible patients were hypertensive despite treatment with ≥3 antihypertensive medications from different classes. After ≥4 weeks of combination therapy (amlodipine/valsartan/hydrochlorothiazide), patients still hypertensive received single-blind placebo for a run-in period, followed by a 4-week double-blind part (APRO 12.5 mg, 25 mg, or placebo), a 32-week single-blind part (APRO 25 mg) and a 12-week double-blind withdrawal part (APRO 25 mg or placebo). The primary endpoint was change from baseline to Week 4 in mean trough office SBP.
Results: Out of 730 patients, 395 (54%) had diabetes (APRO 12.5 mg, n=112; 25 mg, n=107; placebo, n=116).
At Week 4, APRO reduced office SBP (12.5 mg: −14.6; 25 mg: −14.1 mmHg) vs placebo (−9.4 mmHg) in diabetic patients, with no treatment/diabetes status interaction (p=0.77). The reduction was maintained at Week 36 (−16.2 mmHg). APRO also reduced mean 24-hour ambulatory SBP at Week 4 (12.5 mg: −7.4 mmHg; 25 mg: −9.5 mmHg) vs placebo (−2.2 mmHg), most pronounced on night-time values (12.5 mg: −8.9 mmHg; 25 mg: −13.1 mmHg; placebo: −1.6 mmHg).
At Week 40, after 4 weeks of withdrawal, office SBP increased in placebo patients (+3.6 mmHg) and remained stable with APRO 25 mg (+0.2 mmHg).
A substantial reduction in urine albumin–creatinine ratio of 33% and 37% was observed at Week 4 for APRO 12.5 mg and 25 mg, respectively, compared with an increase of 11% for placebo.
Edema/fluid retention were the most common adverse events; they were mild-to-moderate in most cases and dose dependent (9%, 23%, and 2% of patients receiving APRO 12.5 mg, 25 mg, and placebo, respectively, up to Week 4). During the study, 11 patients were hospitalized for heart failure (10 treated with APRO 25 mg and one with placebo). Among these, 6 had chronic kidney disease stage 3–4, and 5 had medical history of heart failure; no cases were fatal.
Conclusion: APRO produced clinically relevant and sustained BP reduction in diabetic patients with RHT, consistent with the effect observed in the overall population.