Differential Sex-Specific Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin Receptor Blocker Therapy on Arterial Function in Hypertension: CALIBREX Trial

Background: Increased arterial stiffness is associated with adverse cardiovascular outcomes. We studied the sex-specific impact of angiotensin antagonists on vascular function in hypertension with the hypothesis that their effects on arterial stiffness may be variable in men and women. Methods: In 141 hypertensive participants with mild cognitive impairment (age 65.9±7.7, 57% female), candesartan (up to 32 mg, n=77) or lisinopril (up to 40 mg, n=64) were administered to achieve blood pressure <140/90 mm Hg. Pulse wave velocity, central pulse pressure, and central augmentation index were measured using applanation tonometry (SphygmoCor, Australia). Multivariate linear regression and mixed model analyses were performed using intention-to-treat and per protocol analyses for those completing the study. Results: Blood pressure reduction was similar among candesartan and lisinopril groups. Compared with candesartan, lisinopril therapy resulted in lower pulse wave velocity (0.5±0.8 versus -0.7±0.4 m/s, respectively; P=0.003) and central pulse pressure (-1±3 versus -7±4 mm Hg; P=0.03) after 1 year. There was a significant interaction by sex whereby the improvements in pulse wave velocity and central pulse pressure with lisinopril compared with candesartan were only observed in women. In contrast, there was greater improvement in augmentation index with candesartan compared with lisinopril (-4±7% versus -1.5±8%; P=0.05), with no sex differences. Conclusions: Despite equipotent antihypertensive effects, lisinopril was more effective than candesartan at lowering arterial stiffness in women. In contrast, candesartan was more effective than lisinopril in improving pulse wave reflections in both sexes. These findings demonstrate differential sex-specific effects of renin-angiotensin system antagonists on arterial function in hypertension that may contribute to long-term cardiovascular and neurocognitive outcomes in this population.