Abstract: Drugs & Aging https://doi.org/10.1007/s40266-021-00886-y ORIGINAL RESEARCH ARTICLE Sex Differences in Association Between Anti‑Hypertensive Medications and Risk of COVID‑19 in Middle‑Aged and Older Adults Yue Ma1 · Yuan Zhang1 · Shu Li1 · Hongxi Yang1 · Huiping Li1 · Zhi Cao1,2 · Fusheng Xu1 · Li Sun1,3 · Yaogang Wang1 Accepted: 8 July 2021 © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021 Abstract Background There is ongoing debate about the associations between drug therapies targeting the renin–angiotensin–aldosterone system (RAAS) and adverse outcomes in coronavirus disease 2019 (COVID-19). Objective This study aims to examine the associations between using medications for the cardiovascular system and the risks associated with COVID-19 in middle-aged and older adults. Methods A total of 77,221 participants (aged 50–86 years) from UK Biobank were tested for SARS-CoV-2 RNA. The medications included angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), β-blockers, calcium channel blockers (CCB), statins, and aspirin. COVID-19 outcomes comprised a positive test result and severity of COVID-19 (defined as mild, hospitalization or death). We evaluated the risk among total participants and for sub-groups based on sex. Propensity score matching was performed 1:1 and logistic regression models were used. Results Among the middle- and older aged participants, no significant associations between any class of medications and the likelihood of COVID-19 infection were observed. ACEI were associated with a higher mortality risk from COVID-19 (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.01–1.32) and CCB were associated with a lower hospitalization risk for COVID-19 (OR 0.87, 95% CI 0.79–0.96) among the male patients with COVID-19, while a lower mortality risk from COVID-19 (OR 0.67, 95% CI 0.47–0.96) was observed with ARB among the female patients with COVID-19. Conclusions The study suggested sex differences in the risk of death from COVID-19 with the use of ACEI and ARB among middle-aged and older adults. Sex differences in the risk of hospitalization for COVID-19 with the use of CCB was observed as well. It is of clinical importance that clinicians adopt different CVD treatment approaches for female and male patients with COVID-19. Key Points It is important to determine sex differences in the association between using renin–angiotensin–aldosterone system (RAAS) inhibitors and the risks of COVID-19. Sex differences in the association between RAAS inhibitors and risks of COVID-19 may be stronger at older ages. * Yaogang Wang YaogangWANG@tmu.edu.cn 1 School of Public Health, Tianjin Medical University, Tianjin 300070, China 2 Department of Epidemiology and Health Statistics, School of Public Health, Zhejiang University, Hangzhou, China 3 School of Nursing, Tianjin Medical University, Tianjin, China There was a potential mortality risk for male patients with COVID-19 in using angiotensin-converting enzyme inhibitors and a protective effect of using calcium channel blockers. For female patients with COVID-19, using angiotensin-receptor blockers was associated with a lower risk of COVID-19 mortality. Vol.:(0123456789) Y. Ma et al.