Angiotensin II-stimulating versus inhibiting antihypertensives and risk of dementia: a nested case-control study...

Midlife hypertension is a modifiable risk factor for dementia. The effects of angiotensin II (Ang-II) stimulating versus inhibiting antihypertensive medications (AHMs) on the risk of developing dementia remain unclear. This nested case-control study compared the association between treatment with Ang-II stimulating versus inhibiting AHMs and dementia risk using an Australian general practice dataset, MedicineInsight among 25,134 matched participants. We included 25,134 participants aged ≥ 45 years (6303 cases and 18,831 matched controls) with hypertension and at least one year of AHM therapy between January 1, 2011, and December 31, 2020. Exposure was classified using the proportion of days covered into high (≥ 80%) and lower (< 80%) categories. Participants with high AHM exposure were further classified based on dominant AHM type. Conditional logistic regression was used to assess associations. Using Ang-II stimulating AHMs was associated with a significantly lower risk of development of dementia (adjusted odds ratio: 0.82, 95% CI 0.75-0.89, p < 0.001) compared to using Ang-II inhibiting AHMs. Subgroup analyses revealed a significantly stronger association in males (p_interaction = 0.019), prevalent AHM users (initiated before January 1, 2011; p_interaction < 0.001), and older individuals (≥ 65 years, p_interaction < 0.001). However, no significant interaction was observed with follow-up duration (p_interaction = 0.085) and mean systolic (p_interaction = 0.063) or diastolic (p_interaction = 0.334) blood pressure during follow-up. The findings support the potential role of Ang-II stimulating AHMs (e.g., ARBs [thiazides, DHP CCBs]), relative to Ang-II inhibiting AHMs (e.g., ACEIs [BBs, non-DHP CCBs]), in reducing the risk of dementia in people with hypertension.