Background:

Hypertension is a modifiable risk factor for dementia affecting over 70% of individuals older than 60. Lowering dementia risk through preferential treatment with antihypertensive medication (AHM) classes that are otherwise equivalent in indication could offer a cost-effective, safe, and accessible approach to reducing dementia incidence globally. Certain AHM-classes have been associated with lower dementia risk, potentially attributable to angiotensin-II-receptor (Ang-II) stimulating properties. Previous study results have been inconclusive, possibly due to heterogeneous methodology and limited power. We aimed to comprehensively investigate associations between AHM (sub-)classes and dementia risk using large-scale continuous, real-world prescription and outcome data from primary care.

Methods:

We used data from three Dutch General Practice Registration Networks. Primary endpoints were clinical diagnosis of incident all-cause dementia and mortality. Using Cox regression analysis with time-dependent covariates, we compared the use of angiotensin-converting enzyme inhibitors (ACEi) to angiotensin receptor blockers (ARBs), beta blockers, calcium channel blockers (CCBs), and diuretics; and Ang-II-stimulating- to Ang-II-inhibiting AHM.

Findings:

Of 133,355 AHM-using participants, 5877 (4.4%) developed dementia, and 14,079 (10.6%) died during a median follow-up of 7.6 [interquartile range = 4.1-11.0] years. Compared to ACEi, ARBs [HR = 0.86 (95% CI = 0.80-0.92)], beta blockers [HR = 0.81 (95% CI = 0.75-0.87)], CCBs [HR = 0.77 (95% CI = 0.71-0.84)], and diuretics [HR = 0.65 (95% CI = 0.61-0.70)] were associated with significantly lower dementia risks. Regarding competing risk of death, beta blockers [HR = 1.21 (95% CI = 1.15-1.27)] and diuretics [HR = 1.69 (95% CI = 1.60-1.78)] were associated with higher, CCBs with similar, and ARBs with lower [HR = 0.83 (95% CI = 0.80-0.87)] mortality risk. Dementia [HR = 0.88 (95% CI = 0.82-0.95)] and mortality risk [HR = 0.86 (95% CI = 0.82-0.91)] were lower for Ang-II-stimulating versus Ang-II-inhibiting AHM. There were no interactions with sex, diabetes, cardiovascular disease, and number of AHM used.

Interpretation:

Among patients receiving AHM, ARBs, CCBs, and Ang-II-stimulating AHM were associated with lower dementia risk, without excess mortality explaining these results. Extensive subgroup and sensitivity analyses suggested that confounding by indication did not importantly influence our findings. Dementia risk may be influenced by AHM-classes' angiotensin-II-receptor stimulating properties. An RCT comparing BP treatment with different AHM classes with dementia as outcome is warranted.

Funding:

Netherlands Organisation for Health, Research and Development (ZonMw); Stoffels-Hornstra Foundation.