Lower Dementia Rates Linked to Angiotensin-II Stimulating Antihypertensives

Edo Richard, PhD

Post-hoc analysis of the preDIVA trial published in Neurology showed support of the angiotensin hypothesis, with results demonstrating lower dementia rates in angiotensin-II stimulating antihypertensive users compared with those on angiotensin-II inhibiting antihypertensives.

The use of angiotensin-II stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers [DiCCB], and angiotensin-1 receptor blockers [ARB]) led to a 5.6% (27 of 480 patients) dementia incidence rate, compared to 8.2% (59 of 721 patients) in angiotensin-II inhibiting (angiotensin-converting enzyme inhibitors [ACEIs], beta blockers, and non-dihydropyridine calcium channel blockers [non-DiCCB]) users for a hazard ratio (HR) of 0.57 (95% CI, 0.35–0.93; P = .02)

Senior author Edo Richard, PhD, neurologist, University of Amsterdam, and colleagues used Cox regression analyses of incident dementia (and/or mortality as competing risk) during 6–8 years of follow-up among 1909 non-demented community-dwelling individuals (54% women), aged 70–78 (mean ±2.5) years.

Angiotensin-II stimulating antihypertensive users had a 45% lower incident dementia rate (HR, 0.55; 95% CI, 0.34–0.89) without excess mortality (HR, 0.86; 95% CI, 0.64–1.16) compared to angiotensin-II inhibiting antihypertensive users after adjusting for dementia risk factors including blood pressure and medical history. This corresponded to an approximate absolute risk reduction (ARR) of 3.6% (HR, 0.57; 95% CI, 0.6–5.4).

Richard and colleagues wrote, "If replicated, the beneficial effects associated with angiotensin-II-stimulating antihypertensives could have major influence on clinical practice, providing a treatment strategy that is easy and cheap to implement on a large scale and could markedly reduce dementia risk on a population level.”

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Overall, the dementia incidence rate was 6.9% (46 of 669) for users on both types of antihypertensives. Individuals using both types had a non-significant 20% lower dementia rate (HR, 0.80; 95% CI, 0.53–1.20) without excess mortality (HR, 0.97; 95% CI, 0.76–1.24) compared to angiotensin-II inhibiting antihypertensive users.

Midlife hypertension has been associated with an increased risk of incident dementia. After 6–8 years of follow-up (median, 6.7 years; interquartile range, 5.8–7.0), dementia outcome was available for 98% (1870 of 1909) and mortality for >99% (1904 of 1909) of participants.

Model 3 of the regression analyses adjusted for other dementia risk factors including body mass index (BMI), cholesterol lowering medication use, estimated glomerular filtration rate (eGFR), and trial intervention allocation to ensure the trial intervention did not influence the results.

Within this model, researchers found there was an interaction with the history of cardiovascular disease (CVD) for both angiotensin-II-stimulating (P = .08) and angiotensin-mixed (P = .04) groups. These suggested that the lower dementia risk for angiotensin-II-stimulating (HR, 0.50; 95% CI, 0.28–0.90) agents versus angiotensin-II-inhibiting antihypertensives (HR , 1.08; 95% CI 0.46–2.53) was particularly evident in individuals without CVD.

Researchers also noted that the HR was neutral in individuals without CVD (HR, 0.95; 95% CI, 0.58–1.58) and markedly lower in those with CVD (HR, 0.55; 95% CI, 0.26–1.14) in the angiotensin-mixed group, but the difference was deemed non-significant.

Exploratory analyses comparing individual antihypertensive subclasses showed no statistically significant associations with dementia risk. Thiazide, DiCCB, ARB, non-DiCCB, ACEIs, and loop diuretics all had HRs for dementia ≤1 but only angiotensin-II-stimulating (thiazides, DiCCB and ARB) also had a HR ≤1 for mortality and dementia/mortality combined.

“Our findings warrant replication in other longitudinal cohorts. Being observational, they cannot establish definitive causal relationships. Causality could be strengthened by combining clinical observations with dementia-associated neuropathology,” Richard et al. concluded.

REFERENCE

William van Dalen J, Marcum ZA, Gray SL, et al. Association of angiotensin-II stimulating antihypertensive use and dementia risk. Neurology. Published online November 5, 2020. doi: 10.1212/WNL.00000000000010996