Prevalent use of regimens that include antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors is associated with lower rates of incident cognitive impairment, according to a study published in JAMA Network Open.

Previous research has found antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, are linked to a lower risk of developing dementia. However, the researchers explained that their link to cognitive outcomes in hypertension trials, while adhering to current blood pressure guideline recommendations, has not been assessed. The objective of the current study was to assess the prevalent use of antihypertensive medication regimens that stimulate vs inhibit type 2 and 4 angiotensin II receptors on the risk for mild cognitive impairment (MCI) or dementia.

The researchers conducted a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), in which participants were followed up from a 6-month study visit until an outcome event or the end of active trial follow-up (April 2011 to July 2018).

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Participants were 50 years of age or older with systolic blood pressure (SBP) between 130 and 180 mm Hg and increased cardiovascular risk but without a history of diabetes, stroke, or dementia.

The primary outcome was a composite of adjudicated amnestic MCI or probable dementia. Participants in both antihypertensive treatment groups were pooled and grouped into 1 of 2 mutually exclusive exposure categories according to their prevalent antihypertensive medication regimen at the 6-month visit.

Among the 8685 participants who were consistent users of antihypertensive medication regimens at 6 months (mean [SD] age, 67.7 [11.2] years; 5586 [64.3%] male; 4983 [57.4%] non-Hispanic White), 2644 (30.4%) were users of exclusively stimulating, 1536 (17.7%) inhibiting, and 4505 (51.9%) mixed antihypertensive medication regimens.

After a median of 4.8 years of follow-up (95% CI, 4.7-4.8 years), 45 vs 59 cases per 1000 person-years of amnestic MCI or probable dementia occurred in prevalent users of regimens containing exclusively stimulating vs inhibiting antihypertensives, respectively (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87; n=783 total events).

Amnestic MCI alone (n=685 total events) occurred at rates of 40 and 54 cases per 1000 person-years in stimulating vs inhibiting antihypertensive users, respectively (HR, 0.74; 95% CI, 0.64-0.87). Probable dementia alone (n=140 total events) occurred at rates of 8 and 10 cases per 1000 person-years in stimulating vs inhibiting antihypertensive users, respectively (HR, 0.80; 95% CI, 0.57-1.14).

The findings were consistent in subgroups according to age, sex, race and ethnicity, cardiovascular disease, chronic kidney disease, body mass index, number of antihypertensive medication classes, systolic blood pressure, and SPRINT treatment group, as well as in sensitivity analyses using different covariate adjustment strategies.

Among several study limitations, SPRINT did not include patients with type 2 diabetes, history of stroke, advanced kidney disease, or symptomatic heart failure. Also, underadjustment caused by unmeasured confounding and overadjustment caused by inclusion of covariates measured after treatment initiation are possible.

“Given the high prevalence of hypertension, even a small reduction in dementia risk achieved by prescribing certain antihypertensives could have a measurable effect on the overall burden of dementia,” the researchers stated.

Disclosure: Azilsartan and chlorthalidone (combined with azilsartan) were provided by Takeda Pharmaceuticals International Inc. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 


Marcum ZA, Cohen JB, Zhang C, et al. Association of antihypertensives that stimulate vs inhibit types 2 and 4 angiotensin II receptors with cognitive impairment. JAMA Netw Open. Published online January 28, 2022. doi:10.1001/jamanetworkopen.2021.45319

This article originally appeared on Neurology Advisor