Angiotensin II receptor type 2 and 4-stimulating antihypertensives associated with reduced long-term cognitive impairment compared to receptor inhibitors

1. This secondary analysis of the SPRINT cohort study demonstrated that type 2 and 4 angiotensin II receptor (AT2R/AT4R)-stimulating antihypertensives decreased the risk of amnestic mild cognitive impairment or probable dementia by approximately 25% compared to AT2R/AT4R-inhibiting antihypertensives.

Evidence Rating Level: 2 (Good)

Study Rundown: Hypertension is a well-known, highly prevalent, modifiable risk for dementia. There are no disease-modifying drugs for dementia; therefore, prevention is critical. It is not known whether certain antihypertensives are more effective at reducing the risk of dementia than others. This secondary analysis of the SPRINT trial evaluated whether antihypertensive medications that stimulate or inhibit type 2 and 4 angiotensin II receptors (AT2R/AT4R) reduce the risk of mild cognitive impairment (MCI) or probable dementia. Participants (n= 8685) included were 50 years or older and had systolic blood pressures between 130-180 mm Hg; they had cognitive assessments at baseline, at 2-years, 4-years, and the end of the trial. The primary outcome was a composite of amnestic MCI or probable dementia. After a median follow-up of 4.8 years (95% CI: 4.7-4.8), there were 45 compared to 59 cases of amnestic MCI or probable dementia per 1000 person-years in participants using stimulating versus inhibiting antihypertensives, respectively (hazard ratio [HR]: 0.76 [95% CI: 0.66-0.87]). In the AT2R/AT4R-stimulating cohort compared to the AT2R/AT4R-inhibitor cohort, there were significantly fewer events per 1000 person-years of amnestic MCI alone (HR: 0.74 [95% CI: 0.64-0.87]); additionally, there was a non-statistically significant reduction in risk of dementia alone (HR: 0.80 [95% CI: 0.57-1.14]). The risk of cognitive impairment remained consistent across all measured covariant adjustment strategies, such as age (<75 vs. >75), sex, race, kidney impairment, body mass index, and systolic blood pressure tertiles. Overall, AT2R/AT4R-stimulating antihypertensives reduced amnestic MCI or probable dementia by approximately 25% compared to AT2R/AT4R-inhibitors. One limitation of this study, however, is that the covariate adjustment analysis variables were only measured at the start of the trial, despite most patients initiating their antihypertensives before this time.

Click to read the study in JAMA Network Open

Relevant Reading: Association of angiotensin II-stimulating antihypertensive use and dementia risk: post hoc analysis of the PreDIVA trial

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