Association of Antihypertensives That Stimulate vs Inhibit Types 2 and 4 Angiotensin II Receptors With Cognitive Impairment

Abstract

Importance: Use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, has been associated with a lower risk of dementia. However, this association with cognitive outcomes in hypertension trials, with blood pressure levels in the range of current guidelines, has not been evaluated.

Objective: To examine the association between use of exclusively antihypertensive medication regimens that stimulate vs inhibit type 2 and 4 angiotensin II receptors on mild cognitive impairment (MCI) or dementia.

Design, setting, and participants: This cohort study is a secondary analysis (April 2011 to July 2018) of participants in the randomized Systolic Blood Pressure Intervention Trial (SPRINT), which recruited individuals 50 years or older with hypertension and increased cardiovascular risk but without a history of diabetes, stroke, or dementia. Data analysis was conducted from March 16 to July 6, 2021.

Exposures: Prevalent use of angiotensin II receptor type 2 and 4-stimulating or -inhibiting antihypertensive medication regimens at the 6-month study visit.

Main outcomes and measures: The primary outcome was a composite of adjudicated amnestic MCI or probable dementia.

Results: Of the 8685 SPRINT participants who were prevalent users of antihypertensive medication regimens at the 6-month study visit (mean [SD] age, 67.7 [11.2] years; 5586 [64.3%] male; and 935 [10.8%] Hispanic, 2605 [30.0%] non-Hispanic Black, 4983 [57.4%] non-Hispanic White, and 162 [1.9%] who responded as other race or ethnicity), 2644 (30.4%) were users of exclusively stimulating, 1536 (17.7%) inhibiting, and 4505 (51.9%) mixed antihypertensive medication regimens. During a median of 4.8 years of follow-up (95% CI, 4.7-4.8 years), there were 45 vs 59 cases per 1000 person-years of amnestic MCI or probable dementia among prevalent users of regimens that contained exclusively stimulating vs inhibiting antihypertensive medications (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87). When comparing stimulating-only vs inhibiting-only users, amnestic MCI occurred at rates of 40 vs 54 cases per 1000 person-years (HR, 0.74; 95% CI, 0.64-0.87) and probable dementia at rates of 8 vs 10 cases per 1000 person-years (HR, 0.80; 95% CI, 0.57-1.14). Negative control outcome analyses suggested the presence of residual confounding.

Conclusions and relevance: In this secondary analysis of SPRINT, prevalent users of regimens that contain exclusively antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors had lower rates of incident cognitive impairment. Residual confounding cannot be ruled out. If these results are replicated in randomized clinical trials, certain antihypertensive medications could be prioritized to prevent cognitive decline.

Figure 1.. Study Design

This is a prevalent-user study design, with the exposure of interest being antihypertensive use at the 6-month visit. Antihypertensive use was categorized into angiotensin II receptor type 2 and 4–stimulating (angiotensin II receptor blockers, dihydropyridine calcium channel blockers, and/or thiazides) and/or –inhibiting (angiotensin-converting enzyme inhibitors, β-blockers, and/or nondihydropyridine calcium channel blockers) antihypertensives. Three mutually exclusive antihypertensive use categories were created: stimulating only, inhibiting only, and mixed (use of both stimulating and inhibiting). Covariates were measured using data from Systolic Blood Pressure Intervention Trial (SPRINT) randomization as well as at the 6-month visit. Dementia screening was conducted at 24 and 48 months after SPRINT randomization as well as at the SPRINT closeout visit and an extended follow-up visit.

Figure 2.. Cumulative Incidence Curves for Probable Dementia or Amnestic Mild Cognitive Impairment

Cumulative incidence curves demonstrating the risk for probable dementia or amnestic mild cognitive impairment in Systolic Blood Pressure Intervention Trial participants between exposure groups were generated from Cox proportional hazards regression models using inverse probability treatment weighting. Participants are censored at death. Angiotensin II receptor type 2 (AT2R) and 4 (AT4R)–stimulating antihypertensives were defined as angiotensin II receptor blockers, dihydropyridine calcium channel blockers, and/or thiazides. Angiotensin II receptor type 2 and 4–inhibiting antihypertensives were defined as angiotensin-converting enzyme inhibitors, β-blockers, and/or nondihydropyridine calcium channel blockers. We omitted the number at risk over time because this model was generated using weighted samples. HR indicates hazard ratio.