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

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle. Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Division of Health System Innovation and Research, Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City. Clinical and Translational Research Accelerator, Yale University School of Medicine, New Haven, Connecticut. George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah. Institute for Health Research, Kaiser Permanente Colorado, Aurora. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Division of Geriatrics, University of Utah School of Medicine, Salt Lake City. Department of Pathology and Neurology and Neurosurgery, McGill University School of Medicine, Montreal, Quebec, Canada. MedStar Health Research Institute and Georgetown University, Washington, DC. Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina. Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina.

JAMA network open. 2022;(1):e2145319
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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.