Association of New Use of Antihypertensives That Stimulate vs Inhibit Type 2 and 4 Angiotensin II Receptors With Dementia Among Medicare Beneficiaries

Abstract

Importance: Prevalent 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, previous studies were limited by inclusion of individuals with prevalent hypertension and a history of antihypertensive use prior to the start of the study, which can introduce bias.

Objective: To examine the association of new use of antihypertensive medication regimens that stimulate vs inhibit type 2 and 4 angiotensin II receptors with Alzheimer disease and related dementias (ADRD) among Medicare beneficiaries.

Design, setting, and participants: This cohort study was conducted among 57 773 Medicare fee-for-service beneficiaries (January 1, 2006, through December 31, 2018) aged 65 years or older with incident hypertension. Data analysis was conducted from January 1 through June 30, 2022.

Exposures: Initiation of antihypertensive medication regimens that stimulate or inhibit type 2 and 4 angiotensin II receptors, or mixed regimens (both stimulating and inhibiting), with the time-dependent measure being each 30-day interval.

Main outcomes and measures: The primary outcome was time to first occurrence of ADRD (Centers for Medicare & Medicaid Services Chronic Conditions Data Warehouse definition). Cox proportional hazards regression modeling with time-dependent variables was performed to estimate the association between time-dependent treatment groups and time to ADRD, after adjusting for sociodemographic and clinical characteristics.

Results: The sample included 57 773 Medicare beneficiaries (36 348 women [62.9%]; mean [SD] age, 73.8 [6.3] years; 2954 [5.1%] Black, 1545 [2.7%] Hispanic; 50 184 [86.9%] White, and 3090 [5.4%] Other individuals [the Other category included individuals of American Indian, Asian, other, or unknown race and ethnicity]). During a median of 6.9 years (IQR, 4.7-9.3 years) of follow-up, the unadjusted incidence density rate of ADRD was 2.2 cases per 100 person-years (95% CI, 2.1-2.4 cases per 100 person-years) for the group receiving regimens that stimulate type 2 and 4 angiotensin II receptors compared with 3.1 cases per 100 person-years (95% CI, 3.0-3.2 cases per 100 person-years) for the group receiving regimens that inhibit type 2 and 4 angiotensin II receptors and 2.7 cases per 100 person-years (95% CI, 2.6-2.9 cases per 100 person-years) for the group receiving mixed treatment regimens. In adjusted Cox proportional hazards regression modeling, stimulating treatment was associated with a statistically significant 16% reduction in the hazard of ADRD compared with inhibiting treatment (hazard ratio, 0.84; 95% CI, 0.79-0.90). Mixed regimen use was also associated with reduced hazards of ADRD compared with the inhibiting group (hazard ratio, 0.90; 95% CI, 0.84-0.96).

Conclusions and relevance: This cohort study of Medicare beneficiaries suggests that use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors was associated with lower risk of ADRD compared with antihypertensive medications that inhibit these receptors. Confirmation is needed in a randomized trial.

Figure 1.. Study Design

This is a new-user study design, with the exposure of interest being antihypertensive medication use after the first hypertension diagnosis (index date). Patients were included in the study if they had a new diagnosis of hypertension between January 1, 2007, and December 31, 2014. To ensure patients had a new diagnosis of hypertension, a 365-day baseline washout period prior to the index date was applied. Use of antihypertensive medication was ascertained starting on the index date. The day of the first fill of an antihypertensive medication after the index date was defined as the treatment initiation date. Outcome events were measured starting 360 days after the treatment initiation date because Alzheimer disease and related dementia and vascular dementia develop over time; therefore, a minimum exposure was assumed to be needed before collecting outcome events. Outcome events were assessed from the end of the blanking period to death, disenrollment, or end of the study period (December 31, 2018).

Figure 2.. Proportion of Patients in Each Time-Dependent Exposure Group During Follow-up

Treatment group was defined in a time-dependent fashion, at each 30-day interval. Type 2 and 4 angiotensin II receptor–stimulating antihypertensive medications were defined as angiotensin II receptor blockers, dihydropyridine calcium channel blockers, and/or thiazides. Type 2 and 4 angiotensin II receptor–inhibiting antihypertensive medications were defined as angiotensin-converting enzyme inhibitors, β-blockers, and/or nondihydropyridine calcium channel blockers. Mixed antihypertensive medications were defined as both type 2 and 4 angiotensin II receptor–stimulating and –inhibiting antihypertensive medications.

Figure 3.. Multivariable Cox Proportional Hazards Regression Model for Primary (Alzheimer Disease and Related Dementia [ADRD]) and Secondary (Vascular Dementia) Outcomes

Type 2 and 4 angiotensin II receptor–stimulating antihypertensive medications were defined as angiotensin II receptor blockers, dihydropyridine calcium channel blockers, and/or thiazides. Type 2 and 4 angiotensin II receptor–inhibiting antihypertensives were defined as angiotensin-converting enzyme inhibitors, β-blockers, and/or nondihydropyridine calcium channel blockers. Mixed antihypertensive medications were defined as both type 2 and 4 angiotensin II receptor–stimulating and –inhibiting antihypertensive medications. NSAID indicates nonsteroidal anti-inflammatory drug.