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

Marcum, Zachary A.; Cohen, Jordana B.; Zhang, Chong; Derington, Catherine G.; Greene, Tom; Ghazi, Lama; Herrick, Jennifer S.; King, Jordan B.; Cheung, Alfred K.; Bryan, Nick; Supiano, Mark A.; Sonnen, Joshua A.; Weintraub, William S.; Williamson, Jeff D.; Pajewski, Nicholas M.; Bress, Adam P.

doi:10.1001/jamanetworkopen.2021.45319

Cited by 29 publications

(29 citation statements)

References 57 publications

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“…10,11 ARBs, which selectively block the AT1Rs without inhibiting ACE and result in the relatively upregulated activities of AT2Rs and AT4Rs, and keep the pathway of Aβ degradation mediated by ACE intact, may offer superior protection than simultaneously lowering all the angiotensin receptors' activities with ACE inhibitors. Recent studies recognized that compared with angiotensin-inhibiting antihypertensives, angiotensin-stimulating antihypertensives conveyed a lower risk of incident cognitive impairment and dementia, 12,34 supporting the angiotensin hypothesis.…”

Section: Biological Plausibilitymentioning

confidence: 99%

Angiotensin Receptor Blockers Are Associated With a Lower Risk of Progression From Mild Cognitive Impairment to Dementia

et al. 2022

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Background: Previous studies found that antihypertensive medications (AHMs) acting on the renin-angiotensin system had the potential to reduce the progression from mild cognitive impairment to dementia. However, it remains unclear whether this association differs between ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers. methods: We conducted a retrospective cohort study in the Alzheimer’s Disease Neuroimaging Initiative among 403 participants with hypertension and mild cognitive impairment at baseline. Information on AHMs received during the follow-up period, including angiotensin receptor blockers, ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics, were self-reported. Cox proportional hazards models adjusted for potential confounders were used in the time to event analysis with progression to dementia as outcome. Results: Of the 403 participants, the mean (SD) age was 74.0 (7.3) years, 152 (37.7%) were female, 158 (39.2%) progressed to dementia over a median follow-up time of 3.0 years. Angiotensin receptor blockers were associated with a lower risk of progression to dementia as compared to ACE inhibitors (adjusted hazard ratio=0.45 [95% CI, 0.25–0.81]; P =0.023), other classes of AHMs (beta-blockers, calcium channel blockers, diuretics; adjusted hazard ratio, 0.49 [95% CI, 0.27–0.89]; P =0.037), and none of AHMs (adjusted hazard ratio, 0.31 [95% CI, 0.16–0.58]; P =0.001). Conclusions: In patients with hypertension and mild cognitive impairment, angiotensin receptor blockers were associated with a lower risk of progression to dementia compared with ACE inhibitors and other classes of AHMs. Our findings may have important implications for clinical practice but still warrant further investigations in larger prospective cohorts or clinical trials.

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Section: Biological Plausibilitymentioning

confidence: 99%

Angiotensin Receptor Blockers Are Associated With a Lower Risk of Progression From Mild Cognitive Impairment to Dementia

et al. 2022

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“…Previous observational studies have reported that prevalent use of regimens containing antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not, were associated with lower rates of incident mild cognitive impairment and dementia . However, those studies were limited by the inclusion of individuals with prevalent hypertension and relatively small sample sizes.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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ImportancePrevalent 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.ObjectiveTo 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 ParticipantsThis 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.ExposuresInitiation 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 MeasuresThe primary outcome was time to first occurrence of ADRD (Centers for Medicare &amp; 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.ResultsThe 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 RelevanceThis 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.

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“…We observed that, specifically, these angiotensin II (ATII)-stimulating antihypertensive users had a 45% lower dementia risk compared with users of other AHM types in the Prevention of Dementia by Intensive Vascular care (preDIVA) population [ 15 ]. This finding was recently replicated in the SPRINT-MIND trial population, wherein ATII-stimulating AHM users had a 24% lower dementia risk when compared with other AHM users [ 16 ]. Moreover, we previously observed that individuals who used ARBs and CCBs at baseline had an approximately 40% lower dementia risk compared with individuals using other AHM types over 6.7 years of follow-up [ 17 ].…”

Section: Introductionmentioning

confidence: 81%

“…Several hypotheses exist around the potential neuroprotective effects of CCBs and ARBs, ranging from their abilities to improve cerebral blood flow, reduce cerebral oxidative stress markers, and protect against neuronal death [32]. In addition, dihydropyridine CCBs and ARBs stimulate AT2 and AT4 receptors through the ATII pathway, which potentially protects against ischemia and preserve memory, respectively [15,16,[33][34][35][36]. An important potential challenge in studies with dementia as outcome is the competing risk of mortality before the development of dementia.…”

Section: Interpretation Of Findingsmentioning

confidence: 99%

“…A potential mechanism underlying these findings is the ‘angiotensin hypothesis’, which suggests that antihypertensive agents that stimulate the angiotensin II type 2 (AT2) and 4 (AT4) receptors, including ARBs, dihydropyridine CCBs and thiazide diuretics, may reduce dementia risk by inhibiting neuronal damage and preserving memory function [ 15 , 16 ]. We observed that, specifically, these angiotensin II (ATII)-stimulating antihypertensive users had a 45% lower dementia risk compared with users of other AHM types in the Prevention of Dementia by Intensive Vascular care (preDIVA) population [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Antihypertensive medication classes and the risk of dementia over a decade of follow-up

Schroevers¹,

Eggink²,

Hoevenaar‐Blom

et al. 2022

Journal of Hypertension

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Introduction: Use of angiotensin II (ATII)-stimulating antihypertensive medication (AHM), including angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs), has been associated with lower dementia risk. Previous studies had relatively short followup periods. The aim of this study is to investigate if these effects are sustained over longer periods.Methods: This post hoc observational analysis was based on data from a dementia prevention trial (preDIVA and its observational extension), among Dutch community-dwelling older adults without prior diagnosis of dementia. Differential associations between AHM classes and incident dementia were studied after 7.0 and 10.4 years, based on the median follow-up durations of dementia cases and all participants.Results: After 7 years, use of ATII-stimulating antihypertensives [hazard ratio ¼ 0.68, 95% confidence interval (CI) ¼ 0.47-1.00], ARBs (hazard ratio ¼ 0.54, 95% CI ¼ 0.31-0.94) and dihydropyridine CCBs (hazard ratio ¼ 0.52, 95% CI ¼ 0.30-0.91) was associated with lower dementia risk. After 10.4 years, associations for ATIIstimulating antihypertensives, ARBs and dihydropyridine CCBs attenuated (hazard ratio ¼ 0.80, 95% CI ¼ 0.61-1.04; hazard ratio ¼ 0.75, 95% CI ¼ 0.53-1.07; hazard ratio ¼ 0.73, 95% CI ¼ 0.51-1.04 respectively), but still suggested lower dementia risk when compared with use of other AHM classes. Results could not be explained by competing risk of mortality. Conclusion:Our results suggest that use of ARBs, dihydropyridine CCBs and ATII-stimulating antihypertensives is associated with lower dementia risk over a decade, although associations attenuate over time. Apart from methodological aspects, differential effects of antihypertensive medication classes on incident dementia may in part be temporary, or decrease with ageing.

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

Cited by 29 publications

References 57 publications

Angiotensin Receptor Blockers Are Associated With a Lower Risk of Progression From Mild Cognitive Impairment to Dementia

Angiotensin Receptor Blockers Are Associated With a Lower Risk of Progression From Mild Cognitive Impairment to Dementia

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

Antihypertensive medication classes and the risk of dementia over a decade of follow-up

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