Impact of ARBs plus beta-blockers and other antihypertensives on cognitive impairment: a longitudinal study

Q: What are the key findings of this study?

ARBs combined with selective beta-blockers reduced the risk of cognitive impairment compared with other combinations (HR 0.54, 95% CI 0.29-0.99; p=0.049), as did loop diuretic monotherapy (HR 0.76).

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Hypertension (n=28057). Intervention: Angiotensin II receptor blockers (ARBs) plus selective beta-blocking agents vs. Other antihypertensive combination regimens. Primary outcome: Incident cognitive impairment (mild cognitive impairment or Alzheimer's disease, ICD-10-CM codes G30 and G31) (HR 0.54, 95% CI 0.29, 0.99, p=0.049).

Q: What does this research mean for the field?

The combination of angiotensin receptor blockers with beta-blockers and loop diuretic monotherapy reduce the risk of cognitive impairment in older adults with hypertension, whereas ACE inhibitors and beta-blocker monotherapy are associated with increased risk. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Mar García-Zamora; Gemma García‐Lluch; Lucrecia Moreno; Juan Pardo; Consuelo Cháfer‐Pericás

doi:10.3389/fphar.2026.1954416

October 21, 2026Frontiers in PharmacologyOpen Access

Impact of ARBs plus beta-blockers and other antihypertensives on cognitive impairment: a longitudinal study

View Full Paper

Ask AI

Bookmark

Share

Key result

ARBs plus selective beta-blockers linked to ~46% lower risk of cognitive impairment.

HR 0.54
95% CI 0.29, 0.99
P=0.049
n=28,057

Why the study?

Hypertension is a major modifiable risk factor for dementia, but the specific neuroprotective benefits of different antihypertensive drug classes used as monotherapy or combination therapy remain unclear.

Does the use of specific antihypertensive drug classes in monotherapy or combination therapy reduce the risk of developing cognitive impairment (MCI or Alzheimer's disease) in adults aged ≥65 years?

Key Points

To evaluate the association between various antihypertensive drug classes, prescribed as monotherapy or combination regimens, and the risk of developing cognitive impairment in older adults.
Retrospective population-based cohort study utilizing electronic health records from 2002 to 2021 across two hospitals in Valencia, Spain.
Included 28,057 individuals aged ≥ 65 years receiving antihypertensive therapy for at least 6 months, requiring a minimum 1-year lag between treatment initiation and cognitive impairment diagnosis.
Time-to-event outcomes were evaluated using Kaplan–Meier survival analyses and multivariable Cox proportional hazards models adjusted for demographic and cardiometabolic covariates.
Loop diuretics, angiotensin-receptor blockers (ARBs), and the combination of ARBs with beta-blockers were associated with a reduced risk of cognitive impairment.
Monotherapy with selective beta-blockers and angiotensin-converting enzyme (ACE) inhibitors was associated with an increased probability of cognitive impairment.

Study Design

Type

Cohort (n=28,057)

Multicenter

Yes

Structured PICO

Does the use of specific antihypertensive drug classes in monotherapy or combination therapy reduce the risk of developing cognitive impairment (MCI or Alzheimer's disease) in adults aged ≥65 years?

P

Population

28,057 older adults (aged ≥65 years, 57.4% female) receiving antihypertensive therapy for at least 6 months without prior cognitive impairment, followed for a mean of 1,438 days.

E

Exposure

Specific antihypertensive drug classes used for at least 6 months as monotherapy (alpha-adrenoreceptor antagonists, loop diuretics, selective beta-blocking agents, dihydropyridine derivatives, ACE inhibitors, ARBs) or in combination therapy (≥2 antihypertensive medications, such as selective beta-blocking agents plus ARBs).

C

Comparator

For each specific antihypertensive class evaluated in monotherapy, the reference group comprised participants receiving any other antihypertensive class in monotherapy. For each specific combination therapy evaluated, the reference group comprised participants receiving all other antihypertensive combination regimens.

O

Outcome

Clinical diagnosis of cognitive impairment, defined as mild cognitive impairment (MCI) or Alzheimer's disease (AD) ascertained using ICD-10-CM diagnostic codes beginning with G30 and G31, over a mean follow-up of 1438 ± 879.3 days (with a minimum 1-year lag period required between treatment initiation and clinical diagnosis).hard clinical

Main Result

Hazard Ratio: 0.54 (95% CI 0.29–0.99)

p-value: p=0.049

In older adults receiving antihypertensive therapy, loop diuretic monotherapy and the combination of ARBs plus selective beta-blockers were associated with a lower risk of developing cognitive impairment, whereas ACE inhibitor and selective beta-blocker monotherapies were associated with higher risk, suggesting class-specific differences in neuroprotection.

Limitations

Drug exposure was inferred from electronic health record prescriptions without data on actual medication adherence.
Lack of baseline clinical parameters (such as actual blood pressure levels), lifestyle habits, and socioeconomic factors leaves room for residual confounding.
Follow-up did not include mortality data.
Potential confounding by indication, as underlying clinical diagnoses driving specific prescriptions were not directly captured.
No adjustment for multiple comparisons was performed, increasing the risk of false-positive findings.
Requirement of ≥6 months of exposure and a 1-year lag period may introduce selection or immortal time bias.
Incomplete historical prescription data prior to cohort entry precluded a washout period, potentially introducing prevalent-user and survivor bias.
Potential surveillance bias due to frequent medical encounters among chronically monitored patients.
No adjustment for multiple comparisons was applied, increasing the probability of false-positive findings
Complete historical prescription data prior to study entry were unavailable to enforce a formal washout period, so the cohort includes both incident and prevalent active users
Potential confounding by indication, particularly for drugs prescribed for more severe cardiovascular conditions
Cannot separate whether findings are due to better blood pressure control or direct drug actions
Certain drug classes (e.g., thiazides, aldosterone antagonists, non-selective beta-blockers) were not analysed due to insufficient number of participants with a diagnosis of a neurodegenerative disorder using these drugs (n < 3)

Implication

ARBs plus selective beta-blockers or loop diuretic monotherapy were associated with lower cognitive impairment risk; hypothesis-generating and should not yet change practice.

Abstract

Background Hypertension is a major modifiable risk factor for dementia, yet the specific neuroprotective benefits of different antihypertensive drug classes remain unclear. This longitudinal population-based cohort study evaluated the association between various antihypertensive agents, used as monotherapy or combination therapy, and the risk of cognitive impairment. Methods The present work is a retrospective cohort study based on electronic health records (EHR) provided by the Consellería de Sanitat Universal i Salut Pública (Valencian Regional Health Authority, Spain) from two different hospitals in Valencia: Arnau de Villanova and Hospital La Fe. The study included 28057 individuals aged ≥ 65 years receiving antihypertensive therapy. Cox proportional hazards models, adjusted for demographic and clinical covariates, and Kaplan–Meier survival analyses were performed to estimate time-to-event outcomes and hazard ratios for cognitive impairment. Results Loop diuretics and the combination of ARBs with beta-blockers, were associated with a reduced risk of cognitive impairment. Conversely, selective beta-blockers and angiotensin-converting enzyme (ACE) inhibitors were associated with an increased probability of impairment. Conclusion Antihypertensive classes display divergent neuroprotective profiles. Loop diuretics, ARBs, and ARB–beta-blocker combinations appear protective, whereas ACE inhibitors and beta-blocker monotherapy show less favorable cognitive outcomes, highlighting the need for tailored pharmacological selection in aging populations.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

García-Zamora et al. (2026) conducted a cohort in Hypertension (n=28,057). Angiotensin II receptor blockers (ARBs) plus selective beta-blocking agents vs. Other antihypertensive combination regimens was evaluated on Incident cognitive impairment (mild cognitive impairment or Alzheimer's disease, ICD-10-CM codes G30 and G31) (HR 0.54, 95% CI 0.29, 0.99, p=0.049). ARBs combined with selective beta-blockers reduced the risk of cognitive impairment compared with other combinations (HR 0.54, 95% CI 0.29-0.99; p=0.049), as did loop diuretic monotherapy (HR 0.76).

synapsesocial.com/papers/6adc966ca704d151585a5e04 https://doi.org/10.3389/fphar.2026.1954416

View Full Paper

Ask AI

Bookmark

Share

Impact of ARBs plus beta-blockers and other antihypertensives on cognitive impairment: a longitudinal study

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Impact of ARBs plus beta-blockers and other antihypertensives on cognitive impairment: a longitudinal study

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading