Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.
Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.
“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.
The findings were published online in JAMA Network Open.
Medicare beneficiaries
Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.
The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.
Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.
Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.
“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.
The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.
For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.
The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.
Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
Unanswered questions
After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).
The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.
As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).
Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).
A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.
“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
Stimulators instead of inhibitors?
The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.
But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.
Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.
“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.
However, “we’re not suggesting [that all patients] have their regimen switched,” he added.
That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.
As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.
The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
‘More convincing’
Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.
Dr. Carlos G. Santos-Gallego
“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.
However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.
As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.
For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.
He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.
Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.
“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.
Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.
Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.
She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”
The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.