Candesartan May Improve Cognition Independent of Blood Pressure

August 10, 2020

The angiotensin receptor blocker (ARB) candesartan is associated with superior neurocognitive outcomes compared with lisinopril in older adults with hypertension and mild cognitive impairment, a new randomized study suggests.

"Although further larger and longer-term studies are needed, this randomized clinical trial provides additional and incremental support to the positive neurocognitive effects of candesartan that are likely independent and additive to their blood pressure-lowering effects," the authors, led by Ihab Hajjar, MD, Emory University School of Medicine, Atlanta, Georgia, conclude.

"While these findings would fall into hypotheses generation and justify larger trials, ARBs in general, and candesartan in particular, offer an intriguing therapeutic possibility for cognitive disorders in relation to vascular brain injury, and especially when considered cumulatively with prior observational studies," they say. 

"Currently, there are no available drugs for executive mild cognitive impairment or other cognitive disorders that are becoming more prevalent as populations age. Hence, further investigations of ARBs in this area are critical," they add.

The study was published online in JAMA Network Open on August 6.

Commenting on the findings for Medscape Medical News, Jeff Williamson, MD, professor of gerontology and geriatric medicine at Wake Forest School of Medicine, Winston-Salem, North Carolina, who was not involved in the study, said: "These are important results and add to an emerging picture that ARBs may be superior to ACE inhibitors and perhaps even other antihypertensive agents in terms of their neurocognitive benefits."

Williamson, who headed up the recent SPRINT MIND trial, which showed that aggressive blood pressure control lowered the risk of mild cognitive impairment, added: "This work is from a scientifically careful and rigorous team, but I also noticed that the dropouts are pretty significant and the duration of the trial is short, so this speaks to the need for a larger study."

In the article, Hajjar and colleagues explain that clinical trials have suggested lowering blood pressure using antihypertensive therapy provides cognitive protection in individuals without impaired cognition, but it is unclear if this is also true in individuals who have symptoms of cognitive impairment.

In addition, studies designed to compare the neurocognitive effects of antihypertensive classes in individuals who are cognitively impaired are limited. It is also unclear if these effects are related to the reduction in blood pressure or to possible pleiotropic blood pressure-independent effects of certain antihypertensive medications. Therefore, comparing antihypertensive drug classes independent of the degree of blood pressure lowering is critical, they note.

For the current study, 176 individuals aged 55 years or older with mild cognitive impairment and hypertension were withdrawn from prior antihypertensive therapy and randomized to candesartan (up to 32 mg) or lisinopril (up to 40 mg) both once daily. Participants underwent cognitive assessments at baseline and at 6 and 12 months. Brain MRI was conducted at baseline and 12 months.

Overall, 141 participants completed the trial: 77 in the candesartan group and 64 in the lisinopril group. Both the candesartan and lisinopril groups achieved similar mean blood pressure levels at 12 months (130 vs 134 mmHg). 

After adjusting for systolic blood pressure and stratification variables, candesartan was superior to lisinopril in terms of the primary outcome of executive function measured by Trail Making Test Part B (effect size = –12.8). But there was no significant difference in the other primary outcome measure of executive function — the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research score — between the two groups (effect size = –0.03).

Candesartan was also superior to lisinopril in terms of the secondary outcome of episodic memory as measured by the Hopkins Verbal Learning Test-Revised delayed recall (effect size = 0.4) and retention (effect size = 5.1).

There were no significant differences in the additional secondary cognitive outcomes of the Boston Naming Test and Digit Span Tests or in the functional measures of Instrumental Activities of Daily Living or Dysexecutive Functioning Questionnaire.

The researchers suggest that lack of an effect on functional measures may be due to the short duration of the study combined with a possible ceiling effect as the population involved was functionally independent at baseline.

MRI results showed that those randomized to candesartan had less white matter lesion accumulation compared with lisinopril (0.2 vs 0.8 mm3). Correcting for baseline levels did not alter the results significantly.

"Those randomized to lisinopril had significant accumulation of white matter lesions, whereas those randomized to candesartan had no significant increase in white matter lesions," the researchers note.

"This study suggests that when the blood pressure effects are matched in a clinical trial, ARBs provide neurocognitive protection on executive function even over the short term. This is the second clinical trial in hypertension and mild cognitive impairment suggesting these favorable effects," Hajjar and colleagues say. 

"However, in this trial we also observed that candesartan may positively affect memory, which suggests a role in amnestic disorders, such as Alzheimer's disease," they add.

The researchers suggest that the neurocognitive benefits of candesartan may be due to selective blockade of the AT1 receptor, allowing the AT2 receptor to remain active. They cite animal studies showing beneficial effects in the brain of AT2 receptor agonists including increased cerebral perfusion after brain injury, decreased superoxide production, and decreased inflammation and axonal degeneration. 

Additionally, ARBs reduce inflammatory markers more than ACE inhibitors and potentially restore endothelial dysfunction via AT2 receptor stimulation, they report.

Williamson called for future trials with harder clinical outcomes: "While these results based on cognitive scales are promising, further research on clinical endpoints such as mild cognitive impairment and dementia is critical to changes in treatment recommendations."

"There have been trials that looked at best first choice agent for blood pressure lowering to prevent cardiovascular outcomes. Perhaps the time has come for similar trials looking at brain health outcomes such as mild cognitive impairment and dementia," he added.

This study was supported by a grant from the National Institutes of Health.  Hajjar has reported no relevant financial relationships.

JAMA Netw Open. Published online August 6, 2020. Full text

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