More Evidence That ARBs Have Cognitive Benefits

Megan Brooks

March 23, 2012

March 23, 2012 — Results of a small study provide more evidence that antihypertensive therapy with angiotensin-receptor blockers (ARBs) has benefits on cognitive function in older adults with early cognitive impairment.

The researchers say the study is the first to their knowledge to show a benefit of ARB therapy specifically on executive function. Ihab Hajjar, MD, MS, from University of Southern California, Los Angeles, and colleagues reported their study in the March 12 issue of Archives of Internal Medicine.

Roughly half of older hypertensive adults have difficulties with executive function, and these patients have a high rate of conversion to dementia, they note in their paper. Recent evidence suggests that the renin-angiotensin system plays a key role in linking hypertension to cognitive function.

Dr. Hajjar and colleagues hypothesized, therefore, that an ARB-based regimen would be superior to other antihypertensive regimens for cognitive protection. They tested their hypothesis in a 12-month randomized, double-blind trial involving 53 hypertensive adults with evidence of executive dysfunction based on the executive clock draw test (CLOX1 score < 10).

After stopping their antihypertensive medications, the patients were randomly assigned to the ARB candesartan (n = 20), the angiotensin-converting enzyme inhibitor (ACEI) lisinopril (n = 18), or the diuretic hydrochlorothiazide (n = 15). Forty-seven patients completed 6 months of treatment and 31 completed all 12 months.

Blood Pressure and Brain Benefits With ARB

At baseline, systolic blood pressure was > 140 mm Hg and diastolic blood pressure was > 90 mm Hg. The 3 antihypertensive treatments were well tolerated and equally effective in lowering blood pressure; blood pressure control was achieved in all of the patients taking candesartan and hydrochlorothiazide and in 91% of those taking lisinopril. Systolic blood pressure reductions were also similar, with mean reductions of 27, 21, and 28 mm Hg for the 3 groups, respectively.

After adjustment for age and baseline score on the Mini-Mental State Examination, patients taking candesartan showed the greatest improvements on tests assessing executive function: namely, the Trail-Making Test (TMT) part B (P = .008); the adjusted TMT (parts A and B), which adjusts for motor speed (P = .01); and the recognition portion of the Hopkins Verbal Learning Test-Revised (P = .03).

Dr. Hajjar and colleagues note that prior clinical trials that assessed cognitive outcomes of antihypertensive medications excluded patients with existing cognitive impairment and used tests "not sensitive to the domains related to frontal lobe executive dysfunction. Our findings further support observational data showing that ARB use is associated with lower risk of dementia and Alzheimer disease compared with the use of ACEIs or other antihypertensives."

Reached for comment on the study, Patrick G. Kehoe, PhD, coleader of the Dementia Research Group, University of Bristol, United Kingdom, told Medscape Medical News that the findings in this study "offer more good news in supporting the evidence for the potential benefits that ARBs may offer in general in delaying the onset or progression of various forms of cognitive decline or dementia."

"Similarly, these findings further support the involvement of the renin angiotensin pathway in cognitive decline," he said.

As reported previously by Medscape Medical News, Dr. Kehoe and colleagues recently published a study showing a 53% lower risk for Alzheimer's disease in older adults prescribed an ARB compared with those prescribed other antihypertensive agents. In this study, a nested case-control study within the United Kingdom general practice research database, the risk was 24% lower in patients prescribed an ACEI.

Possible Mechanisms

In their paper, Dr. Hajjar and colleagues say the mechanisms of the potential superior effects of ARBs on cognition may be related to restoring proper central endothelial function, decreasing inflammation, and preventing neuronal degeneration through the selective noninhibition of the type 2 angiotensin receptors in the brain. ARBs block type 1 but not type 2 receptors in the brain, whereas ACEIs decrease activation of both receptors.

Dr. Kehoe said, "One interesting point in this study is their use of 3 different blood pressure drugs, which all seem to contribute to comparable levels of blood pressure reduction, and yet just the ARB seemed to elicit some specific benefits on executive function. Thus, it suggests that these benefits were not blood pressure related and might be more attributable to some specific drug effects or due to interruption with the specific pathway that the drug is acting on. Therefore, the different mechanisms of action of the drugs may give clues as to where some of these benefits lie or possible mechanisms that may be underpinning the cognitive decline."

Dr. Hajjar and colleagues say that if their findings are confirmed in a larger trial, ARBs "may be the optimal antihypertensive treatment for elderly patients with hypertension and cognitive impairment."

Dr. Kehoe agrees that larger studies are needed. "Certainly, while the findings of this study are consistent with some other trial data and observational studies, this particular study is very small and as such the findings need to be considered with this in mind."

The study was supported by grants from the National Institute on Aging, the Irving and Edith S. Usen and Family Chair in Geriatric Medicine at Hebrew Senior Life, the National Institutes of Health, and Hinda Marcus. The authors and Dr. Kehoe have disclosed no relevant financial relationships.

Arch Intern Med. 2012;172:442-444. Abstract