Does an ARB a Day Keep Dementia at Bay?

Darrell Hulisz, PharmD; Darren J. Hein, PharmD


July 26, 2019

Do antihypertensive drugs differ with respect to slowing age-related cognitive decline? That has been the subject of considerable debate.[1,2,3,4,5,6]

Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are two such drugs commonly used to treat patients with hypertension. As generic ARBs have hit the market, many providers and patients are turning to ARBs over ACEIs owing to their similar effectiveness and improved tolerability. Evidence suggesting that ARBs have other benefits over ACEIs might really tip the scales in the favor of ARBs. Of note, researchers have postulated that ARBs might play a role in decreasing cognitive decline as a result of vascular changes in both hypertension and dementia.[1] Observational studies and prospective clinical trials have investigated this potential neuroprotective benefit and found slight improvements in cognitive function with ARBs relative to other antihypertensive drugs.[2,3,4,5,6,7,8,9]

Snapshot of Selected Studies

Li and colleagues[3] evaluated the incidence of dementia and the rate of disease progression among hypertensive patients aged 65 years or older (n = 819,491) taking ARBs, lisinopril, or other cardiovascular comparators (eg, beta-blockers, calcium-channel blockers). Patients were followed over a 4-year period, with results adjusted for age, diabetes, stroke, and cardiovascular disease. In patients without a prior diagnosis of Alzheimer disease or dementia, the use of ARBs was associated with a 19% lower risk of developing Alzheimer disease or dementia versus lisinopril; compared with other antihypertensives, the risk was 16% lower for Alzheimer disease and 24% lower for dementia. In addition, ARB use was associated with a significantly lower risk for nursing home admissions and death compared with lisinopril and other antihypertensive drugs.

Goh and colleagues[4] compared the risk for dementia among patients (n = 426,089) receiving therapy with ACEIs or ARBs. Almost all patients were being treated for hypertension, and about 75% were older than 55 years and did not have diabetes. Compared with ACEIs, use of an ARB was associated with an 8% reduction in the risk for dementia in the adjusted analysis. The impact of ARB exposure on dementia diagnoses was most apparent within the first year, as their use was associated with a 40% lower risk for dementia versus ACEIs during this time frame. However, no long-term neuroprotective benefit was observed beyond 3 years of therapy.

More recently, Ho and colleagues[5] examined whether the use of ARBs was associated with improved memory preservation compared with the use of other antihypertensive drugs. A total of 1626 adults without dementia aged 55-91 years were included. Researchers assessed data from three groups: hypertensive patients treated with ARBs, hypertensive patients treated with other antihypertensives, and patients without hypertension. In general, over 3 years of follow-up, hypertensive patients in the non-ARB group had worse cognitive outcomes compared with both normotensive patients and hypertensive patients treated with ARBs, whereas hypertensive patients treated with ARBs had similar improvements in short- and long-term memory compared with normotensive patients. In addition, patients using blood-brain barrier (BBB)–crossing ARBs (ie, valsartan, telmisartan, and candesartan) were compared with those using non-BBB–crossing ARBs. Users of BBB-crossing ARBs had improved long-term memory-related outcomes and a smaller volume of white-matter hyperintensities. The researchers concluded that ARBs, particularly BBB-crossing ARBs such as valsartan, telmisartan, and candesartan, are probably associated with greater memory preservation and less white-matter volume than other antihypertensive medications.

Potential Neuroprotective Mechanism

To further explain the potential neuroprotective mechanism, recall that the renin-angiotensin-aldosterone system (RAAS) has effects on the pathophysiology of dementia through other mechanisms outside of the effects on cerebral blood flow and vascular resistance. These mechanisms include tau phosphorylation, amyloid metabolism, and oxidative stress. In addition, angiotensin II blocks the release of acetylcholine in cholinergic neurons, adding to the neurodegenerative effect seen in Alzheimer disease.[2] These additional mechanisms help explain why RAAS blockade is superior to blood pressure control alone for improving cognition-related outcomes.

In addition, two types of angiotensin II receptor exist in humans. ARBs only block activity at the damaging angiotensin II receptor type 1 (AT1), whereas ACEIs reduce receptor activity at both the damaging AT1 receptor and the beneficial AT2 receptor. Therefore, some have suggested that ARBs provide a neuroprotective effect for memory, whereas ACEIs may have paradoxical neurotoxicity.[10]

Also of note, a clinical trial is actively recruiting patients aged 65-80 years with a family history of dementia to evaluate the effects of aerobic exercise and pharmacologic treatment (ie, losartan, amlodipine, atorvastatin) on the risk for Alzheimer disease. Hopefully, these results will help to further clarify the benefit of ARBs in memory preservation and dementia prevention.

Multiple studies show a statistical correlation between memory preservation and the use of ARBs in patients with hypertension. And although no large-scale prospective, randomized, controlled studies have defined the magnitude of cognitive decline (or preservation) with ARBs relative to other antihypertensive drugs, it seems prudent to start patients with hypertension or diabetes and a strong family history of dementia on therapy with ARBs versus ACEIs or other antihypertensive drugs. Unfortunately, the widespread recalls of popular ARBs contaminated with the potential carcinogen N-methylnitrosobutyric acid has limited the number of ARBs available for patients initiating or switching to this class. If this issue is resolved, it seems likely that the popularity of ARBs over ACEIs will continue to grow. However, any therapy should be individualized and tempered by other compelling concurrent disease state considerations.

Acknowledgment: The lead author wishes to thank Danielle Cenin for providing technical assistance.

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