ARBs May Reduce Incidence of Alzheimer's Over ACE Inhibitors, but Combination May Be Best
February 3, 2010 — A new study shows a significant reduction in the incidence of Alzheimer's disease (AD) and dementia among subjects taking angiotensin receptor blockers (ARBs) compared with those taking angiotensin-converting enzyme (ACE) inhibitors or other cardiovascular drugs.
Further, there appeared to be a reduction in rates of disease progression, indicated by the time to admission to a nursing home or death, among those taking ARBs, the study authors note.
"We also saw that the people who did the best appeared to be those who were taking ARBs together with ACE inhibitors, " senior author Benjamin Wolozin, MD, PhD, from Boston University School of Medicine in Massachusetts and the Center for Health Quality Outcomes and Economic Research, Veterans Affairs Medical Center, Bedford, Massachusetts, told Medscape Neurology.
"There, the data actually gets very striking; we saw a 55% lower incidence of Alzheimer's or dementia, and a 70% decrease in nursing home admissions," Dr. Wolozin added.
Their report was published online January 12 in the BMJ.
Protective Effect
ARBs selectively inhibit the AT1 receptor, and although slightly less effective at lowering blood pressure than ACE inhibitors, they have been shown in an increasing number of studies to be related to preservation of cognitive function through a mechanism independent of their antihypertensive action, the study authors write.
In this study, Dr. Wolozin and colleagues used data from the US Veterans Affairs administrative database to look at time to incident AD or dementia during a 4-year period in 3 prospective cohorts. Participants were predominantly male and 65 years and older, with a diagnosis of cardiovascular disease. One group included subjects taking an ARB, a second included those taking the ACE inhibitor lisinopril, and a third comparator group were taking other cardiovascular drugs, excluding ARBs, ACE inhibitors, and statins.
Among those with a previous diagnosis of AD or dementia, disease progression was defined for these purposes as the time to admission to a nursing home or death.
After adjustment for age, diabetes, stroke and cardiovascular disease, incident AD, and particularly incident dementia were reduced with the ARB vs both the ACE inhibitor and the cardiovascular comparator group.
Table 1. Risk for Incident Alzheimer's Disease and Dementia With ARB Treatment vs Lisinopril and a Cardiovascular Comparator
| Outcome | Hazard Ratio (95% CI) | P Value |
| Incident Alzheimer's disease | ||
| ARB vs lisinopril | 0.81 (0.68 – 0.96) | .016 |
| ARB vs cardiovascular comparator | ||
| Incident dementia | 0.84 (0.71 – 1.00) | .045 |
| ARB vs lisinopril | 0.81 (0.73 – 0.90) | <.001 |
| ARB vs cardiovascular comparator | 0.76 (0.69 – 0.84) | <.001 |
Among those who already had AD, treatment with an ARB was associated with a significantly lower risk of admission to a nursing home or death during the follow-up period.
"Angiotensin receptor blockers exhibited a dose response as well as additive effects in combination with angiotensin-converting enzyme inhibitors," the study authors note. Compared with the ACE inhibitor alone, the combination was associated with a significantly reduced risk of incident AD and dementia and admission to a nursing home.
Table 2. Risk for Dementia and Nursing Home Admission With Combined ARB and ACE Inhibitors vs ACE Inhibitor Alone
| Outcome | Hazard Ratio (95% CI) | P Value |
| Incident Alzheimer's disease | 0.45 (0.41 – 0.50) | <.001 |
| Incident dementia | 0.54 (0.51 – 0.57) | <.001 |
| Nursing home admission | 0.33 (0.22 – 0.49) | <.001 |
"I actually find that nursing home finding very striking because you can imagine the big impact if you could avoid going to a nursing home," Dr. Wolozin told Medscape Neurology. Still, other factors play a role in this decision, including caregivers' situations and financial resources, he added.
The investigators point out that stroke was consistently ranked the most important covariate in this data set, suggesting the importance of vascular factors in the progression of cognitive loss. ARBs also have been shown to be effective in preventing vascular damage induced by amyloid-β that accumulates in AD, they note.
"Because vascular dysfunction and stroke are associated with cognitive decline, our data raise the possibility that combined use of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors might confer superior protection against cognitive decline (compared with other cardiovascular drugs) by reducing neuronal damage associated with stroke and vascular dysfunction," the study authors speculate.
Complex Mechanisms
In an editorial appearing with the paper, Colleen J. Maxwell and David B. Hogan, both from the University of Calgary, Alberta, point out that the reason that ARBs may be superior to ACE inhibitors is that the AT1 and AT2 receptors have "complex and nonidentical mechanisms of action."
"Stimulation of type 1 receptors causes vasoconstriction, whereas stimulation of type 2 receptors reportedly leads to vasodilatation, neuronal differentiation, apoptosis, and axonal regeneration," they write. ARBs selectively inhibit the type 1 receptors, which might translate to improved cerebral blood flow and enhanced neuroprotective effect.
Still, they point out that the randomized clinical trials SCOPE (Study on Cognition and Prognosis in the Elderly) and PRoFESS (PReventiOn regimen For Effectively avoiding Second Strokes) showed no significant effect on either the rate of cognitive decline or incident dementia with an ARB.
Limitations of the study include the nonrandomized allocation of treatment, which they call a "serious problem" because racial disparities have been reported in the use of antihypertensives, such as ARBs, among American veterans and the ethnic origin of most subjects was not reported.
"The public health implications of finding an effective way of preventing dementia are immense, but further work is needed to verify the usefulness of antihypertensives in general and angiotensin receptor blockers in particular," they conclude.
The study was supported by a grant to Dr. Wolozin from the Retirement Research Foundation and a donation from the Casten Foundation. Dr. Wolozin reports having received these grants as disclosure of competing interests in the paper. The editorialists have disclosed no relevant financial relationships.
BMJ. Published online January 12, 2010 .
Clinical Context
Previous research has found a link between cardiovascular disease and the risk for AD. A study by Luchsinger and colleagues of 1138 older adults with normal cognition examined the association between cardiovascular risk factors and the risk for incident AD. Their results, which were published in the August 23, 2005, issue of Neurology, found that diabetes, hypertension, heart disease, and current smoking were all independently associated with a higher risk for AD, with diabetes and smoking associated with the highest risk. In addition, the risk for AD increased with the incremental addition of more cardiovascular risk factors.
Inhibitors of the renin-angiotensin system may improve cardiovascular outcomes in selected patients, and there is some evidence that angiotensin may help promote some of the changes associated with dementia. The current trial examines whether renin-angiotensin inhibitors can reduce the risk for incident dementia among a cohort of older men with preexisting cardiovascular disease.
Inhibitors of the renin-angiotensin system may improve cardiovascular outcomes in selected patients, and there is some evidence that angiotensin may help promote some of the changes associated with dementia. The current trial examines whether renin-angiotensin inhibitors can reduce the risk for incident dementia among a cohort of older men with preexisting cardiovascular disease.
Study Highlights
- Study subjects were members of the Veterans Affairs health system who were at least 65 years old in 2002. All included individuals had not previously received a diagnosis code for AD or dementia.
- Based on records from their health database, study patients were divided into 1 of 3 groups: patients receiving ARBs, patients receiving the ACE inhibitor lisinopril, and patients receiving other cardiovascular medications excluding renin-angiotensin inhibitors and statins (cardiovascular comparator group).
- The main outcome of the study was the effect of ARBs on the risk for incident AD and dementia during 4 years of follow-up. Researchers also examined the treatment effect on the progression of dementia, which was defined by admission to a nursing home or death.
- Researchers focused on patients with similar health profiles to try to reduce bias. Their analyses accounted for disease factors that could promote dementia.
- 819,491 patients provided data for the study analysis of incident AD. 98% of subjects were men, and the average age of the study cohort was 74 years.
- The prevalence of cardiovascular disease and stroke was lower in the ARB and lisinopril groups vs the cardiovascular comparator group, but patients receiving ARBs and lisinopril had higher rates of diabetes. Blood pressure levels were similar between medication groups.
- ARBs were significantly superior to both lisinopril and cardiovascular comparators in reducing the incidence of AD (hazard rate vs each respective treatment: 0.81 and 0.84).
- The hazard rate for any dementia in comparing ARBs vs lisinopril was significant at 0.81, as was the comparison between ARBs and the cardiovascular comparator (0.76).
- ARBs were also superior in reducing the risks for nursing home admission or death vs the cardiovascular comparator among patients with AD.
- Higher doses of ARBs were associated with progressively lower risks for dementia.
- Changing to an ARB from an ACE inhibitor was associated with a lower risk for incident dementia, whereas the converse was not true.
- The combination of ARB plus an ACE inhibitor reduced the risk for incident AD and dementia to a greater degree than the use of either medication alone.
Clinical Implications
- A previous study found that diabetes, hypertension, heart disease, and current smoking were all independently associated with a higher risk for AD, with diabetes and smoking associated with the highest risk. In addition, the risk for AD increased with the incremental addition of more cardiovascular risk factors.
- The current study demonstrates that ARBs may reduce the risk for incident dementia and AD among older men with cardiovascular disease. There was a dose-response effect of ARBs in reducing dementia, and the combination of ARB plus an ACE inhibitor was even more effective in reducing the risk for dementia. ARBs were also associated with reducing the risk for progression of AD.
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