Taking an ACE inhibitor that crosses the blood-brain barrier reduced the risk of being diagnosed with dementia and delayed the time to a diagnosis of dementia in people with HIV receiving care in Veterans Affairs clinics in the United States, researchers report.
The study compared people who took an ACE inhibitor that crosses the blood-brain barrier and those who took no medication or another type of medication to treat high blood pressure.
The findings have been published as a pre-print but await full peer review.
Angiotensin-converting enzyme (ACE) inhibitors are prescribed for the management of high blood pressure. They are also given to people with a history of heart disease, kidney disease, diabetes or heart failure whose blood pressure is on the borderline of hypertension.
ACE inhibitors work by preventing the conversion of angiotensin I to angiotensin II, the enzyme which enables constriction of blood vessels. By constricting blood vessels, angiotensin II influences blood pressure, so suppressing the activity of angiotensin II helps to maintain blood pressure at a healthy level. Inhibiting angiotensin activity also improves insulin uptake and prevents damage to the kidneys caused by high blood pressure.
Blood pressure is reported as two numbers, the systolic and the diastolic pressure. The systolic number shows blood pressure when the heart is pumping, and the diastolic pressure shows the pressure when the heart is resting between beats. In the UK, high blood pressure is defined as systolic pressure over 140 or diastolic pressure over 90, or both, when measured at the doctor's surgery. If you measure your blood pressure at home, measurements above 135 or 85 are considered to be high blood pressure.
ACE inhibitors may be prescribed at lower blood pressure levels (130/80) in the United States for people with heart disease, kidney disease or diabetes. ACE inhibitors work less well in people over 55 and in Black people, so not everyone with high blood pressure will be treated with this type of drug.
Over the past 15 years, evidence has accumulated that lowering blood pressure reduces the risk of developing dementia or cognitive impairment. Moreover, people taking ACE inhibitors or angiotensin receptor blockers which cross the blood-brain barrier tend to have a lower risk than people taking other types of medication to lower their blood pressure.
Studies in animals show that as well as regulating blood pressure, ACE inhibitors that cross the blood-brain barrier also reduce inflammation in the brain and protect neurons from injury. The renin-angiotensin system in the brain is also involved in the regulation of learning, memory and anxiety.
The impact of ACE inhibitor use on neurocognitive function in people with HIV had not been investigated, so researchers at the University of South Carolina and the Veterans Affairs health care system in Columbia, South Carolina, used electronic health records to assess the relationship between use of ACE inhibitors that cross the blood-brain barrier and the diagnosis of dementia in people with HIV.
Although HIV itself or the inflammation it causes can directly affect the brain and cause cognitive disorders, people with HIV are also at risk of dementia due to the same risk factors associated with Alzheimer’s disease and vascular dementia in the rest of the population. These include old age, high blood pressure, coronary artery disease, diabetes, smoking and heavy alcohol use.
People were eligible for inclusion in the study if they had been diagnosed with high blood pressure after being diagnosed with HIV and had at least one year of follow-up after hypertension diagnosis. The study excluded people with a diagnosis of dementia before their hypertension diagnosis and anyone who took both brain-penetrating and non-brain-penetrating ACE inhibitors during the study period.
For a sub-analysis, researchers divided the cohort into two groups according to medication exposure: people exposed to ACE inhibitors that cross the blood-brain barrier (captopril, fosinopril, lisinopril, perindopril, ramipril or trandolapril) and people exposed to ACE inhibitors that do not (benazepril, moexipril, enalapril and quinapril). The primary outcome of the study was a clinical diagnosis of any form of dementia.
Overall, 18,250 people were eligible for inclusion in the analysis, of which, 9419 had been exposed to an ACE inhibitor that crosses the blood-brain barrier. The cohort was 96% male, approximately half were Black, and the mean age was 51 years in those exposed to an ACE inhibitor that crosses the blood-brain barrier.
Common comorbidities in the cohort included obesity (25%), hyperlipidaemia (14%) and depression (16%). People taking an ACE inhibitor that crosses the blood-brain barrier were significantly more likely to have type 2 diabetes (7% vs 3%) and to smoke (49% vs 44%) but less to have hyperlipidaemia (14% vs 17%).
A multivariate analysis that controlled for demographic and health-related risk factors for dementia showed that any treatment with an ACE inhibitor that crosses the blood-brain barrier was associated with a 17% lower risk of being diagnosed with dementia.
To eliminate the possibility of bias through reliance on health insurance claims for medication, the researchers matched 15,594 cohort members one to one, based on whether or not they had been exposed to an ACE inhibitor that crosses the blood-brain barrier. In this analysis, participants were matched by baseline characteristics so there were no significant differences in the two groups. Multivariate analysis that controlled for risk factors for dementia showed that any treatment with an ACE inhibitor that crosses the blood-brain barrier was associated with a 15% lower risk of being diagnosed with dementia.
In the sub-analysis restricted to people exposed to an ACE inhibitor (8768 people exposed to an ACE inhibitor that crosses the blood-brain barrier and 343 exposed to an ACE inhibitor that does not cross the blood-brain barrier, after controlling for risk factors associated with dementia, people exposed to an ACE inhibitor that crosses the blood-brain barrier had a 52% lower risk of dementia.
The study also found that people exposed to ACE inhibitors that cross the blood-brain barrier had a longer time free from dementia.
The researchers say that studies in other groups of people with HIV are needed to confirm the effect seen in this study. One limitation of the study is that it does not report on the relationship between the duration of treatment with ACE inhibitors and the risk of dementia.
The researchers conclude that when ACE inhibitors are needed in people with HIV, choosing a drug of this type that crosses the blood-brain barrier may have a major impact on quality of life by delaying or preventing age- and HIV-related dementia.
Cummings TH et al. Exposure to angiotensin-converting enzyme inhibitors that cross the blood-brain barrier and the risk of dementia among patients with human immunodeficiency virus. Med RxIV, published online 17 January 2024.