Specific combinations of statins and antihypertensives may reduce risk for Alzheimer’s disease

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Specific combinations of statins and antihypertensives may also reduce risk for Alzheimer‘s disease, according to a new USC study of nearly 700,000 Medicare beneficiaries.

The findings suggest that treatments already in use for blood pressure and cholesterol control could reduce the number of people with Alzheimer’s and related dementias, researchers said.

The study was published in PLOS One.

“Our research found dementia risk may be reduced with a specific combinations of drug treatments for vascular health,” said lead author Julie Zissimopoulos, director of the Aging and Cognition program at the USC Leonard D. Schaeffer Center for Health Policy & Economics.

“This is the first study to investigate the association of different combinations of these frequently used drugs and dementia risk in a large and broadly representative sample of older Americans and to illuminate the differences in effect for women compared to men, and for whites, Hispanics and African Americans.”

Dementia affects about 7 million Americans and is projected to grow to 12 million over the next two decades.

With no proven treatments, there has been increased global attention on prevention and risk reduction of dementia, including maintenance of a healthy lifestyle and management of risk factors such as high blood pressure and high cholesterol.

Approximately one in four adults over age 65 use both antihypertensives and statins for these conditions.

“We know that managing hyperlipidemia and hypertension is important, and this study tells us there might be certain combinations of drugs that have additional benefits for Alzheimer’s and other dementias beyond the management of those targeted conditions,” said co-author Douglas Barthold, research assistant professor with the Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute at the Department of Pharmacy at the University of Washington, Seattle.

Specific combinations of drugs may hold the key to reduced risk

The study examined the medical and pharmacy claims of a random 20% sample of Medicare beneficiaries, aged 67 and higher, enrolled in traditional Medicare from 2007 to 2014.

Researchers linked claims from Medicare Parts A (inpatient care), B (outpatient care) and D (prescription drugs) to enrollment files that included beneficiaries’ characteristics such as race and sex.

To be included in the analysis, individuals had to have used both an antihypertensive and a statin for the two previous years and have no prior dementia diagnoses and no prior use of Alzheimer’s disease-specific medications.

The study found the use of cholesterol-lowering drugs pravastatin and rosuvastatin, combined with ACE inhibitors or angiotensin II receptor blockers (ARBs) for high blood pressure, was associated with reduced risk for dementia as compared to other combinations of drugs.

The risk was especially lower for people using pravastatin and rosuvastatin in combination with ARBs, and more so for men than women.

The magnitudes of estimated risk reductions were meaningful; for example, using ARBs combined with pravastatin was associated with 21% lower odds of a dementia diagnosis, as compared to individuals using other combinations of drugs.

“We don’t currently have drugs that are proven to treat dementia, but even small delays in onset can dramatically reduce the burden on patients, caregivers and the health system as a whole,” Zissimopoulos said.

The study authors say more research is needed but that if their findings are replicated, specific combinations of statins and antihypertensives might be recommended in the interest of reducing the risk of Alzheimer’s disease and related dementias.


Alzheimer’s disease and related dementias (ADRD) are a large and growing public health issue. There are approximately 7 million individuals aged 65 and older living with ADRD in the United States, and this number is projected to grow to 12 million by 2040 [1].

With no disease-modifying treatments for ADRD, there has been increased global attention on prevention and risk reduction of ADRD by maintenance of a healthy lifestyle and management of diseases such as hypertension and dyslipidemia [25].

A reduction in risk of ADRD would bring significant health and financial benefits to individuals, societies, and families [6].

Antihypertensive therapies are effective pharmaceutical treatments for hypertension, and statins for dyslipidemia.

Statins are hypothesized to act on Alzheimer’s disease (AD) pathology through their effect on cholesterol as well as through other nonlipid effects such as reduced inflammation, although heterogeneity in molecular structure, efficacy, and pharmacokinetics across statins suggests potential variability in effects [712].

Randomized controlled trials and reviews in this area have failed to find a beneficial effect of statins on AD, although limitations of these studies (e.g., short follow-up periods, non-representative samples, and removal of hyperlipidemic subjects) are well recognized [1315].

There is, however, a growing body of observational evidence showing that statins are associated with reduced ADRD risk [1622], including our own work that featured robust control for confounding in a large and representative dataset [16].

Recent evidence also suggests that some subgroups may be more responsive to statin therapy than others [2324]. Though potential influence of statins on AD pathology is still unclear, some trials suggest statin-related attenuation of tau in middle age participants, which aligns with the findings from a community based-autopsy cohort [2526].

Systematic analysis of observational, randomized controlled trials, and meta-analyses found AHT treatment was protective against cognitive decline and incident dementia [2730]

Several studies have implicated the renin-angiotensin system (RAS) in AD, in particular over-activation of the classical hypertension-promoting RAS (cRAS), and more recently dysfunction of the regulatory RAS (rRAS), which ordinarily regulates cRAS activity [3137]. A recent study confirmed these results and reported that RAS AHT users (vs. other AHT users) exhibited fewer neurofibrillary tangles in predetermined brain regions involved in AD [38].

These findings are consistent with hypotheses that therapeutic classes of AHTs operating to reduce RAS activity (i.e., angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs)), may affect AD differently than other AHT drug classes (e.g., calcium channel blockers, beta blockers, loop diuretics, or thiazide diuretics) [3941].

Moreover, in vitro and animal studies of AD show that ARBs were more protective than ACEIs because of ACEI’s potential role in amyloid-beta degradation, and in Tg2576 mice that enhancement of rRAS can prevent and reverse cognitive decline and reduce amyloid-beta pathology [35404243]. Our recent observational study confirmed this relationship in a longitudinal, population study [44].

Approximately one quarter of older Americans used both a statin and an AHT in 2014. Despite the high prevalence of use and hypothesized variation in effects across different types of statins and AHTs, there are no existing analyses of the association of use of specific combinations of AHT and statins and ADRD risk.

The widespread use of these drugs increases the importance of analyses examining the combinations of therapies that are associated with the greatest and least reduction in ADRD risk and for specific populations.

The purpose of this study is to use data from a large population-based cohort to examine the hypothesis that some combinations of statins and AHTs may be more protective against ADRD onset than others, and analyze variation by sex and race/ethnicity in order to inform about the potential for population-specific health benefits.

Results

Table 1 depicts the characteristics of our analytic sample. The annual ADRD incidence rate in this sample is 2.07% among persons using a RAS-acting AHT and any statin, and 2.64% among persons using a non-RAS-acting AHT and any statin. Generally, rates were lower persons using ARBs compared to ACEI with the exception of no difference in rates among persons using them in combination with rosuvastatin.

Those using a RAS-acting AHT were younger, more likely to be male, non-white, and have a lower mean HCC score. There were no differences in percent high school graduate or median income. ACEI users compared to ARB users, across statin types, are about 0.5 years younger, more likely to be male, white, and have fewer physician visits, and lower HCC scores. There were no differences in percent high school graduate or median income.

Fig 1 reports odd ratios (ORs) and 95% confidence intervals from logistic regressions of ADRD incidence that adjust for the patient and setting characteristics described above. Compared to individuals using statins combined with non-RAS AHTs, use of pravastatin and rosuvastatin in combination of ARB or ACEI was associated with reduced risk of ADRD (ACEI+pravastatin OR = 0.942 (CI: 0.899–0.986, p = 0.011), ACEI+rosuvastatin OR = 0.841 (CI: 0.794–0.892, p<0.001), ARB+pravastatin OR = 0.794 (CI: 0.748–0.843, p<0.001), ARB+rosuvastatin OR = 0.818 (CI: 0.765–0.874, p<0.001)). There was no reduced risk associated with ACEI use and either atorvastatin or simvastatin, but a reduced risk when combined with ARBs (ARB+atorvastatin OR = 0.896 (CI: 0.861–0.932, p<0.001), ARB+simvastatin OR = 0.877 (CI: 0.848–0.908, p<0.001)).

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Fig 1. Adjusted odds ratios of ADRD incidence associated with use of statin-AHT combinations, relative to users of other statin-AHT combinations, with 95% confidence intervals.

Logistic regression results for ADRD incidence in sample of 2009–2014 Medicare person-years (N = 2,017,786) with 90 possession days and 2 claims of both an AHT and a statin in both years t-1 and t-2. AHTs are antihypertensive (AHT) prescription drugs (angiotensin converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), beta-blockers, calcium channel blockers, loop diuretics, and thiazide diuretics), and statins are atorvastatin, pravastatin, rosuvastatin, and simvastatin. Sample restricted to person-years with 3 years fee-for-service, 3 years Part D, age 67+, no deaths in the reference year (year t), no prior ADRD diagnoses, and no prior use of acetylcholinesterase inhibitors (AChEIs) or memantine. Controls are age, age squared, sex, education, income quartiles, statin use (t-1), years since hypertension and hyperlipidemic diagnoses, HCC comorbidity index, number of physician visits, and indicators for past diagnoses of diabetes, atrial fibrillation, acute myocardial infarction, and stroke. Standard errors are clustered at the county level.

https://doi.org/10.1371/journal.pone.0229541.g001

Table 2 reports results of ORs separately for men and women. Combined use of ACEIs with three statins (atorvastatin, simvastatin, and pravastatin), compared to combined use statins and non-RAS-acting AHTs, was not associated with reduced ADRD risk among women. ACEI+rosuvastatin and ARB+rosuvastatin were associated with lower odds of ADRD among women (ACEI+rosuvastatin OR = 0.832 (CI: 0.776–0.892, p<0.001), ARB+rosuvastatin OR = 0.833 (CI: 0.774–0.895, p<0.001). Among men, with the exception of simvastatin, combine use of any statin and either ACEI or ARB was associated with lower odds of ADRD incidence.

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Table 2. Adjusted odds ratios of ADRD incidence associated with use of statin-AHT combinations, relative to users of other statin-AHT combinations.

https://doi.org/10.1371/journal.pone.0229541.t002

Table 2 also reports results of ORs separately by race/ethnicity. Among Hispanics, there is no combination of statins and RAS-acting AHTs compared to combinations of statins and non-RAS acting AHTs that is associated with lower risk of ADRD. Among blacks, the reduced risk associated with combined use of rosuvastatin and ACEI is large (OR = 0.672, CI: 0.548–0.825, p<0.001). Among blacks there is also reduced risk associated with combined use of simvastatin and ARBs (OR = 0.856, CI: 0.763–0.960, p = 0.008), atorvastatin and ARBs (OR = 0.869, CI: 0.757–0.999, p = 0.048), and pravastatin and ARBs (OR = 0.770, CI: 0.620–0.956, p = 0.018). Among whites, combined use of ARBs and any statin is associated with lower odds of ADRD relative to non-RAS acting AHTs and any statin.


More information: Douglas Barthold et al. Association of combination statin and antihypertensive therapy with reduced Alzheimer’s disease and related dementia risk, PLOS ONE (2020). DOI: 10.1371/journal.pone.0229541

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