Association of combination statin and antihypertensive therapy with reduced Alzheimer's disease and related dementia risk

Abstract

Background: Hyperlipidemia and hypertension are modifiable risk factors for Alzheimer's disease and related dementias (ADRD). Approximately 25% of adults over age 65 use both antihypertensives (AHTs) and statins for these conditions. While a growing body of evidence found statins and AHTs are independently associated with lower ADRD risk, no evidence exists on simultaneous use for different drug class combinations and ADRD risk. Our primary objective was to compare ADRD risk associated with concurrent use of different combinations of statins and antihypertensives.

Methods: In a retrospective cohort study (2007-2014), we analyzed 694,672 Medicare beneficiaries in the United States (2,017,786 person-years) who concurrently used both statins and AHTs. Using logistic regression adjusting for age, socioeconomic status and comorbidities, we quantified incident ADRD diagnosis associated with concurrent use of different statin molecules (atorvastatin, pravastatin, rosuvastatin, and simvastatin) and AHT drug classes (two renin-angiotensin system (RAS)-acting AHTs, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers (ARBs), vs non-RAS-acting AHTs).

Findings: Pravastatin or rosuvastatin combined with RAS-acting AHTs reduce risk of ADRD relative to any statin combined with non-RAS-acting AHTs: ACEI+pravastatin odds ratio (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). ARBs combined with atorvastatin and simvastatin are associated with smaller reductions in risk, and ACEI with no risk reduction, compared to when combined with pravastatin or rosuvastatin. Among Hispanics, no combination of statins and RAS-acting AHTs reduces risk relative to combinations of statins and non-RAS-acting AHTs. Among blacks using ACEI+rosuvastatin, ADRD odds were 33% lower compared to blacks using other statins combined with non-RAS-acting AHTs (OR = 0.672 (CI: 0.548-0.825, p<0.001)).

Conclusion: Among older Americans, use of pravastatin and rosuvastatin to treat hyperlipidemia is less common than use of simvastatin and atorvastatin, however, in combination with RAS-acting AHTs, particularly ARBs, they may be more effective at reducing risk of ADRD. The number of Americans with ADRD may be reduced with drug treatments for vascular health that also confer effects on ADRD.

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.

Fig 2. Percent of Medicare beneficiaries with use of selected statin and antihypertensive prescription drugs, 2007–2014.

Sample is Medicare beneficiaries with fee-for-service and Part D coverage in the year of the horizontal axis. Use of a drug is defined as 90 days and 2 claims. Abbreviations: ACEI (angiotensin converting enzyme inhibitors), ARB (angiotensin-II receptor blockers), RAS (renin-angiotensin system), non-RAS AHTs (beta-blockers, calcium channel blockers, loop diuretics, and thiazide diuretics).