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New uses for old drugs : Investigating whether antihypertensives can be repurposed for the prevention of dementia

Bristol student theses: Doctoral ThesisDoctor of Philosophy (PhD)

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Abstract

Background: Drug repurposing applies existing drugs to novel indications to identify potential treatments in a more rapid and cost-effective manner than traditional drug development. Antihypertensive drugs are priority repurposing candidates for dementia prevention, however current evidence for their use is inconclusive. Furthermore, little research has been conducted into the factors that influence prescribing of licensed dementia drugs, which will be an important consideration should a drug repurposing candidate be identified.

Methods: Join point analysis was used to identify factors that have potentially influenced prescribing trends for the licensed dementia drugs in the Clinical Practice Research Datalink (CPRD). Instrumental variable analysis was then conducted in two ways to assess the potential for repurposing antihypertensives for dementia prevention. The first analysis used physicians’ prescribing preference as an instrument, also in the CPRD. While the second analysis used genetic variants to proxy the targets of antihypertensive drugs in a two-sample Mendelian Randomization framework.

Results: Prescriptions of dementia drugs have increased since their launch, but the join point analysis suggested that different classes of drugs have been affected by different factors during this time. The instrumental variable analysis using physician’s prescribing preference suggested that small differences exist between antihypertensive drug classes in terms of their effect on dementia prevention, but the magnitude of the differences is smaller than previously reported. Finally, Mendelian randomization provided limited evidence that lowering systolic blood pressure, via antihypertensive drug classes, affected Alzheimer’s disease risk. This suggests that if specific antihypertensive drug classes affect the risk of Alzheimer’s disease, they may not do so via systolic blood pressure.

Conclusions: This thesis has provided new evidence concerning the potential repurposing of antihypertensives for dementia prevention using causal inference methods. In addition, it has examined factors that may have affected dementia drug prescribing, which may also have implications for repurposed drug candidates.

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Original languageEnglish
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Award date13 Sep 2019

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