Bile acid sequestrants and risk of selected age-related diseases

Date of Approval: 
2018-08-01 00:00:00
Lay Summary: 
Bile acid sequestrants (BAS) have been used for the past 4 decades to lower blood cholesterol level. They work by binding to certain bile acids in the gut stimulating the liver to produce more bile that lower cholesterol production. BAS are known to lower the pool of bile acids by around 40%. Studies have shown that altering certain bile acid levels result in decreasing the level of inflammatory products in the immune system. In this study, we plan to evaluate the effect of use of BAS on selected age-related diseases, namely dementia, Alzheimer disease (AD), and cancer.
Technical Summary: 
BAS are a class of lipid modifying treatments (LMTs) used to lower LDL cholesterol levels by binding to bile acids in the gut and lowering their levels in blood. Evidence from animal models suggests that bile acids may have important roles to play in influencing neurodegeneration and carcinogenesis. Using a metabolomics approach, Dr. Thambisetty’s group (study co-investigator) previously showed altered levels of some bile acids in patients with mild cognitive impairment (MCI), a condition that may represent early stages of Alzheimer’s disease (AD). He also recently observed that serum concentrations of bile acids are associated with patterns of brain atrophy similar to those seen in patients with AD 1. Studies of the effect of bile acid on cancers suggest possible organ-specific variations. There is a line of evidence that excessive bile acid increases the risk of gastrointestinal cancers. On the other hand, a recent In-Vitro study showed that lithocholic acid, a secondary bile acid reduced breast cancer cell proliferation. Here, we propose to evaluate the effect of BAS on individual’s risk of age-related neurodegenerative diseases (namely, dementia and AD), and cancer. We propose a matched double cohort design in which we will compare the risk of study outcomes between new users of BAS and new users of other non-statin lipid lowering drugs. Both groups will be matched on age, sex, practice, and prior statin use.
Health Outcomes to be Measured: 
Dementia • Alzheimer’s disease • Cancer (all and by site)
Application Number: 
18_173
Collaborators: 

Shahinaz Gadalla - Chief Investigator - National Cancer Institute ( NCI )
Shahinaz Gadalla - Corresponding Applicant - National Cancer Institute ( NCI )
Jodi Segal - Collaborator - Johns Hopkins School of Medicine
Madhav Thambisetty - Collaborator - National Institutes of Health - USA
Vijay Varma - Collaborator - US-NIH
Youjin Wang - Collaborator - National Cancer Institute ( NCI )

Linkages: 
Practice Level Index of Multiple Deprivation