Author + information
- Brian A. Ference,
- David Neff,
- Martin Cabot,
- Alberico Catapano and
- Kausik Ray
Background: Bempedoic acid is a novel oral agent that reduces hepatic cholesterol synthesis by inhibiting ATP-citrate lyase (ACL) leading to upregulation of the LDL receptor and a reduction in plasma low-density lipoprotein cholesterol (LDL-C). Although this mechanism of action is similar to that of statins, the effect of lowering LDL-C by inhibiting ACL on the risk of cardiovascular events is unknown.
Methods: We constructed a genetic score consisting of independently inherited variants in the ACL gene that are associated with lower LDL-C to mimic the effect of ACL inhibition. We used this score as an instrument to naturally randomize participants to higher or lower LDL-C and evaluated the effect of lower LDL-C mediated by ACL variants on the risk of cardiovascular events in a Mendelian randomization study. The primary outcome was major cardiovascular events (MVE) defined as a composite of coronary death, MI, stroke or coronary revascularization.
Results: A total of 101,236 participants (13,964 MVE) from 14 prospective cohort or case-control studies were included in the analysis. Participants with an ACL score below the median had 2.0 mg/dL lower LDL-C, 1.8 mg/dL lower APOB, and a corresponding 3.5% lower risk of MVE (OR: 0.965, 95%CI: 0.942-0.988, p=0.003). This effect was similar in all subgroups studied. In analyses standardized for a common decrement of 10 mg/dL lower LDL-C, variants that mimic the effect of an ACL inhibitor had a very similar effect on the risk of cardiovascular events (OR: 0.832, 95%CI: 0.736-0.940) as compared to variants that mimic the effect of statins (OR: 0.844, 95%CI: 0.806-0.885), ezetimibe (OR: 0.833, 95%CI: 0.755-0.920) and PCSK9 inhibitors (OR: 0.843, 95%CI: 0.805-0.882), all of which lower LDL-C through the LDL receptor pathway.
Conclusions: Lower LDL-C mediated by variants in the ACL gene is causally associated with the risk of cardiovascular events. Because, genetic variants that mimic the effect of an ACL inhibitor have the same effect on the risk of cardiovascular events per unit change in LDL-C as variants that mimic the effect of statins, bempedoic acid should reduce the risk of cardiovascular events by the same amount as statins per unit absolute reduction in LDL-C.
Room 147 A
Sunday, March 19, 2017, 8:51 a.m.-9:01 a.m.
Session Title: Highlighted Original Research: Prevention and the Year in Review
Abstract Category: 32. Prevention: Clinical
Presentation Number: 911-10
- 2017 American College of Cardiology Foundation