Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins

Abstract

1. Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events.

2. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug–drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use.

3. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.

Keywords::

• drug development
• drug–drug interaction
• efficacy
• HMG-CoA reductase inhibitors
• pharmacogenetics
• transporters

Acknowledgements

The authors would like to thank Annette Gross, John Keogh, Christopher Matheny, Eric Olson, Joseph Polli and Dennis Sprecher for their helpful discussions and review of the manuscript. The authors would also like to thank Catherine Cartwright and Joan Humphreys for generating the passive permeability data shown in Table 2.

Declaration of Interest

The authors report no declarations of interest.