Metformin Pharmacogenomics: Biomarkers to Mechanisms

摘要

Pharmacogenomics is the study of the contribution of inheritance to variation in drug response-variation that can range from a loss of the desired therapeutic effect at one end of the spectrum to an adverse drug reaction at the other. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) recently sponsored a workshop on the pharmacogenomics of metformin, the most widely prescribed drug for the treatment of type 2 diabetes. Metformin displays wide variation in efficacy and occasional serious adverse reactions. A report of that workshop is published in this issue. Pawlyk et al. provide an overview of the current status of metformin pharmacogenomics as well as insight into the current state of pharmacogenomics as a discipline. Pharmacogenomic information is increasingly being implemented clinically and is being used to adjust drug dosage or to avoid adverse drug reactions. At the same time, pharmacogenomic research has moved from a focus on the contribution of genetics to variation in processes that we already understand-for example, drug metabolism and known drug target(s)-to also become a tool for discovery by using techniques as diverse as genome-wide association studies (GWAS), next-generation DNA sequencing, genomic studies of patients enrolled in very large clinical consortia, or the addition to genomic information of other, complementary "omics" data sets. Application of these techniques has made it possible to move beyond merely identifying biomarkers to obtaining novel mechanistic insights. Several of these experimental approaches have already been applied to study inherited variation in metformin response or were suggested by participants in the NIDDK workshop. There has already been significant progress in our understanding of metformin pharmacogenomics, particularly with regard to its pharmacokinetics, i.e., factors that determine the concentration of drug that reaches its target(s). However, many questions remain unanswered, especially with regard to metformin pharmacodynamics, i.e., targets for the drug,downstream signals from those targets, and mechanisms of drug action.