PGx7680 Exploratory Meta-analysis of METRO (metformin response) and MetGen (Metformin response consortium)

Trial description: Metformin is a widely used first-line treatment for type 2 diabetes mellitus (T2DM) that reduces glucose absorption from the gastro-intestinal tract, reduces glucose production in the liver, and improves glucose utilization. Effect of metformin on long term glucose levels is measured as reduction in hemoglobin A1c (HbA1c), and HbA1c reductions in the range of 1 to 2 percent are generally observed. Despite widespread use, the glycemic response to metformin is unpredictable and over 35 percent of subjects fail to achieve acceptable glycemic control with this first-line treatment. Many factors are proposed to influence response including genetics.Genetics is also thought to be a predictor of glycemic response to metformin with heritability estimates of 20-34 percent depending on the definition of glycemic response. Numerous candidate gene studies have been employed to study metformin pharmacogenomics with inconsistent results. More recently, the GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group along with the Wellcome Trust Case Control Consortium 2 reported the first genome-wide association study (GWAS) of treatment response to metformin, in European populations. The authors discovered and replicated a single nucleotide polymorphism (SNP) in chromosome 11q22.3, which was associated with glycemic response to metformin in T2DM and proposed that the ataxia telangiestasia mutated gene (ATM), was the effector gene based on its reported function. Interestingly, the authors observed that the effect of this SNP explains only 2.5 percent of the variance in metformin response. In collaboration with University of California San Francisco (UCSF), and Kaiser Permanente Northern California (KPNC) under a collaborative research agreement, a genome-wide association of approximately 1000 extreme responders to metformin was previously conducted. The proposed meta-analysis will contribute those findings to a GWAS meta-analysis effort of metformin response. This will be done in collaboration with the MetGen consortium who have similar numbers of comparable cases and controls to those already analyzed (derived from the GoDarts study), as well as an additional UCSF cohort.