Genetic variants in the epithelial sodium channel and related pathway genes that associate with PPARγ induced fluid retention and oedema in Type 2 diabetic patients receiving Farglitazar
Peroxisome Proliferation Activation Factor gamma (PPARγ) ligands, such as rosiglitazone and pioglitazone are highly effective in the treatment of Type 2 Diabetes (T2D). PPARγ ligands have a common side effect of fluid retention/oedema, which in some cases may lead to more serious cardiovascular complications, including congestive heart failure. A pharmacogenetic study was undertaken to investigate the effect of gene variations in fluid and electrolyte regulation pathways on PPARγ induced oedema using Phase III clinical trials of the investigational PPARγ ligand Farglitazar (alone or in combination with insulin or glyburide) in the treatment of T2D. Using oedema adverse event reporting as phenotype, consistent and significant associations were observed for three polymorphisms in the epithelial sodium channel beta subunit (SCNN1B) (p<0.05 to 0.0005). These associations were observed for GI262570 combination treatment groups (plus glyburide or insulin), but not in the group receiving GI262570 as monotherapy. Sequencing of SCNN1B in 207 Caucasian subjects receiving combination therapy identified additional polymorphisms that were also significantly associated with oedema (p<0.0005). Furthermore, two distinct loci within SCNN1B were associated with oedema for the two combination treatment groups. These studies provide clinical pharmacogenetic to support a pivotal role for epithelial sodium channel regulation in PPARγ induced oedema and provide insight into mechanisms and possible management of this side effect.