Abstract
Pioglitazone is the most widely used thiazolidinedione and acts as an insulin-sensitizer through activation of the Peroxisome Proliferator-Activated Receptor-γ (PPARγ). Pioglitazone is approved for use in the management of type 2 diabetes mellitus (T2DM), but its use in other therapeutic areas is increasing due to pleiotropic effects. In this hypothesis article, the current clinical evidence on pioglitazone pharmacogenomics is summarized and related to variability in pioglitazone response. How genetic variation in the human genome affects the pharmacokinetics and pharmacodynamics of pioglitazone was examined. For pharmacodynamic effects, hypoglycemic and anti-atherosclerotic effects, risks of fracture or edema, and the increase in body mass index in response to pioglitazone based on genotype were examined. The genes CYP2C8 and PPARG are the most extensively studied to date and selected polymorphisms contribute to respective variability in pioglitazone pharmacokinetics and pharmacodynamics. We hypothesized that genetic variation in pioglitazone pathway genes contributes meaningfully to the clinically observed variability in drug response. To test the hypothesis that genetic variation in PPARG associates with variability in pioglitazone response, we conducted a meta-analysis to synthesize the currently available data on the PPARG p.Pro12Ala polymorphism. The results showed that PPARG 12Ala carriers had a more favorable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype (p = 0.018). Unfortunately, findings for many other genes lack replication in independent cohorts to confirm association; further studies are needed. Also, the biological functionality of these polymorphisms is unknown. Based on current evidence, we propose that pharmacogenomics may provide an important tool to individualize pioglitazone therapy and better optimize therapy in patients with T2DM or other conditions for which pioglitazone is being used.
Highlights
Pioglitazone (PIO) is the most widely used thiazolidinedione (TZD) anti-diabetic drug
TZD, thiazolidinedione; PIO, pioglitazone; T2DM, type 2 diabetes mellitus; QD, once daily; MAF, minor allele frequency; HOMA-IR, Homeostasis Model of Assessment-Insulin Resistance index; OGTT, oral glucose tolerance test; NS, not significant; IMT, carotid intima-media thickness; FG, fasting plasma glucose; PPG, postprandial plasma glucose; OR, odds ratio; 95% CI, 95% confidence interval; ROSI, rosiglitazone
According to PharmGKB, CYP2C8*3 is the only genetic variant annotated for PIO treatment as level 3 evidence, which was defined as “annotation for a variant-drug combination based on a single significant or annotation for a variant-drug combination evaluated in multiple studies but lacking clear evidence of an association”(WhirlCarrillo et al, 2012)
Summary
Pioglitazone (PIO) is the most widely used thiazolidinedione (TZD) anti-diabetic drug. The first TZD, troglitazone, was approved for clinical use by the United States Food and Drug Administration (FDA) in 1997 (Kung and Henry, 2012). Troglitazone was withdrawn from the market due to hepatotoxicity and is not currently available (Kung and Henry, 2012). PIO and rosiglitazone (ROSI) were approved by the FDA in 1999 (Kung and Henry, 2012). Due to an apparent increase in risk of myocardial infarction, ROSI was withdrawn from the European market in 2010; the FDA restricted the use of ROSI in the United States in 2011 (Kung and Henry, 2012). PIO is currently the only TZD available without regulatory restrictions
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