Current clinical evidence on pioglitazone pharmacogenomics

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.

Protective effect of pioglitazone on sepsis-induced intestinal injury in a rodent model

“…Pathogenesis and treatment of inflammatory gut barrier failure is an important problem in critical care. The PPARg agonist pioglitazone is the most widely used thiazolidinedione (TZD) antidiabetic drug and currently the only TZD available without regulatory restrictions [29]. It is an oral drug usually provided in the form of a tablet, and no intravenous forms are available in clinical medicine for now.…”

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

“…and triglycerides in carriers of the 12Ala allele 164,[172][173][174] despite two studies observed no association, 175,176 and one reported that insulin levels and insulin resistance were lower in carriers of the Pro12Pro genotype after PIO treatment. 172 In response to ROSI, Korean T2DM patients carrying the 12Ala variant have been shown to have significantly greater decrease in fasting glucose levels and HbA1c.…”

“…PPARG is a nuclear receptor serving as lipid sensor and the cognate receptor for TZDs; its most common variant, rs1801282 (Pro12Ala), reproducibly associated with decreased risk of T2DM, has been widely addressed in pharmacogenetics studies on TZDs efficacy. Several reports have been meta‐analysed revealing a better response to PIO treatment in terms of improvements in fasting glucose, HbA1c and triglycerides in carriers of the 12Ala allele despite two studies observed no association, and one reported that insulin levels and insulin resistance were lower in carriers of the Pro12Pro genotype after PIO treatment . In response to ROSI, Korean T2DM patients carrying the 12Ala variant have been shown to have significantly greater decrease in fasting glucose levels and HbA1c .…”

Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism

“…After single oral administration or continuous oral administration, the blood active metabolic concentrations in female mice were higher than that in male mice (1.5-3 times) [34] . CYP2C8 is a critical enzyme in the metabolism of pioglitazone, and carrying the CYP2C8*3 allele will accelerate the metabolism of pioglitazone [35] . A population study showed that NASH patients with the CYP2C8*3 allele had less improvement in liver fibrosis after pioglitazone intervention (p = 0.006) [36] .…”