Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes.
OBJECTIVE
To investigate the influence of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) gene variants on the response rate to therapy with the thiazolidinedione (TZD) pioglitazone, because in vitro studies have suggested that genetic variants of the PPAR-gamma gene may influence the drug efficacy of TZD.


METHODS
A total of 131 patients were treated in an open-label, randomized, multicenter study with pioglitazone (45 mg o.d.) during a course of >or=26 weeks. Response to the pioglitazone therapy was defined by either a >20% decrease in fasting plasma glucose or a >15% decrease in HbA(1c) values after 26 weeks of pioglitazone treatment. We evaluated the association between the PPAR-gamma genotype and the response rate to pioglitazone treatment.


RESULTS
The Pro12Ala and the Pro12Pro variants in the PPAR-gamma gene are not associated with the response rate to pioglitazone treatment in patients with type 2 diabetes. However, we identified initial fasting plasma glucose level >11.0 mmol/l, HbA(1c) value >9.0%, BMI >32 kg/m(2), and fasting C-peptide concentrations at baseline >2.5 pmol/l as predominant confounding factors for the responder frequency to pioglitazone treatment.


CONCLUSIONS
The Pro12Ala variant in the PPAR-gamma gene does not affect the therapy efficacy of pioglitazone, suggesting that the drug-treatment response is independent from pharmacogenetic effects between PPAR-gamma and its ligand pioglitazone. Whether the Ala12Ala genotype plays a role in the response rate to TZD therapy remains to be determined.
Blüher
Matthias
M
Medical Department, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
Lübben
Georg
G
Paschke
Ralf
R
D000368:Aged; D000409:Alanine / Q000235:genetics; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D011392:Proline / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013844:Thiazoles / Q000008:administration & dosage*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
D000409:Alanine; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000077205:Pioglitazone; D011392:Proline; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors