TY - JOUR
T1 - The Pro12Ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-γ/α agonist-induced edema in type 2 diabetic patients
AU - Hansen, Lars
AU - Ekstrøm, Claus T.
AU - Tabanera Y Palacios, René
AU - Anant, Madan
AU - Wassermann, Karsten
AU - Reinhardt, Rickey R.
PY - 2006/1/1
Y1 - 2006/1/1
N2 - Context: Activation of peroxisome proliferator-activated receptors (PPARs)-γ by thiazolidinediones (pioglitazone, rosiglitazone) and dual-acting PPARα/γ agonists (pargluva, ragaglitazar) is a widely used pharmacological principle to treat insulin resistance and type 2 diabetes. Clinically, however, fluid retention and edema are worrying side effects with these drugs. Objective: The objective of the present study was to investigate any variation in the PPARG and PPARA genes associated with the risk of fluid retention and development of peripheral edema in patients with type 2 diabetes treated with the dual-acting PPARα/γ agonist ragaglitazar. Design: Single-nucleotide polymorphism and haplotype analyses of the PPARA and PPARG genes were performed on DNA obtained from 345 type 2 diabetic patients randomized to 26-wk monotherapy with the dual-acting PPARα/γ agonist ragaglitazar. Results: At 26 wk, edema was recorded in 48 of the patients (14%) treated with ragaglitazar, and Cox regression analyses identified the common Pro12Ala variant of the PPARG gene as biologically the most important risk factor (hazard ratio 4.42, P = 0.0081) for edema. Other risk factors included female gender (hazard ratio 3.34, P = 0.0005) and weight change during treatment (hazard ratio 1.20, P = 0.0017). Conclusions: A population-attributable risk of approximately 50% for the Pro12Pro genotype indicates that testing for the Pro12Ala of the PPARG gene in addition to the already identified clinical risk factors may become a useful tool to further reduce the risk of PPARγ agonist-induced fluid retention and edema in patients with type 2 diabetes.
AB - Context: Activation of peroxisome proliferator-activated receptors (PPARs)-γ by thiazolidinediones (pioglitazone, rosiglitazone) and dual-acting PPARα/γ agonists (pargluva, ragaglitazar) is a widely used pharmacological principle to treat insulin resistance and type 2 diabetes. Clinically, however, fluid retention and edema are worrying side effects with these drugs. Objective: The objective of the present study was to investigate any variation in the PPARG and PPARA genes associated with the risk of fluid retention and development of peripheral edema in patients with type 2 diabetes treated with the dual-acting PPARα/γ agonist ragaglitazar. Design: Single-nucleotide polymorphism and haplotype analyses of the PPARA and PPARG genes were performed on DNA obtained from 345 type 2 diabetic patients randomized to 26-wk monotherapy with the dual-acting PPARα/γ agonist ragaglitazar. Results: At 26 wk, edema was recorded in 48 of the patients (14%) treated with ragaglitazar, and Cox regression analyses identified the common Pro12Ala variant of the PPARG gene as biologically the most important risk factor (hazard ratio 4.42, P = 0.0081) for edema. Other risk factors included female gender (hazard ratio 3.34, P = 0.0005) and weight change during treatment (hazard ratio 1.20, P = 0.0017). Conclusions: A population-attributable risk of approximately 50% for the Pro12Pro genotype indicates that testing for the Pro12Ala of the PPARG gene in addition to the already identified clinical risk factors may become a useful tool to further reduce the risk of PPARγ agonist-induced fluid retention and edema in patients with type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=33748742987&partnerID=8YFLogxK
U2 - 10.1210/jc.2006-0590
DO - 10.1210/jc.2006-0590
M3 - Journal article
C2 - 16822823
AN - SCOPUS:33748742987
SN - 0021-972X
VL - 91
SP - 3446
EP - 3450
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 9
ER -
