The Pro12Ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients.
BACKGROUND
Activation of peroxisome proliferator-activated receptors (PPARs)-gamma by thiazolidinediones (pioglitazone, rosiglitazone) and dual-acting PPARalpha/gamma 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 PPARalpha/gamma agonist ragaglitazar.


METHODS
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 PPARalpha/gamma 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 PPARgamma agonist-induced fluid retention and edema in patients with type 2 diabetes.
Hansen
Lars
L
Novo Nordisk A/S, D.M.S.C., Krogshoejvej 53A, 9E2.48, DK-2880 Bagsvaerd, Denmark. larh@novonordisk.com
Ekstrøm
Claus T
CT
Tabanera Y Palacios
René
R
Anant
Madan
M
Wassermann
Karsten
K
Reinhardt
Rickey R
RR
D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D004487:Edema / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005905:Glyburide / Q000009:adverse effects / Q000627:therapeutic use; D006239:Haplotypes; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016015:Logistic Models; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use; D010078:Oxazines / Q000009:adverse effects* / Q000627:therapeutic use; D047493:PPAR alpha / Q000819:agonists / Q000097:blood / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics*; D010666:Phenylpropionates / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models
D007004:Hypoglycemic Agents; D010078:Oxazines; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D004247:DNA; D008687:Metformin; C432703:ragaglitazar; D005905:Glyburide