Context. Activation of peroxisome proliferator-activated receptors (PPAR-) by thiazolidinediones, TZDs (pioglitazone, rosiglitazone) and dual acting PPAR-/ agonists (pargluva, ragaglitazar) is a widely used pharmacological principle to treat insulin resistance and type 2 diabetes. Clinically, however, fluid retention and edema is a worrying side effect with these drugs.

Objective. The objective of the present study was to investigate if 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 PPAR-/ 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 weeks monotherapy with the dual acting PPAR-/ agonist ragaglitazar.

Results. At 26 weeks 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).

Conclusion. 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 PPAR- agonist induced fluid retention and edema in patients with type 2 diabetes.