Chronic complication risk and benefits of fenofibrate in type 2 diabetes by a PPARα polymorphism (rs6008845, C/T): a FIELD trial substudy.

OBJECTIVE

Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, cardiac energy balance, vascular inflammation and cell differentiation. We examined whether a PPARα gene variant (rs6008845, C/T) is associated with risk of chronic complications and death, and with benefit of fenofibrate (a PPARα agonist) in adults with type 2 diabetes.

METHODS

The variant was genotyped in 8,159 participants in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. During a median 5-year follow-up, 2,931 (35.9%) developed chronic complications, including 2,004 (24.6%) microvascular and 1,359 (16.7%) macrovascular events.

RESULTS

The association with microvascular complications was non-linear, with the highest risk among T/T homozygotes (hazard ratio (HR) 1.15 (95% CI 1.01-1.31), p = 0.041 vs. C/C homozygotes). Each T allele was associated with higher risk of any vascular complication (HR 1.06 (1.00-1.12), p = 0.029), non-CVD-related mortality (HR 1.18 (1.01-1.36), p = 0.032), and cancer-related mortality (HR 1.19 (1.01-1.41), p = 0.041). A significant genotype-by-dyslipidemia interaction was observed for cancer-related mortality under the atherogenic dyslipidemia definition. Fenofibrate reduced microvascular, macrovascular, and composite vascular events (HR 0.79-0.87, all p < 0.02) with no evidence of treatment-by-genotype interaction.

CONCLUSIONS

PPARα rs6008845 T allele was associated with a higher risk of microvascular complications and cancer death. Fenofibrate showed consistent vascular protection irrespective of PPARα genotype.