Uric Acid Predicts Long-Term Cardiovascular Risk in Type 2 Diabetes but Does Not Mediate the Benefits of Fenofibrate: the FIELD Study.

AIMS: Fenofibrate may lower long-term cardiovascular events. The biological mediators of its mechanisms of action are not fully understood. The current study aimed to determine whether the cardioprotective effects of fenofibrate are partly mediated through its uric acid (UA) lowering effects. METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was utilised, comprising 9795 adults with type 2 diabetes (T2D) randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6-week active fenofibrate run-in phase in all participants. Cox proportional hazards models were used to explore the relationships between baseline UA, pre-to-post run-in reductions in UA and long-term cardiovascular outcomes. RESULTS: Mean baseline plasma UA was 0.33 mmol/L (SD 0.08). Baseline UA was a significant predictor of long-term cardiovascular events with every 0.1 mmol/L higher UA conferring a 21% increase in event rate (HR 1.21, 95% CI 1.13-1.29, p<0.001). This remained significant after adjustment for treatment allocation, cardiovascular risk factors, and renal function. The extent of UA reduction during fenofibrate run-in was also significant predictor of long-term cardiovascular events, with every 0.1 mmol/L greater reduction conferring a 14% lower long-term risk (HR 0.86, 95% CI 0.76-0.97, p = 0.015). This effect was not modified by treatment allocation (pinteraction = 0.77). CONCLUSIONS: UA is a strong independent predictor of long-term cardiovascular risk in adults with T2D. Although greater reduction in UA on fenofibrate is predictive of lower cardiovascular risk, this does not seem to mediate the cardioprotective effects of fenofibrate. This article is protected by copyright. All rights reserved.