Fenofibrate effects on arterial endothelial function in adults with type 2 diabetes mellitus: A FIELD substudy

- Endothelial dysfunction is a key early event in the development of atherosclerosis.
- Fenofibrate led to a short-term improvement in arterial endothelial function in adults with type 2 diabetes at 4 months into treatment.
- Significant improvements in total cholesterol, LDL-C, HDL-C and triglycerides did not account for the early benefit on arterial function.
- Mechanisms other than improvement in large-artery endothelial function may account for the long-term benefits of fibrates on clinical outcomes.

ObjectiveDislipidaemia in type 2 diabetes mellitus contributes to arterial endothelial dysfunction and an increased risk of cardiovascular disease. Fenofibrate, a lipid-regulating peroxisome proliferator-activated receptor-α (PPARα) agonist, has been shown to reduce vascular complications in adults with type 2 diabetes. However, the mechanisms for such benefit are not well understood. We examined the effects of fenofibrate on brachial artery endothelial function in adults with type 2 diabetes.MethodsIn a prospectively designed substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, we assessed arterial flow-mediated dilatation (FMD; endothelium-dependent dilatation) and dilator responses to glyceryl trinitrate (GTN, an endothelium-independent dilator) in a subset of 193 representative adults. Traditional risk factors were assessed at baseline, 4 months and 2 years after randomised treatment allocation to fenofibrate (200 mg daily) or placebo. The prespecified primary study endpoint was the difference in FMD between treatment groups at 4 months.ResultsFenofibrate was associated with a significant improvement at 4 months compared with placebo (+1.05% (absolute); P = 0.03); GTN-dilator responses were unchanged (P = 0.77). After 2 years, FMD was similar in both groups (P = 0.46). In multivariable models, none of the fenofibrate-related changes in lipoproteins and lipids were significantly associated with improved FMD on fenofibrate at 4 months.ConclusionTreatment with fenofibrate significantly improved arterial endothelial function after 4 months. However, the effect was no longer apparent after 2 years. The long-term beneficial vascular effects of fenofibrate in type 2 diabetes are likely to be mediated via mechanisms other than improvement in endothelium-dependent dilatation of conduit arteries, and may differ for the microcirculation.