This project is a collaboration with Bronwyn Kingwell; Anthony Keech Alicia Jenkins, Rachael O’Connell (NHMRC Clinical Trials Centre); James Best (University of Melbourne); Gerard Wong (Singapore Institute for Clinical Science)
Patients with type 2 diabetes are at increased risk of cardiovascular disease, in part due to the associated dyslipidemia which can be amenable to fenofibrate treatment. Fibrates are peroxisome proliferator activated receptor α (PPARα) agonists and are reported to lower triglycerides, improve the distribution of LDL subpopulations and raise HDL cholesterol. However, the effects of fenofibrate on lipid fractions can vary with the population under study. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was designed to assess the effect of long-term fenofibrate treatment of coronary morbidity and mortality in type 2 diabetes. While reduction in event rates were observed these are not all significant and the increase in HDL was less than expected at only 2 per cent. The differential response of populations (and individuals) raises questions concerning the mechanism of action, the protective effect and the treatment criteria. A promising approach to address these issues is to apply a “lipidomics” strategy to define the effect of fenofibrate treatment on the plasma lipidome and the association with disease outcomes. We have performed preliminary studies on a subset of the FIELD Trial and have shown that:
- Fenofibrate results in specific changes in multiple lipid classes, some of which are associated with coronary artery disease.
- Plasma lipids are better able to classify treatment and placebo than traditional lipoprotein and cholesterol measures.
- Not all individuals respond equally to fenofibrate treatment.
- Future cardiovascular events tend to cluster in the poor responder group.
The primary goals of this project are to define the influence of fenofibrate on the plasma/lipoprotein lipidome, combine lipidomic and genomic data to map the metabolic pathways influenced, determine which aspects of the effect are associated with CVD risk reduction and to identify those individuals who respond to, and benefit from, fenofibrate treatment.
We hypothesise that:
- Fenofibrate affects specific lipid and lipoprotein metabolic pathways which are associated with risk of future CVE.
- Each individual’s response is related to the level of protection afforded by the treatment.
- A short treatment with fenofibrate is sufficient to identify responders from non-responders.
- In this project we will apply our lipidomics and lipoprotein expertise to the FIELD Trial cohort to test these hypotheses.
The specific aims are to:
- Characterise the changes in the plasma lipidome and in lipoprotein composition resulting from fenofibrate treatment.
- Determine the relationship between the effect of fenofibrate on plasma lipids and the risk of future CVD events.
- Define the lipid profile that best identifies responders who are protected from future events.
The outcome of this project will provide a new understanding of the mode of action of fenofibrate and quantify the reduction in risk resulting from fenofibrate treatment.
Importantly, we will develop a test to identify those individuals who respond to fenofibrate treatment which will allow the targeted application of this treatment to reduce risk of CVE in type 2 diabetes.