Efficacy
Three randomized, double-blind, multicenter, phase III trials have shown that treatment with fenofibric acid plus a statin (atorvastatin, rosuvastatin or simvastatin) improved HDL and triglyceride levels significantly better than statin monotherapy and improved LDL levels better than fenofibric acid monotherapy.[6]
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which is the largest fibrate trial involving 9795 patients with type 2 diabetes mellitus published in 2005 did not show a significantly lower risk for the primary end point (non-fatal myocardial infarction and coronary heart disease death). But, it did report a relative risk reduction of 11% for Non-Fatal MI & CHD, although statistically insignificant. The secondary end-point (total cardiovascular disease events) was statistically significant with a relative risk reduction of 11% for total CVD events. There was a large proportion of placebo patients Adcirca who commenced taking statin drugs during the trial, which in turn might affect the results of the study itself. After an adjustment was done for this statin drop in, the relative risk reductions were 19% for Non-Fatal MI & CHD Death, and 15% for total CVD events.[7]
The FIELD study also showed a beneficial reduction in the risk of microvascular complications in type 2 diabetes patients. Fenofibrate treatment led to reduction in the progression albuminuria (14% less progression and 15% more regression compared with placebo). In addition, there was a 30% reduction in the needs for laser treatment for retinopathy.[7]
The FIELD sub-study analysis, shows that fenofibrate reduces the first laser treatment by 31%. In addition, for macular oedema by 31% and for proliferative retinopathy by 30%.[8] In the ophthalmology sub-study, fenofibrate reduces the development or progression of retinopathy by reducing 22% in all patients and 79% in patients with pre-existing retinopathy.[8]
The FIELD study also showed that fenofibrate reduced the number of non-traumatic amputations by 38%.[9]
Like most fibrates, fenofibrate can cause stomach upsets and myopathy (muscle pain) and very rarely rhabdomyolysis. This risk is increased when used together with statins. However, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study provides important information that long-term treatment with fenofibrate therapy appears to have a favorable safety profile in patients with type 2 diabetes, even when nonstudy lipid-lowering medications were added. In FIELD, there were no cases of rhabdomyolysis reported in patients on combination therapy with fenofibrate and a statin. Thus, there is an increasing body of evidence that fenofibrate/statin combination therapy is safe and effective at managing dyslipidemia in patients with type 2 diabetes who are at risk for cardiovascular events. The ACCORD study, however, does not support the above statement about effectiveness (see below).
The recent FIELD Sub-analysis study published in Diabetes Care 2009, showed that fenofibrate significantly reduced CVD events in those with low HDL cholesterol and hypertension. The largest effect of fenofibrate to reduce CVD risk was observed in subjects with marked dyslipidemia (TG>2.3 mmol/L & low HDL-C) in whom a 27% relative reduction risk of total CVD event was observed. Some have argued that the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome features are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia[10], however these conclusions are not based on the predetermined endpoints of the study in the full group.
Classic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes. Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor amputations without known large-vessel disease, probably through non-lipid mechanisms. These findings could lead to a change in standard treatment for the prevention of diabetes-related lower-limb amputations.[11]
In 2010, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that fenofibrate plus statins in patients with type 2 diabetes does not reduce cardiovascular events more than use of statins alone.[12] The ACCORD enrolled 5518 patients and followed them up for 4.7 years, providing moderately strong evidence for lack of real life benefit for using fibrates in diabetic patients with high cholesterol.
