Fenofibrate - Efficacy

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.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (2005), the largest, with 9795 patients with type 2 diabetes mellitus did not show a lower risk for the primary end point (non-fatal myocardial infarction and coronary heart disease death). The secondary end-point (total cardiovascular disease events) showed a relative risk reduction of 11% for total CVD events. A large proportion of placebo patients took statins during the trial, which weakened the effect. After an adjustment for statin drop in, the relative risk reductions were 19% for Non-Fatal MI and CHD Death, and 15% for total CVD events.

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 of 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.

A FIELD sub-study analysis found that fenofibrate reduces the first laser treatment by 31%, reduced macular oedema by 31% and proliferative retinopathy by 30%. In the sub-study, fenofibrate reduced the development or progression of retinopathy by reducing 22% in all patients and 79% in patients with pre-existing retinopathy.

The FIELD study also showed that fenofibrate reduced the number of non-traumatic amputations by 38%.

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, 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.

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. 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.

Although ACCORD-Lipid trial did not provide support for the general addition of fenofibrate to statin-treated patients with type 2 diabetes mellitus (T2DM), it added significantly to the results from fibrate monotherapy trials indicative of benefit from such treatment in subgroups of patients who present with significant dyslipidemia. In particular, ACCORD-Lipid trial, in our view, supports the addition of fenofibrate to statin therapy in patients with T2DM and optimal low-density lipoprotein cholesterol levels but persistent, significant hypertriglyceridemia (>200 mg/dll) and low high-density lipoprotein cholesterol levels (<35–40 mg/dl).

Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years (FIELD), despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited.

It also appears to have a beneficial effect on the insulin resistance featured by the metabolic syndrome.