Long-Term Fenofibrate and Ezetimibe
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Synopsis: Long-term, 48-week co-administration of Fenofibrate plus Ezetimibe was well tolerated and more efficacious than Fenofibrate in patients with mixed hyperlipidemia.
Source: McKenney JM, et al. Safety and Efficacy of Long-Term Co-Administration of Fenofibrate and Ezetimibe in Patients with Mixed Hyperlipidemia. J Am Coll Cardiol. 2006;47:1584-1587.
In patients with mixed hyperlipidemia, the role of ezetimibe added to fenofibrate is not clear. Based upon favorable short-term benefits, this long-term trial was conducted. Mixed hyperlipidemia was defined as LDL cholesterol of 130 to 220 mg/dL, or 100 to 180 if diabetic, and a triglyceride level of 200 to 500 mg/dL. Ezetimibe 10 mg, fenofibrate 160 mg, both, or placebo were the groups for the initial 12-week study. This was followed by a 48-week extension comparing fenofibrate alone to fenofibrate plus ezetimibe. Safety and efficacy were the objectives of this double-blind study. The primary safety variables were adverse experiences, liver function tests, and creatinine kinase levels. The primary efficacy end point was percent change in LDL cholesterol. Secondary end points included other lipoprotein components and high-sensitivity C-reactive protein. Of the 587 patients who entered the study, 576 continued into the 48-week extension. The risk-adjusted LDL cholesterol targets were achieved less frequently with fenofibrate alone (48%) than with fenofibrate plus ezetimibe (76%). HDL cholesterol increased more with the combination (21 vs 18%, P = .002) and triglyceride levels decreased more (46 vs 42%; P = .002). Also, apolipoprotein B decreased more (25 vs 16%; P < .001), but there was no difference in high-sensitivity C-reactive protein reductions. About 15% of the subjects experienced adverse events, of which 1% were serious, but there was no difference between groups. Liver function test abnormalities occurred in about 1% of both groups, and no one had marked elevation in creatinine kinase. McKenney and colleagues concluded that the long-term co-administration of fenofibrate and ezetimibe was well-tolerated and was more efficacious than fenofibrate alone in patients with mixed hyperlipidemia.
Fenofibrate has been traditionally used to decrease triglycerides and this was the biggest change in lipids noted on fenofibrate alone (> 40% reduction). In patients with mixed hyperlipidemia, LDL cholesterol is also elevated and often HDL is decreased. One approach has been to add niacin to fenofibrate, as was done in the CLAS study with good outcomes. However, niacin remains a tough sell for many patients. Thus, ezetimibe emerges as a viable alternative. In this study, adding it further reduced triglycerides and increased HDL by small amounts. The major change was a marked augmentation of LDL lowering by adding ezetimibe (-22% vs -7%; P < .001). Since the average baseline LDL was about 160 mg/dL, this is a major beneficial effect and should correlate with reduced vascular events.
Although adverse events were uncommon, few were serious and only about 5% discontinued treatment because of them. There were no cases of myopathy and a very low incidence of significant liver dysfunction. Creatinine elevations have been described with fenofibrate and, in this study, levels > 1.5 mg/dL occurred in about 10%. Fenofibrate can also increase the incidence of gallstones, which was seen in 0.5 to 1.0% of the subjects. No adverse event was significantly greater after the addition of ezetimibe, suggesting that it has few side effects and that there was no adverse event synergy between the 2 drugs.
There are several caveats to this study. The patient population was relatively young: mean age in the early 50s and only 15% > age 65 years. Over half the patients had metabolic syndrome, but only about 15% had diabetes. However, it was a high-risk group based upon a mean high-sensitivity C-reactive protein of 2.5-3.0 mg/dL. These are the type of patients that could benefit greatly from effective lipid changes. Unfortunately, there is no outcome data in the study and it was not powered for cardiovascular events. Regardless, the combination of fenofibrate plus ezetimibe in mixed hyperlipidemia patients appears to be a reasonable choice for first-line therapy or for those in whom fenofibrate is insufficient to meet treatment goals.