Drug Profile

Ezetimibe (ZETIA) is a drug that lowers cholesterol. It is approved to treat high cholesterol due to high low-density lipoprotein cholesterol (LDL-C, "bad" cholesterol) caused by heredity or due to high blood levels of sitosterol and campesterol.[1] Ezetimibe belongs to a family of drugs called azetidinones. Ezetimibe works by partially blocking the absorption of cholesterol in the small intestine.[2]

Although ezetimibe lowers cholesterol levels, there is no evidence that it reduces the risk of heart attacks or strokes. The principal marketing claim for ezetimibe has been its improved safety over other cholesterol-lowering drugs, particularly the statins. However, there is no actual proof that it is, in fact, any safer.[3]

Patients with moderate to severe liver disease should not use ezetimibe.[4] Unlike the statin drugs, ezetimibe does not lower production of cholesterol by the liver. In fact, the liver may compensate by increasing cholesterol production, although overall LDL declines.

Ezetimibe should not be used with fibric acid drugs such as gemfibrozil (LOPID) and fenofibrate (TRICOR).

Patients who take ezetimibe with other cholesterol-lowering drugs should be aware that these drugs also have contraindications, warnings and adverse effects that must be considered in addition to ones for ezetimibe.

All cholesterol-lowering drugs are intended to be part of a therapy that also includes exercise and a diet low in saturated fat and cholesterol. Drugs should be prescribed only after diet and exercise alone prove inadequate.

An article in Prescrire International in 2010 stated that in 2009 the French Transparency Committee (a committee that assesses the comparative effectiveness of new drugs) lowered its rating of ezetimibe for the treatment of primary hypercholesterolaemia from moderate to minor. The change in rating was based on the absence of available clinical data to fully assess the use of ezetimibe for this diagnosis.[5]

Adverse effects

Ezetimibe seems to share psychiatric risks with other cholesterol-lowering drugs. There have been reports of aggressive behavior: memory impairment; mood changes; and cognitive, sleep and perception disorders (such as nightmares) associated with the use of many drugs used to treat high cholesterol: ezetimibe, fenofibrate (TRICOR), gemfibrozil (LOPID), clofibrate and the statin drugs, such as fluvastatin (LESCOL), rosuvastatin (CRESTOR) or simvastatin (ZOCOR).[6],[7]

There also have been reports of depression in users of ezetimibe. Three cases of depressed mood were reported in patients using ezetimibe over a span of three years. In some of these cases, the onset of symptoms was noted within four days of starting the drug.[8]

Though researchers have not yet established a direct link between these reports and the use of the cholesterol-lowering drugs listed, patients should be alert to this possibility and report unexpected changes to their doctor.

Ezetimibe also enhances lowering of cholesterol when used with some other cholesterol-lowering drugs, such as statins.[9],[10],[11],[12] However, adding ezetimibe to statins increases the risk of serious liver adverse events compared with either drug used alone.[13]

Combination of ezetimibe and simvastatin (VYTORIN)

In 2004, the Food and Drug Administration (FDA) approved a pill called VYTORIN which is a combination ezetimibe and simvastatin (ZOCOR). Evidence from the FDA Adverse Events Reports System (AERS) shows that ezetimibe may, on its own, cause rhabdomyolysis (the rapid breakdown of muscle). The FDA reviewer of ezetimibe wrote that:

Pharmacology recommends approval of this drug [ezetimibe] for monotherapy for the proposed indication [use], but preclinical studies do not support safety of ezetimibe in combination with statins [as in VYTORIN]. The toxicity profile appears to be that associated with statins. However the toxicity appears at lower duration and exposure than in statin monotherapy.[14]

The reviewer noted that toxicity seen when ezetimibe was used alone occurred in the heart, lymph nodes, kidneys and bone marrow in laboratory animals; an earlier pharmacology review found lung and liver toxicity as well. When ezetimibe was combined with a statin, toxicity was seen in even more organs: liver, stomach, skeletal muscle, spleen, heart, lungs, testes and prostate.[14]

This finding was given more weight when a 2007 Prescrire International article reviewing the use of the ZOCOR showed an increased risk of adverse effects with the combination drug ZOCOR than with ezetimibe alone.[15]

The results of a trial completed in April 2006 — but not released until January 14, 2008 — showed that the combination of ezetimibe and simvastatin was of no greater benefit than a statin alone in preventing the buildup of plaque in blood vessels.

There also have been reports linking ezetimibe to triggering muscle and tendon pain when it is added to statin treatment. Unexpected muscle pain can be another early signal of rhabdomyolysis.[16]

Ezetimibe's professional product labeling cautions that when the drug is used in combination with a statin, liver function tests should be performed at the initiation of treatment and according to the recommendations for the statin drug being used. Whether those taking ezetimibe alone also need monitoring is not yet known, but ezetimibe does not appear to cause liver toxicity on its own.[1]

Prescrire International published an article in March 2010 concerning the use of ezetimibe and the risk of cancer. The article highlights the results of a clinical trial where, according to the article, patients using ezetimibe (10 mg) with simvastatin showed no clinical cardiovascular benefit compared with those receiving ezetimibe and placebo. However, cancer was more frequent with ezetimibe (10 mg) and simvastatin use than with ezetimibe and placebo. The article also stated that there were more cancer related deaths in the ezetimibe (10 mg) and simvastatin group than in the ezetimibe with placebo group. Another study, a meta-analysis, found that there was no excess cancer incidence with ezetimibe, however the follow up lasted less than three years.[17]

In 2015, The New England Journal of Medicine published the results of a large randomized study comparing treatment with simvastatin to treatment with both simvastatin and ezetimibe in patients who had a recent heart attack or symptoms similar to a heart attack, known as unstable angina.[18] The study showed that the addition of ezetimibe to simvastatin provided little additional benefit beyond using simvastatin alone.

In 2024, Health Canada (agency in Canada similar to the FDA) issued an advisory that ezetimibe may cause liver damage and severe skin reactions.[19]