The Most Common Side Effects of Ezetimibe

Ezetimibe is generally well tolerated, especially when used alone. In clinical trials, most people who experienced side effects reported only mild and manageable symptoms. In fact, many of the side effects were no more common than in those taking a placebo. Nonetheless, it’s helpful to know what to expect. Below are some of the most frequently reported side effects of ezetimibe.

#1: Muscle Pain (Myalgia)

Muscle pain is one of the most frequently reported complaints among patients on cholesterol medications. However, with ezetimibe, the frequency of true drug-related muscle pain is low. In randomized trials, the incidence of myalgia in ezetimibe users was approximately 2 to 3 percent, which is nearly identical to placebo rates.

In fact, when ezetimibe is combined with a statin, it allows for lower statin doses and often reduces the likelihood of statin-associated muscle symptoms. A randomized trial involving 286 patients with chronic kidney disease found that those taking ezetimibe with a standard statin dose had a significantly lower rate of muscle side effects compared to patients who were simply given a higher statin dose (6 percent vs. 20 percent, p < 0.01).

#2: Fatigue

Fatigue is a vague but commonly mentioned symptom among patients starting any new medication. In ezetimibe trials, fatigue has been reported at rates between 1 and 4 percent, which again mirrors placebo groups. While it’s hard to definitively attribute fatigue to ezetimibe, it appears on the label due to its presence in early trial data, even though the statistical significance is weak.

#3: Diarrhea and Gastrointestinal Discomfort

Because ezetimibe works in the small intestine to block cholesterol absorption, it’s logical that gastrointestinal (GI) symptoms could emerge. Diarrhea, abdominal discomfort, and flatulence have been reported in up to 4 to 5 percent of patients, although controlled studies show these rates are not significantly higher than placebo. GI symptoms, when they occur, are typically transient and non-severe.

#4: Upper Respiratory Symptoms

Infections such as nasopharyngitis, sinusitis, or sore throat have been observed in ezetimibe users in clinical trials. However, these are common in the general population and were not significantly more frequent than in placebo groups. Their inclusion on the adverse event profile likely reflects background incidence rather than a true drug-related effect.

#5: Joint Pain (Arthralgia)

Joint pain has also been reported by patients taking ezetimibe, again in the 2 to 3 percent range. This rate is not statistically different from placebo, and the complaints are generally mild and resolve without stopping the medication.

Rare But Serious Ezetimibe Side Effects

While ezetimibe is widely regarded as safe and is well tolerated by most individuals, no medication is entirely without risk. Although uncommon, there are a few serious side effects that have been reported in rare cases. These reactions may require prompt medical attention and are important to be aware of, particularly if you’re taking ezetimibe alongside other cholesterol-lowering medications such as statins.

#1: Rhabdomyolysis

A real-world pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) database uncovered a statistically significant association between ezetimibe and rhabdomyolysis. Although only 19 cases were identified among over 11,000 reports, the signal strength was very high.

Rhabdomyolysis occurs when muscle tissue breaks down rapidly, releasing proteins like myoglobin into the bloodstream. This can overwhelm the kidneys and potentially lead to kidney failure. It typically causes symptoms such as severe muscle pain, weakness, and dark-colored urine.

While this reaction is most often associated with statins, especially at higher doses, the data suggests it may also occur when ezetimibe is used, particularly in patients who are also taking statins, have kidney disease, or are on multiple medications. Still, it remains exceptionally rare.

#2: Unstable Angina

The same FAERS study also flagged unstable angina as a rare but statistically significant adverse event in patients taking ezetimibe. There were 120 cases reported, with a strong reporting odds ratio.

Unstable angina is a form of chest pain that happens when blood flow to the heart is suddenly reduced. Unlike stable angina, which is predictable and often triggered by exertion, unstable angina can occur at rest and may signal a higher risk of heart attack.

This side effect was not observed in clinical trials but has appeared in post-marketing reports. Because these reports are observational and can’t establish direct causation, the association should be interpreted with caution. However, it may be relevant for patients with existing heart disease or multiple cardiovascular risk factors.

#3: Neurological and Psychiatric Symptoms

An unexpected finding from the FAERS data was a signal for “autoscopy,” a type of visual hallucination. Only 7 cases were found, but the association was statistically significant. These types of rare neuropsychiatric effects have not been observed in clinical trials and may reflect isolated idiosyncratic reactions.

Conclusion

Ezetimibe is among the safest lipid-lowering agents currently in use. The most common side effects (fatigue, mild GI symptoms, joint or muscle pain) are generally tolerable and discontinuation rates in clinical practice are low. In a cohort study of 295 patients at a lipid clinic, only 7 percent stopped ezetimibe due to side effects. This is substantially lower than the 20 to 25 percent discontinuation rates commonly seen with statins.

For patients who need an alternative or supplement to statin therapy, ezetimibe offers a proven, low-risk option backed by strong clinical evidence.