What Is Ezetimibe (Zetia) and How Does It Lower Cholesterol?

Cardiovascular disease (CVD) remains the leading cause of death worldwide, claiming an estimated 18 million lives each year, with high cholesterol identified as a major modifiable risk factor. Elevated levels of low-density lipoprotein cholesterol (LDL-C) contribute to the buildup of arterial plaques, significantly increasing the risk of heart attack and stroke. 

While lifestyle changes like diet and exercise are foundational in managing cholesterol, more than one-third of people may require cholesterol-lowering medications to achieve optimal levels. These medications include statins, bile acid sequestrants, nicotinic acid, and fibrates. Ezetimibe, marketed under the brand name Zetia, is an FDA-approved cholesterol-lowering agent that offers an alternative mechanism of action by inhibiting cholesterol absorption in the intestine.

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What Is Ezetimibe (Zetia)?

Ezetimibe is an oral cholesterol-lowering medication that works by inhibiting cholesterol absorption in the small intestine. Unlike statins, which reduce cholesterol production in the liver, ezetimibe targets the digestive system to prevent cholesterol from entering the bloodstream. This leads to reduced liver cholesterol stores and increased cholesterol clearance from the blood.  

Ezetimibe was approved by the United States Food and Drug Administration (FDA) in 2002 to treat high cholesterol in adults and pediatric patients at least 10 years old. It is often prescribed for individuals who cannot achieve desired cholesterol levels with statins alone or who experience adverse effects from statin therapy. 

How Ezetimibe (Zetia) Works in the Body

Cholesterol enters the intestine from three main sources:

• Dietary intake
• Bile secreted by the liver to aid digestion
• Intestinal epithelial sloughing (the natural shedding/turnover of cells lining the intestinal walls)

Specialized cells in the small intestine use a protein called Niemann-Pick C1-Like 1 (NPC1L1) to transport cholesterol from the intestine into the bloodstream, where it becomes part of cholesterol-carrying proteins called lipoproteins.

Ezetimibe inhibits the NPC1L1 protein on the lining of the small intestine to block NPC1L1-dependent intestinal cholesterol uptake. The liver compensates by breaking down stored cholesterol and increasing the uptake of circulating LDL particles, further lowering cholesterol levels. 

Clinical Use of Ezetimibe (Zetia)

Specifically, ezetimibe is indicated to treat: 

• Primary Hyperlipidemia: A genetic condition characterized by elevated levels of lipids in the blood due to inherited abnormalities in lipid metabolism 
• Mixed Hyperlipidemia: A disorder involving elevated levels of both cholesterol and triglycerides in the blood
• Homozygous Familial Hypercholesterolemia (HoFH): An inherited condition resulting from mutations in the LDL receptor gene, leading to extremely high LDL-C levels
• Homozygous Familial Sitosterolemia (HoFS): A rare genetic disorder caused by gene mutations regulating plant sterol metabolism, leading to excessive absorption and accumulation of plant sterols in the body

Dosage and Administration

Zetia is available as a 10-mg tablet that is swallowed. The only FDA-approved dosage is 10 mg once daily by mouth, with or without food, regardless of the patient's age or the condition being treated. 

Zetia should be taken at least two hours before or four hours after bile acid sequestrants, including colesevelam, colestipol, and cholestyramine. 

If a dose is missed, it should be taken as soon as remembered unless it is almost time for the next scheduled dose. Do not take double or extra doses to make up for the missed one.  

Combination Therapy

Zetia can be combined with a statin or fenofibrate (a fibric acid) for enhanced cholesterol management. Ezetimibe is also available in a combination drug that contains simvastatin, sold under the brand name Vytorin. 

Effectiveness of Ezetimibe (Zetia) in Cholesterol Management

The primary benefit of ezetimibe is LDL-C reduction through inhibiting intestinal cholesterol absorption. Used alone, ezetimibe decreases LDL-C by 10-18%. A total LDL-C-lowering effect of 34-61% can be observed when combined with statin therapy.  

In addition to lowering LDL-C, ezetimibe enhances cardiovascular health by reducing: 

• Total cholesterol
• Non-high-density lipoprotein (non-HDL) cholesterol
• Triglycerides
• Apolipoprotein B (ApoB)
• High-sensitivity C-reactive protein (hs-CRP)

In the IMPROVE-IT trial, the combination of ezetimibe and simvastatin significantly reduced LDL-C levels (median 54 mg/dL) compared to simvastatin alone (median 70 mg/dL). This reduction translated into a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years.

​​Ezetimibe has been shown to reduce the risk of myocardial infarction (heart attack) by 13.5% and stroke by 16%. The American College of Cardiology recommends ezetimibe as an additional lipid-lowering therapy for secondary prevention in high-risk patients with LDL-C ≥70 mg/dL despite maximally tolerated statin therapy.

Individual results may vary and clinical decisions should be based on healthcare provider recommendations.

How Long Does Ezetimibe (Zetia) Take to Work?

Cholesterol levels can begin to improve as soon as two weeks after starting Zetia. Most clinical trials study the drug's efficacy over at least 8-12 weeks. Your doctor will remeasure your cholesterol levels about four weeks after initiating therapy. 

Side Effects and Precautions of Ezetimibe (Zetia)

Ezetimibe's safety profile has been evaluated in over 4,700 patients in clinical trials. The most commonly reported side effects (occurring in >2% of patients) include:

• Back pain
• Joint pain
• Diarrhea
• Sinusitis
• Abdominal pain
• Sore throat
• Cough
• Viral upper respiratory infection
• Fatigue

Serious Side Effects

In rare cases, ezetimibe may cause more serious issues, including:

• Severe allergic reactions: symptoms may include difficulty breathing, racing heart, fever, swelling of the face or mouth, skin rash
• Liver damage: symptoms may include nausea, vomiting, right-sided abdominal pain, fatigue, light color stool, yellowing of the skin
• Rhabdomyolysis (muscle breakdown): symptoms may include muscle pain, weakness, fatigue, dark-colored urine

If you experience any of the serious symptoms listed above, discontinue taking ezetimibe immediately and seek medical attention. 

Contraindications and Warnings

Ezetimibe may not be safe for everyone. Talk to your doctor before taking ezetimibe if you have any of these conditions: 

• Liver Disease: Including active liver dysfunction or unexplained elevations in liver enzymes.
• Kidney Disease: Severe renal impairment may require dosage adjustments or alternative therapies.
• Gallstones: Individuals with a history of gallstones should discuss potential risks with their doctor.
• Pregnancy or Breastfeeding: Ezetimibe is not recommended for use during pregnancy or while breastfeeding.
• Concomitant Use of Certain Medications: Including cyclosporine or fibrates other than fenofibrate, as these may interact adversely with ezetimibe.
• Allergy to Ezetimibe: Individuals with a known hypersensitivity to ezetimibe or any component of the formulation should avoid its use.
• Contraindication to Other LDL-C Lowering Therapies: Such as statins or fenofibrate

Ezetimibe (Zetia) vs. Other Cholesterol Medications

Statin medications are recommended as a first-line pharmaceutical intervention for reducing LDL-C and preventing cardiovascular events in high-risk populations. Including medications like lovastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin, statins can lower LDL-C by less than 30% to greater than 50% by blocking the liver's ability to produce cholesterol through the inhibition of an enzyme called HMG-CoA reductase.

Up to 63% of statin users report at least one side effect on statin therapy, most commonly muscle-related side effects (MRSEs), which often lead to therapy discontinuation. Because ezetimibe is associated with fewer MRSEs, it can be used as an alternative lipid-lowering agent for statin-intolerant patients. 

PCSK9 inhibitors are a newer class of cholesterol-lowering drugs that increase the liver's ability to remove LDL-C from the blood. They are usually reserved for patients with very high cholesterol levels or those who cannot achieve their targets with statins and ezetimibe. Compared to ezetimibe, PCSK9 inhibitors are injectable and more expensive, but they offer a substantial LDL-C reduction of 55-60%.

*Cost classifications are approximate and can vary based on insurance coverage, location, and specific healthcare plans. Patients should consult with their healthcare providers and insurance representatives for precise cost information.

Common Questions about Ezetimibe (Zetia)

1. Can ezetimibe be used alone?

Ezetimibe can be used as monotherapy to lower LDL-C levels. However, it is often more effective when combined with a statin, especially in patients who require significant cholesterol reduction or who have a high risk of cardiovascular events.

2. How long should I take ezetimibe?

Ezetimibe is typically taken long-term as part of a cholesterol management plan. Taking the medication as prescribed by your healthcare provider maintains its cholesterol-lowering effects and reduces cardiovascular risk.

3. Does ezetimibe interact with other medications?

Ezetimibe holds the potential to interact with fibrates, bile acid sequestrants, cyclosporine, and warfarin. Drug interactions can increase the risk of side effects and interfere with treatment efficacy. Inform your doctor of all medications and supplements you are taking before starting ezetimibe to avoid potential interactions. 

Is Ezetimibe (Zetia) Right for You? Consulting Your Healthcare Provider

Managing high cholesterol often requires a comprehensive approach that includes medication, lifestyle modifications, and regular monitoring. Ezetimibe offers a promising treatment option for patients who:

• Have high LDL-C levels despite being on maximally tolerated statin therapy
• Cannot tolerate statins due to side effects
• Have familial hypercholesterolemia

Open discussions with your healthcare provider help determine if ezetimibe is the right choice for your individual health needs. Consider asking your doctor the following questions when discussing ezetimibe: 

1. Is ezetimibe appropriate for my cholesterol levels and overall health?
2. What are the potential benefits and risks of taking ezetimibe?
3. How does ezetimibe interact with my current medications?
4. What lifestyle changes should I implement alongside taking ezetimibe?
5. How will my cholesterol levels be monitored while on ezetimibe?

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Key Takeaways

• Ezetimibe (Zetia) is a lipid-lowering medication that can successfully lower high cholesterol levels and reduce the risk of adverse cardiovascular events, especially for patients who do not achieve optimal results with statins alone. 
• Its favorable side effect profile and compatibility with other cholesterol-lowering therapies make it a versatile option in integrative cholesterol management plans.
• If you or someone you know is struggling with high cholesterol, consider sharing this guide and consulting a healthcare provider to explore whether ezetimibe might be an appropriate addition to your treatment regimen.