Evidence Based

Zetia (Ezetimibe) Uses, Side Effects + 9 Natural Alternatives

Written by Anastasia Naoum, MS (Health Informatics) | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Anastasia Naoum, MS (Health Informatics) | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Zetia is a prescription drug indicated primarily for lowering total and LDL cholesterol, but can also decrease triglycerides and increase HDL cholesterol. It may also prevent heart disease. Read on to learn more about its dosage, uses, side effects, and natural alternatives.

What is Zetia (Ezetimibe)?

Zetia is the brand name of ezetimibe, a drug that lowers high cholesterol levels and plant sterols. It is a prescription drug in the form of an oral tablet. It can be used alone or in combination with other cholesterol-lowering drugs, such as statins. It should always be used alongside a diet low in saturated fats [1, 2, 3, 4].

Zetia can lower total cholesterol, LDL cholesterol, apolipoprotein B, and triglyceride levels [1, 2, 3, 5].

It is used to treat hypercholesterolemia (very high levels of LDL cholesterol) and sitosterolemia (very high levels of plant sterols) [6, 7, 8, 9, 10, 11].

It may also prevent heart diseases and decrease the risk of heart-related deaths [12, 13, 14].

Mechanism of Action

NPC1L1 (Niemann-Pick C1-Like 1) is a protein that transports sterols and cholesterol across the gut lining and absorbs them in the body [15, 16, 17].

Zetia binds to NPC1L1 and blocks the absorption of cholesterol and plant sterols in the intestine. Since less cholesterol is absorbed, less of it is delivered to the liver. This means that less cholesterol can be stored in the liver and more of it is cleared from the blood. The end result is lower cholesterol blood levels [16, 17, 18, 3, 1].

Overall, Zetia decreases total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides [1, 2, 3, 5].

Zetia does not affect the absorption of [3, 19, 20]:

Uses of Zetia (Ezetimibe)

Zetia is indicated for:

  • Hyperlipidemia, high levels of blood fats
  • Hypercholesterolemia, with high LDL cholesterol levels
  • Sitosterolemia, high plant sterol levels

Zetia can also increase HDL cholesterol levels, and reduce heart disease risk and complications in some populations [1].

1) Lowering High Blood Fats (Hyperlipidemia)

Hyperlipidemia is a condition in which the blood levels of any or all fats (lipids) are increased, including total, LDL, VLDL cholesterol and ApoB. It can be [21, 22, 23, 24]:

  • Familial, caused by genetic mutations (in APOB, LDLR, LDLRAP1, and PCSK9 genes)
  • Non-familial, caused by lifestyle, diet, drugs, metabolic or chronic diseases [25, 23].
  • Combined hyperlipidemia, caused by genetic mutations that increase both cholesterol and triglycerides [26].

In a meta-analysis with over 2,700 people, Zetia reduced LDL cholesterol by 18% and total cholesterol by 13% [27].

Fenofibrate is a fibrate drug that increases fat breakdown and the removal of fats from the blood and lowers LDL. It’s drug often used in combination with Zetia and indicated for people with high triglycerides or combined hyperlipidemia [28, 29, 30].

In clinical studies of over 900 people with combined hyperlipidemia, Zetia with fenofibrate reduced LDL-cholesterol more than fenofibrate alone [31, 32, 33].

2) Reducing High LDL-Cholesterol (Hypercholesterolemia)

Hypercholesterolemia is a type of hyperlipidemia that mostly affects LDL-cholesterol (>130 mg/dl) and increases the risk of heart diseases and stroke. It’s either [34, 35, 4].

  • Inherited, due to a genetic mutation (in LDLR or APOB gene).
  • Due to lifestyle, diet, drugs, diabetes or other diseases [34, 36, 25].

In clinical trials of over 2,500 people with the inherited type, Zetia (10 mg/day) decreased LDL-cholesterol levels by up to 20% and the total cholesterol by 15% over 2 – 12 weeks. It additionally decreased LDL-cholesterol in this population when combined with fenofibrate [6, 7, 8, 37, 38, 39, 40, 41, 42].

Zetia added to statins lowers LDL and total cholesterol by an extra 16 – 25%, according to many clinical trials of over 7,500 people [43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 41, 58, 59, 60, 61].

In 48 people with HIV, Zetia decreased LDL levels by only by 5% after 6 weeks [62].

In animals, Zetia prevented the absorption of the cholesterol in the intestines by up to 95% [63, 64, 65, 66].

3) Increasing HDL-Cholesterol

Aside from reducing LDL, Zetia can slightly increase HDL cholesterol in people with high LDL and low HDL. Zetia increases HDL-cholesterol levels by 1 – 3.5%, according to clinical trials and analyses of over 5,000 people [6, 7, 37, 40, 27].

Added to statins, it increased HDL cholesterol by an extra 1-3% in trials of almost 7,000 people [43, 46, 47, 49, 50, 51, 52, 54, 55, 59].

4) Triglycerides

In trials of over 3,500 people with hypercholesterolemia, Zetia lowers triglyceride levels by 5 – 8% [6, 27].

Zetia added to statin therapy lowers triglycerides by an extra 5 – 8%, according to clinical trials with ~6,000 people [43, 46, 47, 49, 51, 52].

It also additionally lowers triglycerides combined with fenofibrate, based on studies of over 800 people [67, 42, 31].

5) May Decrease Heart Disease Risk

Zetia may reduce heart disease risk, but this is still uncertain. It prevents heart complications in specific populations only.

High LDL-cholesterol increases the risk of heart disease while reducing it in time can decrease this risk and heart-related deaths [68, 69, 70].

In a clinical trial with over 18,000 people with heart disease, Zetia together with statin therapy reduced the risk of stroke. In 9,000 people with kidney disease, this combination decreased the risk of heart-related deaths and complications, such as heart attack and stroke [13, 14, 71].

Zetia and statins also decreased the plaque degeneration of arteries in an analysis of 583 people [61].

However, in a clinical study of ~2,000 people, Zetia added to statin therapy did not decrease heart-related deaths or complications such as heart disease, heart failure, and stroke [72].

6) Improving Sitosterolemia (High Plant Sterol Levels)

Plant sterols or phytosterols are fats from vegetable oils, nuts, and other plant-based foods. Sitosterolemia is a rare genetic disorder that causes high plant sterol levels in the blood and tissues. It leads to abnormally high cholesterol, fatty lumps under the skin (xanthomas), hardening of the arteries (atherosclerosis) or anemia [73, 9, 11, 74, 75].

Zetia can decrease the absorption of plant sterols in the intestine and can reduce their blood levels. It also decreases fatty lumps, cholesterol, and risk of heart disease [9, 10, 11, 74, 75].

In a clinical trial of 37 people with sitosterolemia, Zetia decreased sitosterol levels by 21% compared to placebo [76].

7) Lowering Inflammatory Markers

Consumption of fat cream increased the production of inflammatory proteins (IL-1b, MMP-9, TNFa) in 20 obese people. Zetia together with a statin (simvastatin) blocked the expression of these inflammatory proteins [58].

Side Effects

The potential side-effects of Zetia vary according to dosage and length of treatment and may include [2, 3, 44, 52, 57, 77, 78]:

  • Body pain or swelling
  • Skin rash
  • Back, stomach or chest pain
  • Chills or stuffy nose
  • Constipation
  • Diarrhea
  • A cough or a sore throat
  • Moving with difficulty
  • Muscle pain or stiffness
  • Back or joint pain
  • Pain or tenderness around eyes and cheekbones
  • Shortness of breath or difficulty breathing
  • Difficulty swallowing
  • Dizziness, unusual tiredness or weakness
  • Increased liver enzymes (transaminases)

Muscle Pain and Injury

Creatine kinase is an enzyme essential for muscle function. Increased creatine kinase points to muscle, brain, or heart injury [79, 80].

10 cases have been reported of increased creatine kinase and muscle pain (myopathy) in people taking Zetia. In all cases, the muscle pain decreased and creatine kinase levels returned to normal after stopping Zetia [81, 82, 83, 84, 85, 86, 87].

Liver Damage

Increased levels of AST and ALT liver enzymes point to liver damage [88].

Zetia together with statin therapy can increase liver these enzymes [89, 90, 91].

At least 6 cases have been reported of high liver ALT or AST levels and liver injury in people taking Zetia. Zetia may be toxic to the liver and in rare cases can cause liver damage [92, 78, 93, 94, 95].

Pancreas Damage

Zetia may have caused pancreas damage in 2 people [95, 96].


The combination of Zetia with statins is not recommended in people with liver disease or people with increased liver transaminase levels [91, 94].

Pregnancy and Breastfeeding

There are no clinical studies with Zetia in pregnant or breastfeeding women. Therefore, Zetia is not recommended in pregnancy and in breastfeeding [97].


There is a lack of clinical trials with Zetia in children under 10 years old, therefore, the use of Zetia is not recommended [97, 98, 91].

Drug Interactions

Bile Acid Sequestrants

Bile acid sequestrants are drugs that lower LDL cholesterol by blocking the absorption of bile acids. These drugs include cholestyramine and colestipol [99].

Cholestyramine can reduce the effectiveness of Zetia. Generally, Zetia should be taken at least 2 hours before or at least 4 hours after taking cholestyramine [97, 2, 44].


Cyclosporine is an immunosuppressive drug usually given before organ transplantations to prevent organ rejection [100].

In clinical studies on 20 people, cyclosporine increased Zetia blood levels and Zetia increased cyclosporine blood levels [101, 102, 97].

Caution is advised when both drugs are taken.


Fibrates, such as fenofibrate and gemfibrozil, are fat-lowering drugs. They can lower LDL cholesterol and triglycerides, and increase HDL cholesterol [103].

Caution is advised when Zetia is taken with fibrates. Although Zetia is often prescribed with fenofibrate, your doctor and pharmacist will make sure that the dosages are adequately adjusted [98].

In 32 people, fenofibrate increased the concentration and blood levels of Zetia, although the safety and effectiveness of the drugs did not change [67].

In 12 people, gemfibrozil increased Zetia blood levels, although both drugs were well tolerated [104].


If added to warfarin, bleeding should be closely monitored (INR).


Zetia is a tablet for oral use. In most trials, the dosage for Zetia was 10mg daily [1, 6, 2, 44, 12].

People who use Zetia should also follow a cholesterol-lowering diet. Zetia can be taken with or without food [2, 1, 3, 44].

In case you take bile acid sequestrants (cholesterol-lowering drugs), you should take Zetia at least 2 hours before or at least 4 hours after taking the other drug [2, 44].


Zetia can block the CYP3A4 and CYP2C8 activity [105, 91].

Zetia decreases the production of NPC1L1 (Niemann-Pick C1-Like 1) gene but increases the production of:

  • LDLR (low-density lipoprotein receptor)
  • SREBP-2, a protein which activates genes involved in cholesterol production
  • HMG-CoAR, an enzyme responsible for cholesterol production [106, 107, 108]

Natural Alternatives to Zetia (Ezetimibe)

Zetia can lower cholesterol levels by blocking cholesterol absorption in the gut, but has its side-effects and contradictions. Many natural alternatives can also safely lower cholesterol levels. Please consult your doctor before trying any of these if you are taking cholesterol-lowering drugs.

1) Fiber

Fiber can decrease LDL cholesterol levels by preventing cholesterol absorption in the intestine. Water-soluble fibers include pectin, beta-glucans, fructans, gums, and resistant starch. [109, 110, 111, 112].

In clinical trials of almost 7k people, fibers reduced LDL-cholesterol by 5 – 7% [113, 114, 115, 116, 117].

Fiber may cause bloating, burping or gas, but is well tolerated and with no serious side-effects [118].

2) Phospholipids

Phospholipids are key structural and functional components of cell membranes in all animals and plants. They determine what enters and what exits every cell [119, 120].

Dietary phospholipids include phosphatidylcholine, lecithin, and sphingomyelin [121].

Phospholipids can block the absorption of cholesterol in the intestine and decrease cholesterol levels in the blood [122].

In 30 people, lecithin decreased LDL cholesterol by 56% and total cholesterol by 42% [123].

Dietary sphingomyelin, lecithin, and phosphatidylcholine reduced cholesterol absorption and decreased blood cholesterol levels in rats and mice [124, 125, 126, 127, 128, 129, 130, 131, 132, 133].

Phospholipids are found in foods rich in lecithin, such as [121, 134, 122]:

  • Egg yolk
  • Organ meats: Pig and chicken liver
  • Meats: chicken breast, beef
  • Vegetables: spinach, carrots
  • Seafood: Squid and cod
  • Vegetable oils
  • Soy and peanuts
  • Wheat germ
  • Apples
  • Milk

3) Plant Sterols

Plant sterols are present in vegetables and vegetable oils (corn oil, canola oil, soybean oil, and sunflower oil), nuts, and some cereals. They are also available as supplements [135, 136].

Plant sterols include campesterol, beta-sitosterol, stigmasterol, avenasterol, brassicasterol, and beta-sitostanol [135, 136].

In the gut, plant sterols take the place of cholesterol in the fat micelles that dissolve fats and help absorb them. This way, plant sterols reduce the amount of absorbed cholesterol [137, 138, 139, 140].

In clinical trials with over a million people, 2 g/day of plant sterols decreased LDL cholesterol by 9 – 14% compared to placebo [141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167].

Caution: Not recommended for people with high plant sterol levels (sitosterolemia).

4) Probiotics

Probiotics promote digestive health, but specific probiotics can also bind to NPC1L1 and block the absorption of cholesterol in the intestine [168, 169].

In a meta-analyses of over 2,300 people, probiotics decreased total cholesterol (by ~8 mg/dL), and LDL cholesterol (by ~7 mg/dL) [170, 171].

In 127 people with high cholesterol, one probiotic (Lactobacillus reuteri NCIMB 30242) lowered LDL cholesterol by 11%, total cholesterol by 9%, other non-HDL-cholesterols by 11% and ApoB by 8% [172].

5) Berberine

Berberine is an extract of the plant Berberis Vulgaris L. that has been used since ancient times [173, 174].

In 228 people, berberine decreased LDL-cholesterol by ~32 %, whereas Zetia decreased LDL-cholesterol by only 25%. Moreover, berberine was better tolerated than Zetia [175].

In a 12-week clinical trial of 7 people, 500 mg 3X day berberine reduced total cholesterol levels by 12% and triglycerides by 23% [176].

In an observational study with over 2,500 people, berberine had no serious side effects, lowered triglycerides and increased HDL cholesterol better than typical cholesterol-lowering drugs [177].

In rats, berberine decreased total cholesterol by 9% and triglycerides by 34.7% [176].

Aside from these top 5 natural alternatives, there are a few others with less clear mechanisms of action or fewer clinical data to support their use, such as:

6) Stearic Acid

Stearic acid is a fatty acid found in vegetables, oils, and animal fats. Foods rich in stearic acid include [178]:

  • Beef fat
  • Butter substitutes, such as oils from cocoa and nuts
  • Kokum fruits and mango oil

Stearic acid can decrease cholesterol absorption and lower LDL cholesterol [179, 180].

In a systematic review of over 700 people, stearic acid used as a replacement for trans fatty acids in the diet decreased LDL cholesterol. It also reduced cholesterol absorption in rats and hamsters [181, 182, 183, 184, 185, 186, 187].

However, stearic acid is a saturated fat and can cause insulin resistance.

7) Guggul

Guggulu is a plant resin from the Guggul tree that grows in India (Commiphora wightii). It has been used since ancient times to reduce inflammation, obesity, and metabolic disorders [188].

Guggulu binds to FXR (farnesoid X receptor), a key hormone receptor for cholesterol breakdown activated by bile acids. It increases cholesterol breakdown and clearance from the body, which lowers blood cholesterol [189, 190, 191].

In 59 people with hyperlipidemia, guggulu decreased total cholesterol by ~6%, triglycerides by 17%, and VLDL by 18% [192].

Guggulu also lowered blood cholesterol levels in rabbits and chickens [193, 194].

8) Policosanols

Policosanols are a mix of long-chain alcohols from purified sugar cane [195].

In 89 people with hypercholesterolemia, 20mg/day policosanols reduced LDL-cholesterol by 27% and total cholesterol by 15% after 24 weeks [196].

In 29 people with type 2 diabetes and high cholesterol, 10 mg/day policosanols lowered total cholesterol by 17% and LDL cholesterol by 22% after 6 weeks [197]. However, in 54 people with HIV, policosanols did not affect blood fat levels [198].

9) Alkylresorcinols (Animals)

Alkylresorcinols are fats in wheat and rye grains [199].

Wheat alkylresorcinols blocked the cholesterol absorption in the intestine and lowered cholesterol levels in mice [200, 201].

Limitations and Caveats

There are plenty of clinical trials examining the effectiveness of Zetia. Most people included had heart problems or other diseases. There is a lack of studies in pregnant and breastfeeding women and children.

The listed natural alternatives have a similar mechanism of action as Zetia, based on clinical and animal studies. However, they have only been studied in people with high blood fats due to lifestyle factors. None have been tested in people with familial high cholesterol or triglyceride levels.

Want More Targeted Ways to Improve Heart Health?

If you’re interested in natural and more targeted ways of improving heart health, we at SelfHacked recommend checking out this cardiovascular wellness report. It gives genetic-based diet, lifestyle and supplement tips that can help improve your heart health. The recommendations are personalized based on your genes.

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About the Author

Anastasia Naoum

MS (Health Informatics)
Anastasia holds an MSc in Health Informatics from the Sheffield University, an MSc in Health Economics from the Erasmus University of Rotterdam and a BSc in Economics from the University of Macedonia.
Anastasia grew up in a medical environment, as both her parents are doctors and developed from a young age a passion for medicine and health. She has worked in several institutions and associations which promoted healthy living and sustainable healthcare systems. Currently, she is leading a green life, sailing with her boyfriend across Europe, living in their sailboat with the help of solar and wind power, minimizing CO2 production.

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