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.
Disclaimer: By writing this post, we are not recommending this drug. Some of our readers requested that we commission a post on it and we are providing a summary of the information available in the scientific and clinical literature, along with a list of evidence-based natural alternatives. Please discuss your medications with your doctor.
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]:
- Fat-soluble vitamins A and D
- Bile acids
- Ethinyl estradiol (an estrogen drug used in birth control)
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) Lowering High Blood Fats (Hyperlipidemia)
Hyperlipidemia is a condition in which the blood levels of any or all fats (lipids) are increased, including triglycerides, total cholesterol, 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 .
In a meta-analysis with over 2,700 people, Zetia reduced LDL cholesterol by 18% and total cholesterol by 13% .
In 2 trials of over 3,500 people with hypercholesterolemia, Zetia lowered triglyceride levels by 5-8% [6, 27].
Fenofibrate is a fibrate drug that increases fat breakdown and the removal of fats from the blood and lowers LDL. It’s a drug often used in combination with Zetia and indicated for people with high triglycerides or combined hyperlipidemia [28, 29, 30].
Zetia combined with fenofibrate lowered blood triglycerides in 3 studies of over 800 people [31, 32, 33].
This combination also reduced LDL-cholesterol more than fenofibrate alone in clinical studies of over 900 people with combined hyperlipidemia [33, 34, 35].
Zetia added to statin therapy can lower triglycerides by an extra 5-8%, as seen in 6 clinical trials with ~6,000 people [36, 37, 38, 39, 40, 41].
2) High Blood 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 [42, 43, 4]:
- Inherited, due to a genetic mutation (in LDLR or APOB genes).
- Due to lifestyle, diet, drugs, diabetes or other diseases [42, 44, 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 total cholesterol by 15% over 2-12 weeks. It additionally decreased LDL-cholesterol in this population when combined with fenofibrate [6, 7, 8, 45, 46, 47, 48, 49, 32].
Zetia added to statins lowered LDL and total cholesterol by an extra 16-25% in multiple clinical trials of over 7,500 people [36, 50, 51, 37, 38, 52, 39, 53, 40, 41, 54, 55, 56, 57, 58, 49, 59, 60, 61, 62].
In 48 people with HIV, Zetia decreased LDL levels by only 5% after 6 weeks .
In animals, Zetia prevented cholesterol absorption in the intestines by up to 95% [64, 65, 66, 67].
Aside from reducing LDL, Zetia can slightly increase HDL cholesterol in people with high LDL and low HDL. Zetia increased HDL-cholesterol levels by 1-3.5% in 5 clinical trials and analyses of over 5,000 people [6, 7, 45, 48, 27].
Added to statins, it increased HDL cholesterol by an extra 1-3% in trials of almost 7,000 people [36, 37, 38, 39, 53, 40, 41, 55, 56, 60].
3) 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 [68, 9, 11, 69, 70].
Zetia can decrease the absorption of plant sterols in the intestine and reduce their blood levels. It also decreases fatty lumps, cholesterol, and risk of heart disease [9, 10, 11, 69, 70].
In a clinical trial of 37 people with sitosterolemia, Zetia decreased sitosterol levels by 21% compared to placebo .
Possibly Effective for:
1) Preventing 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 [72, 73, 74].
In a clinical trial on 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, 75].
Zetia and statins also decreased the plaque degeneration of arteries in an analysis of 583 people .
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 .
Although some negative results exist, the evidence overall suggests that Zetia may help prevent heart disease when prescribed for lowering blood fat levels.
2) 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 .
Similarly, the combination of Zetia with different statins was more effective at lowering several inflammation markers (especially CRP, but also IL-6, MMP-9, ICAM-1, and prostaglandins) than either drug alone in multiple trials on over 800 people with high blood fats and heart disease [77, 78, 79, 80, 81, 82, 83, 84].
In a clinical trial on 20 people with rheumatoid arthritis, the combination of Zetia and simvastatin reduced an inflammatory marker (CRP) and disease activity while improving blood vessel function .
Again, the evidence suggests that Zetia may lower inflammatory markers when prescribed for high blood fat levels. More clinical research is needed to determine the effectiveness and safety of using it for inflammatory conditions such as rheumatoid arthritis.
Insufficient Evidence for:
Fatty Liver Disease
In the first clinical trial conducted (on 45 people with non-alcoholic fatty liver disease), both monovastatin alone and its combination with Zetia reduced liver damage markers (ALT and AST) .
However, Zetia alone failed to lower liver fat in a clinical trial on 50 people with non-alcoholic fatty liver disease and improved tissue scar but even increased fat buildup in the liver in a trial on 80 people with this condition. A review of 3 clinical trials concluded that Zetia only improves liver scar but has no effect on liver fat levels in people with non-alcoholic fatty liver disease [87, 88, 89].
Taken together, very limited evidence suggests that Zetia may help with tissue scarring but not with fat buildup in people with fatty liver disease. What’s more, some evidence suggests it may cause liver damage in rare cases (see the section below). Further clinical research on the safety and effectiveness of Zetia in people with non-alcoholic liver disease is needed.
This list does not cover all possible side effects. Contact your doctor or pharmacist if you notice any other side effects.
Call your doctor for medical advice about side effects. In the US, you may report side effects to the FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch. In Canada, you may report side effects to Health Canada at 1-866-234-2345.
The potential side effects of Zetia vary according to dosage and length of treatment and may include [2, 3, 50, 41, 58, 90, 91]:
- Body pain or swelling
- Skin rash
- Back, stomach, or chest pain
- Chills or stuffy nose
- 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 [92, 93].
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 [94, 95, 96, 97, 98, 99, 100].
Increased levels of AST and ALT liver enzymes point to liver damage .
Zetia together with statin therapy can increase the levels of these liver enzymes [102, 103, 104].
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 [105, 91, 106, 107, 108].
Zetia may have caused pancreas damage in 2 people [108, 109].
The combination of Zetia with statins is not recommended in people with liver disease or those with increased liver transaminase levels [104, 107].
Pregnancy and Breastfeeding
There are no clinical studies with Zetia in pregnant or breastfeeding women. Therefore, Zetia is not recommended in these situations .
There is a lack of clinical trials with Zetia in children under 10 years old. Therefore, the use of Zetia is not recommended [110, 111, 104].
To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you’re taking. Talk to your healthcare provider to find out how Zetia might interact with something else you are taking.
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 .
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 [110, 2, 50].
Cyclosporine is an immunosuppressive drug usually given before an organ transplantation to prevent organ rejection .
In 3 small clinical studies on 20 people, the combination of cyclosporine and Zetia increased the blood levels of both drugs [114, 115, 110].
Caution is advised when both drugs are taken simultaneously.
Fibrates, such as fenofibrate and gemfibrozil, are fat-lowering drugs. They can lower LDL cholesterol and triglycerides, and increase HDL cholesterol .
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 .
In a clinical trial on 32 people, fenofibrate increased the concentration and blood levels of Zetia, although the safety and effectiveness of the drugs did not change .
In another trial on 12 people, gemfibrozil increased Zetia blood levels, although both drugs were well tolerated .
If added to warfarin, bleeding should be closely monitored (INR).
Zetia is a tablet for oral use. The recommended dose is 10 mg daily for both adults and children older than 10 years old. Below this age, the use of Zetia is not recommended [1, 6, 2, 50, 12].
People who use Zetia should also follow a cholesterol-lowering diet. Zetia can be taken with or without food [2, 1, 3, 50].
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, 50].
Zetia can block the activity of CYP3A4 and CYP2C8 [118, 104].
Zetia decreases the production of the NPC1L1 (Niemann-Pick C1-Like 1) protein 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 [119, 120, 121]
Potential Natural Alternatives to Zetia
Zetia can lower cholesterol levels by blocking cholesterol absorption in the gut. There are several substances and herbs that may also lower cholesterol levels through similar mechanisms. You may try these complementary approaches if your doctor determines that they may be appropriate in your case. Note, however, that none of them should ever be taken in place of what your doctor recommends or prescribes.
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 [122, 123, 124, 125].
In several trials of almost 7k people, fibers reduced LDL-cholesterol by 5-7% [126, 127, 128, 129, 130].
Fiber may cause bloating, burping or gas, but is well-tolerated and causes no serious side effects .
2) 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 [132, 133].
Plant sterols include campesterol, beta-sitosterol, stigmasterol, avenasterol, brassicasterol, and beta-sitostanol [132, 133].
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 [134, 135, 136, 137].
In multiple clinical trials on over a million people, 2 g/day of plant sterols decreased LDL cholesterol by 9-14% compared to placebo [138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164].
While plant sterols may help lower blood cholesterol in people with hypercholesterolemia or hyperlipidemia, people with high blood levels of these compounds (sitosterolemia) should avoid them.
Probiotics promote digestive health, but specific probiotics can also bind to NPC1L1 and block the absorption of cholesterol in the intestine [165, 166].
In a meta-analysis of over 2,300 people, probiotics decreased total cholesterol (by ~8 mg/dL), and LDL cholesterol (by ~7 mg/dL) [167, 168].
In a clinical trial on 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% .
Berberine is an extract of the plant Berberis vulgaris L. that has been used since ancient times [170, 171].
In a clinical trial on 228 people, berberine decreased LDL-cholesterol by ~32 %, whereas Zetia decreased LDL-cholesterol by only 25%. Moreover, berberine was better tolerated than Zetia .
In a 12-week clinical trial of 7 people, 500 mg 3X day berberine reduced total cholesterol levels by 12% and triglycerides by 23% .
In an observational study with over 2,500 people, berberine had no serious side effects and lowered triglycerides and increased HDL cholesterol better than typical cholesterol-lowering drugs .
In rats, berberine decreased total cholesterol by 9% and triglycerides by 34.7% .
5) Stearic Acid
Stearic acid is a fatty acid found in vegetables, oils, and animal fats. Foods rich in stearic acid include :
- 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 [176, 177].
In a systematic review of studies on 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 [178, 179, 180, 181, 182, 183, 184].
However, stearic acid is a saturated fat and can cause insulin resistance.
Phospholipids are key structural and functional components of cell membranes in all animals and plants. They determine what enters and what exits every cell [185, 186].
Dietary phospholipids include phosphatidylcholine, lecithin, and sphingomyelin .
Phospholipids can block the absorption of cholesterol in the intestine and decrease cholesterol levels in the blood .
In a clinical trial on 30 people, lecithin decreased LDL cholesterol by 56% and total cholesterol by 42%. Similarly, fat-free foods supplemented with soy lecithin lowered cholesterol absorption and blood LDL cholesterol levels in a clinical trial on 45 people .
Dietary sphingomyelin, lecithin, and phosphatidylcholine reduced cholesterol absorption and decreased blood cholesterol levels in multiple animal studies [190, 191, 192, 193, 194, 195, 196, 197, 198, 199].
Phospholipids are found in foods rich in lecithin, such as [187, 200, 188]:
- 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
Although the results are promising, most of the evidence to back the cholesterol-lowering effects of dietary phospholipids comes from animal studies. Larger, more robust clinical trials are needed to confirm these preliminary findings.
Guggulu is a plant resin from the Guggul tree (Commiphora wightii) that grows in India. It has been used since ancient times to reduce inflammation, obesity, and metabolic disorders .
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 [202, 203, 204].
In 2 clinical trials on 120 people with hyperlipidemia, guggulu decreased total cholesterol by 6-12%, triglycerides by 12-17%, LDL by 12.5%, and VLDL by 18% [205, 206].
However, guggulu (standardized to 2.5% guggulsterones) taken for 8 weeks didn’t improve blood LDL cholesterol levels and even raised them in a clinical trial on 100 people. Another trial on 43 women found guggulu only effective at lowering total cholesterol, but not triglycerides and LDL cholesterol. Additionally, it caused several side effects [207, 208].
Guggulu lowered blood cholesterol levels in rabbits and chickens [209, 210].
A few clinical trials with mixed results and some animal research cannot be considered sufficient evidence to attest to the effectiveness of guggul at lowering blood cholesterol. More clinical research is required to shed some light on this potential remedy.
Policosanols are a mix of long-chain alcohols from purified sugar cane .
In a clinical trial on 89 people with hypercholesterolemia, 20 mg/day policosanols reduced LDL-cholesterol by 27% and total cholesterol by 15% after 24 weeks .
In another trial on 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 .
However, policosanols did not affect blood fat levels in a trial on 54 people with HIV .
Again, a few clinical trials with mixed results are insufficient to conclude for certain that policosanols help with blood cholesterol. More clinical trials are needed before drawing firm conclusions.
Animal Research (Lack of Evidence)
No clinical evidence supports the use of the following substances to lower blood cholesterol levels. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies should not be interpreted as supportive of any health benefit.
Alkylresorcinols are fats in wheat and rye grains .
Wheat alkylresorcinols blocked cholesterol absorption in the intestine and lowered cholesterol levels in mice [216, 217].
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. Some of them have only been tested in an insufficient number of clinical trials.