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].
Mechanism of Action
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].
- 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)
- 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% .
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].
2) Reducing High LDL-Cholesterol (Hypercholesterolemia)
- Inherited, due to a genetic mutation (in LDLR or APOB gene).
- Due to lifestyle, diet, drugs, diabetes or other diseases [34, 36, 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 .
2) 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].
4) May Decrease Heart Disease Risk
Zetia may reduce heart disease risk, but this is still uncertain. It prevents heart complications in specific populations only.
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 .
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 .
5) 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].
In a clinical trial of 37 people with sitosterolemia, Zetia decreased sitosterol levels by 21% compared to placebo .
6) 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 .
- 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
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].
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].
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 .
Bile Acid Sequestrants
Cyclosporine is an immunosuppressive drug usually given before organ transplantations to prevent organ rejection .
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 .
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 32 people, fenofibrate increased the concentration and blood levels of Zetia, although the safety and effectiveness of the drugs did not change .
In 12 people, gemfibrozil increased Zetia blood levels, although both drugs were well tolerated .
If added to warfarin, bleeding should be closely monitored (INR).
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.
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].
Fiber may cause bloating, burping or gas, but is well tolerated and with no serious side-effects .
Phospholipids can block the absorption of cholesterol in the intestine and decrease cholesterol levels in the blood .
In 30 people, lecithin decreased LDL cholesterol by 56% and total cholesterol by 42% .
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, 126, 132, 133].
- 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
3) Plant Sterols
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).
In 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, 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% .
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 :
- Beef fat
- Butter substitutes, such as oils from cocoa and nuts
- Kokum fruits and mango oil
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].
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% .
Policosanols are a mix of long-chain alcohols from purified sugar cane .
In 89 people with hypercholesterolemia, 20mg/day policosanols reduced LDL-cholesterol by 27% and total cholesterol by 15% after 24 weeks .
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 . However, in 54 people with HIV, policosanols did not affect blood fat levels .
9) Alkylresorcinols (Animals)
Alkylresorcinols are fats in wheat and rye grains .
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.