What Are Non-Statin Cholesterol Medications?

Cholesterol is a waxy, fatty substance that travels through our bloodstream. It’s crucial for many body functions, but having too much can be dangerous for our health. 

High cholesterol levels are linked to increased low-density lipoprotein (LDL) and/or decreased high-density lipoprotein (HDL) cholesterol levels. 

This scenario is worrying because LDL cholesterol, commonly known as “bad” cholesterol, can form plaques in the arteries. This hardens and stiffens the arteries, which means the heart needs to work harder to pump blood around the body. This increases the risk of developing heart disease, heart attack, or stroke.

Fortunately, safe and effective medications are available to reduce cholesterol. 

Types of cholesterol-lowering drugs

Most cholesterol-lowering drugs are prescription medications, which means one needs to see a doctor to access them. 

Statins are the most well-known cholesterol medication class, but many non-statin medications are also available. 

Statins

Statins are HMG-CoA reductase inhibitors. They block the HMG-CoA reductase activity, a crucial substance in transforming the fat we ingest into cholesterol. Note, however, that statins are not a cure. 

By blocking this HMG-CoA, statins reduce LDL cholesterol and help reabsorb the existing cholesterol. Statins also help with cardiovascular health, preventing heart attacks and strokes, which is essential for people with high cholesterol. By reabsorbing the cholesterol plaques, statins help prevent clots from forming, which otherwise could travel to the heart or brain. 

 Numerous types of statins are available, all of which work in the same way. These include:

• Lipitor (atorvastatin)

• Crestor (rosuvastatin) 

• Zocor (simvastatin)

• Lescol (fluvastatin) 

• Altoprev (lovastatin)

• Livalo (pitavastatin)

• Pravachol (pravastatin) 

Non-statins

Many types of non-statin therapies are available, including the following:

• PCSK9 inhibitors, such as Praluent and Repatha

• Cholesterol absorption inhibitors, such as Zeita 

• Fibrates, such as gemfibrozil and clofibrate

• Bile-acid-binding resins, such as Cholestyramine and Colesevelam

• Omega-3 fatty acid supplements, like fish oil

• Nicotinic acid derivatives (vitamin B3)

• MTP inhibitors, such as Juxtapid 

• ACL inhibitors, such as bempedoic acid 

Non-statin therapies also include alternatives to medications or supplements, such as:

• Making dietary changes (limiting saturated and trans fats)

• Exercising regularly

• Quitting smoking

• Undergoing LDL apheresis, which is a medical procedure that removes LDL cholesterol from the blood and returns the filtered blood to the body

• Losing weight 

Why are statins the first-choice medications?

Statins are commonly considered the gold standard for managing cholesterol and are often the first-choice medication for treating high cholesterol. 

This is because, by lowering LDL cholesterol, statins have been shown to reduce the risk and development of cardiovascular complications, such as heart attacks and atherosclerosis, by 20% to 40%.¹ 

When are non-statin therapies recommended?

Non-statin therapies are sometimes used as adjuvants to statins. In other cases, they’re used instead of statins. This will likely depend on the person’s personal medical history. 

Non-statin therapies are often prescribed as a secondary prevention treatment option and are recommended in several situations. Some people may prefer them for cost and personal preference.

Medical reasons for someone wanting to try non-statins include: 

If the response isn’t clinically meaningful with statins alone 

People who don’t have a sufficient response when using statins alone may be prescribed one or more non-statin therapy to reduce their cholesterol further. This may be particularly important for people who need to reduce their risk of cardiovascular-related complications. 

It’s also advised for people with familial hypercholesterolemia² (FH), who often need to reduce their LDL cholesterol by at least 50%. This may not be achievable with statins alone. 

If the person is unable to take statins 

Statins are safe and effective for most people.

However, some people may be unable to take statins due to the concern that the drug will interact with other medications. Additionally, some people experience adverse side effects and are considered intolerant to statins. They may experience statin-associated muscle symptoms, new-onset diabetes, and possibly neurocognitive effects. 

Because of these effects, people may not adhere to their statin treatment, causing their cholesterol levels to rise again and indicating the need for alternative approaches. 

What non-statin cholesterol meds are worth considering?

Several alternatives to statins have been approved by the US Food and Drug Administration (FDA). 

These medications do not cure high cholesterol like statins, but they can help manage it. Usually, one still needs to adopt lifestyle changes, such as eating a low-fat and low-cholesterol diet and being physically active. 

Some of these medications include:

Ezetimibe (Zetia)

What is ezetimibe?

Ezetimibe (commercialized as Zetia) is the most common non-statin prescription medication for high cholesterol. It’s currently the non-statin therapy of choice, according to the American College of Cardiology (ACC). 

Who should take ezetimibe?

Ezetimibe³ is safe for those aged ten years and over. People who have had liver problems or are pregnant may not be able to take ezetimibe and should speak with their doctor before taking it. 

How effective is ezetimibe?

Ezetimibe was found to reduce LDL cholesterol by around 18%, reduce total cholesterol by about 13%, and increase HDL cholesterol by 3%. 

How does ezetimibe work?

Ezetimibe stops cholesterol from being absorbed into the body, preventing it from entering the bloodstream. 

This is done by inhibiting a sterol transporter, known as NPC1L1, located in the cells bordering the small intestine. By inhibiting this, ezetimibe increases the amount of cholesterol cleared from the blood, decreases the delivery of cholesterol to the liver, and reduces the liver’s cholesterol stores. This causes a reduction in total and LDL cholesterol and an increase in HDL cholesterol. 

Ezetimibe also has benefits for cardiovascular health. It is the only cholesterol absorption inhibitor approved by the FDA so far. 

How to take ezetimibe 

Ezetimibe is taken orally, at a dose of 10 mg⁴ daily. It can be taken with or without food. 

Ezetimibe can be taken as an alternative to statins, but it can also be taken in addition to them. It has a complementary mechanism and provides additional reductions in LDL cholesterol that might not be achieved with statins alone. 

The LDL-lowering effects of the combination of ezetimibe and statins are equivalent to those of high-dose statins alone. Thus, people who experience adverse reactions to higher doses of statins could consider taking a lower statin dosage alongside ezetimibe. 

After starting ezetimibe, it takes around two weeks for cholesterol levels to reduce noticeably. 

Side effects of ezetimibe 

Potential side effects of ezetimibe include:

• Gastrointestinal issues (such as diarrhea, passing more wind than usual, and stomach pain); severe stomach pain under the ribs can be a sign of pancreas problems

• Muscle pain, tenderness, and joint pain

• A runny or stuffy nose

• Feeling more fatigued than usual

• Allergic reaction, which might include trouble breathing; swelling on the face, mouth, and throat; and/or an itchy and red skin rash 

PCSK9 Inhibitors: Praluent and Repatha

What are PCSK9 inhibitors?

PCSK9 inhibitors⁵ are newer cholesterol medications. They’re monoclonal antibodies produced in a lab by cloning a white blood cell. They inactivate the proprotein convertase subtilisin (PCSK9),⁶ a protein in liver cells. 

Who should take PCSK9 inhibitors?

Most people with high cholesterol won’t need PCSK9 inhibitors. They’re typically recommended as a third-line treatment if:

• LDL cholesterol levels remain over 100 mg/d, despite taking both statins and ezetimibe

• The patient has multiple risk factors for cardiovascular disease

• LDL cholesterol levels remain above 70 mg/dL in someone with a very high risk of cardiovascular diseases, such as someone with familial hypercholesterolemia (FH); for people with homozygous FH, Repatha is usually the preferred PCSK9 inhibitor 

One reason PCSK9 inhibitors are only a third choice is that they aren’t cost-effective. The monthly cost is between $450 and $500. Thus, they may not be accessible to some people with high cholesterol. 

How do PCSK9 inhibitors work?

The PCSK9 protein controls the number of LDL receptors on the surface of cells by binding to the receptors and breaking them down. This prevents cholesterol from being removed from the bloodstream. 

People with high cholesterol tend to have high levels of PCSK9, while people with low cholesterol have low PCSK9 levels. 

Since PCSK9 inhibitors inactivate this protein, they prevent the receptors from being broken down, meaning more LDL cholesterol can be taken up and cleared from the bloodstream. 

How to take PCSK9 inhibitors

PCSK9 inhibitors can be combined with statins and ezetimibe or taken independently. 

PCSK9 inhibitors are given subcutaneously as injections under the skin. This is generally done once or twice a month. This can be done at a medical center, but you may also inject it yourself. A doctor can give you instructions on how to prepare the medication. 

The medication is injected into the stomach area, thighs, or upper arms. To prevent skin problems, alternate the site to be accessed, avoiding injecting in the same site twice in a row. The injection can be performed by a prefilled autoinjector (like a pen), a prefilled syringe, or an on-body infusor with a prefilled cartridge. 

Side effects of PCSK9 inhibitors 

The possible side effects of PCSK9 inhibitors are:

• Skin reactions, such as a rash, itching, redness, or irritation at the injection site; are generally mild, but an allergic reaction can also be severe and needs medical attention

• Headaches

• Cold- and flu-like symptoms, such as a fever, cough, headaches, and/or a sore throat

• Upper respiratory tract infections

• Nausea

• Muscle pain, such as backache

• Joint stiffness

• Urinary tract infections 

Recently, two PCSK9 inhibitors have been approved by the FDA, with more in development. 

Approved PCSK9 inhibitors

Praluent (alirocumab) 

Praluent is initially taken at a dose of 75 mg every two weeks. If the response is inadequate, the dose may be increased to 150 mg every two weeks. 

Alternatively, Praluent can be given as a 300-mg dose once every four weeks. 

A study found that 150 mg of Praluent taken every two weeks reduced LDL by 61% in people with high cholesterol who either had heterozygous FH and/or atherosclerotic cardiovascular disease. The participants in that study were already receiving high doses of statins. 

Repatha (evolocumab) 

The recommended dose of Repatha⁷ is 140 mg every two weeks or 420 mg once a month. The higher dose should be given over five minutes using a single-use infusor or injecting 140 mg three times in three different locations on the body. Children and adults with homozygous FH may tolerate a 420-mg dose every two weeks. 

People with homozygous FH are advised to use the higher and less frequent dose. 

Unlike Praluent, Repatha is also available for children with FH who are over the age of ten. 

Repatha has been shown to reduce LDL cholesterol levels by 54% and 71% in people with cardiovascular disease. Still, LDL levels can be reduced by 60% and 31% in people with heterozygous and homozygous FH, respectively. 

Cholestyramine and colesevelam

Cholestyramine and colesevelam are bile-acid-binding resins, also known as bile acid sequestrants. 

What are bile-acid-binding resins?

Cholestyramine and colesevelam bind to bile acids in the gut and prevent cholesterol from being absorbed into the bloodstream. Bile is a digestive fluid that’s produced in the liver. It helps digestion and fat absorption by breaking them down into their building blocks, fatty acids. 

Bile is usually reabsorbed and recycled in the body. However, cholestyramine and colesevelam form a cholesterol–bile complex. This complex is insoluble and is eliminated through one’s stool. 

Since this process also results in bile loss, the body converts cholesterol into bile acids. This further reduces the cholesterol in the blood. 

Side effects and risks 

Bile-acid-binding resins are one of the safest cholesterol-lowering medications for people who react negatively to statins. However, they can be poorly tolerated by others. 

The side effects are similar for both cholestyramine and colesevelam:

• Abdominal pain

• Heartburn and indigestion 

• Bloating and gas 

• Constipation 

• Diarrhea 

• Nausea 

• Vomiting 

• Headaches

• Weakness

• Muscle pain  

Bile-acid-binding resins are considered long-term medications. Nevertheless, some risks of long-term use are worth mentioning. 

First, they can interfere with the digestion and absorption of fat-soluble vitamins (A, D, and K). People with low levels of these vitamins may not be able to take bile-acid-binding resins. 

They can also interact negatively with other medications, such as warfarin, chlorothiazide, estrogen replacement, and penicillin. Finally, bile-acid-binding resins may lead to swelling of the pancreas (pancreatitis). 

People with complete biliary obstruction (blocked bile ducts) are advised to avoid these medications. 

Who should take them?

Bile-acid-binding resins are suitable for people with high cholesterol who don’t have a sufficient reduction in LDL levels when making dietary changes. 

Cholestyramine and colesevelam are not effective for people with homozygous FH. This is because homozygous FH is associated with having dysfunctional LDL receptors. These receptors are needed in the process of reducing cholesterol with bile-acid-binding resins. 

Approved bile-acid-binding resins

Cholestyramine 

Cholestyramine⁸ is known by several brand names, including Questran, Questran Light, Prevalite, Locholest, and Locholest Light. 

In adults, cholestyramine is taken at a dose of 4 grams once or twice a day. It should be taken before meals. Over time, the dose may be increased up to 24 grams, taken between two and six times across the day. The higher the dose is, the greater the benefit may be. But this also increases the risk of side effects. 

The maximum reduction in LDL cholesterol can usually be attained one to two weeks after starting cholestyramine. A dose of 8 to 12 grams has been associated with a 12% to 18% reduction⁹ in LDL cholesterol. 

Colesevelam

Colesevelam is known by its brand name Welchol. Compared to cholestyramine, it has a six-fold bile acid-binding capacity and presents fewer side effects. 

Colesevelam is available as tablets, a chewable bar, or a powder that can be mixed into a drink. Some people find the powder less palatable and more difficult to drink than swallowing a tablet. 

Colesevelam is taken at 625 mg per tablet, or 375 grams if using powder. Usually, it’s advised to take colesevelam alongside a meal and drink, but it may be necessary to take it four hours apart from certain vitamins and medications. 

Can fish oil lower cholesterol levels?

Fish oil¹⁰ contains two omega-3 fatty acids—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 

Omega-3 fatty acids are polyunsaturated fatty acids. These have been shown to lower triglyceride levels and are a healthy part of diets. Triglycerides are a kind of fat found in the blood that the body can store and use as energy. 

However, it’s not known for sure whether fish oil can reduce LDL cholesterol levels. 

Most studies¹⁰ haven’t found a positive effect on LDL from fish oil. Evidence from a meta-analysis suggests that fish oil in supplements may increase LDL cholesterol levels while eating fresh fish, which naturally contains fish oil, might reduce them. 

However, fish oil may have other beneficial effects on cholesterol. For example, it may 

• Increase HDL cholesterol levels

• Lower VLDL cholesterol and non-HDL cholesterol levels

• Increase the size of LDL cholesterol particles

Although the last benefit doesn’t directly lower cholesterol levels, it’s beneficial because atherosclerosis is associated with small LDL particles. 

Fish oil in food

Fish oil can be consumed naturally by eating fatty fish. This includes salmon, mackerel, trout, albacore tuna, and herring. The fish should be baked or broiled rather than fried to boost the health benefits.

The American Heart Association recommends consuming fatty fish at least two times a week in addition to plant-derived omega 3s, such as soybeans, walnuts, and flaxseed oil. 

Fish oil in supplements

Fish oil can also be ingested at high doses in capsule form.

Fish oil supplements are classified as food by the FDA and do not need to be prescribed, although some are. Those that need to be may be a better option as they may be more likely to have undergone stricter testing. 

However, it’s still advised to speak with a doctor before taking fish oil supplements to ensure the high dose will be safe. 

It’s also important to note that the omega-3 content can vary between different brands of fish oil supplements. Some brands can also contain saturated fats and oxidized oils, which can cause increased total cholesterol and LDL. 

Possible side effects of taking omega-3 fish oil supplements in high doses include:

• Increased bleeding

• Hemorrhagic stroke

• Low blood pressure

• Poor control of blood sugar in people with diabetes

• Allergic reactions in people with fish or shellfish allergies

• Reduced vitamin E levels 

Fish oil supplements may also interact with other medications. These include:

• Anticoagulant and antiplatelet medications

• Medications that reduce blood pressure 

• Contraceptive drugs may affect the impact fish oil has on triglycerides 

• Weight loss drug Orlistat may decrease the absorption of the fatty acids in the fish oil

The lowdown 

Statins are the most well-known and widely used cholesterol-lowering medication, but several other types of treatments are available. These non-statin therapies can be used in addition to, or instead of, statins. 

The best treatment depends on your cholesterol levels and family medical history. As always, consult your doctor to find the best non-statin cholesterol meds that fit your needs.