Non statin cholesterol medication


Statin Alternatives

There are many non-statin medications your doctor might prescribe:

Bile acid-binding resins, like cholestyramine (Locholest, Prevalite, Questran), colesevelam (WelChol), and colestipol (Colestid) stick to cholesterol-rich bile acids in your intestines and lower your LDL levels.

Fibrates such as clofibrate (Atromid-S), fenofibrate (Antara, Fenoglide, Lipofen, TriCor, Triglide, Trilipix), and gemfibrozil (Lopid) mostly help your heart by reducing the amount of blood fat (called triglycerides) and raising “good” HDL levels. They don’t do much to lower LDL though.

Niacin, a B vitamin, affects how your body makes blood fats and can also lower LDL.

Ezetimibe (Zetia) lowers the amount of cholesterol your intestines absorb. When paired with statins, ezetimibe further lowers LDL levels.

Omega-3s are found in fatty fish like mackerel, trout, herring, sardines, albacore tuna, and salmon. You can also get them in supplements and medication. You mainly take them to lower triglycerides.

PCSK9 inhibitors help clear cholesterol from your blood. They “have been developed for people who are not at their goal cholesterol despite current treatments,” Cannon says. The FDA has approved two of these drugs: alirocumab (Praluent) and evolocumab (Repatha). Evolocumab, in particular, has been approved as a preventative treatment for heart attacks, stroke, and coronary revascularizations in adults with cardiovascular disease.

With statins being hailed as the “drug of the century,” some experts have suspected that, within a few years, half of all Americans will be taking some form of this medication. Although statins are the most popular cholesterol-lowering drugs, there are other options. Many of these are used alone or in conjunction with statins.

If medication combined with lifestyle changes doesn’t enable you to reach your LDL goal within three months, your doctor may consider starting you on a second drug to boost results. Combination therapy can help reverse or slow the advance of atherosclerosis and further decrease your risk of a heart attack or death. Also, since both drugs may be prescribed in lower doses than if you were taking either alone, your risk of side effects may decrease.

ComstockCompleteAspirin acts like WD-40 on blood platelets, making them less likely to stick to plaque in blood vessels.
Become familiar with non-statin drugs, their uses, and the possible side effects. But, as always, consult your doctor before starting any cholesterol-lowering medication.

Cholesterol Absorption Inhibitors
Two organs primarily control cholesterol levels in your blood: the liver, which produces cholesterol and bile acids (used to digest fats), and the intestine, which absorbs cholesterol both from food and from the bile. While statins primarily lower cholesterol by preventing its production in the liver, a new class of drug called cholesterol absorption inhibitors lowers cholesterol by preventing it from being absorbed in the intestine. The first approved drug in this class, Zetia (ezetimibe), hit American markets in 2002.

By itself, Zetia reduced cholesterol about 18 percent in studies. When the drug was paired with statin drugs, cholesterol levels dropped 25 percent more than with statins alone. That’s important, since on average only 60 percent of people who take statins get their cholesterol levels as low as they should. In one study just 19 percent of people taking statins alone reached their cholesterol goal; adding Zetia increased that figure to 72 percent. “Taking 10 milligrams of Zetia with a statin is equivalent to tripling the dose of statins,” says Antonio Gotto, Jr., M.D., dean at Weill Cornell Medical College in New York City. Zetia also has fewer side effects than statins. For instance, it doesn’t appear to cause any muscle problems. The treatment doesn’t come cheaply, however; the wholesale cost for a 30-day supply is $57.90. That’s on top of the cost of the statin. Merck & Co., the maker of the statin Zocor, is testing a pill that combines the two.

Side effects: The most common side effects include back, stomach, and joint pain.

Warnings: Not recommended for use in conjunction with fibrates.

Recommended dose: Zetia is administered as a once-daily tablet in a single 10-milligram strength and is taken with or without food.

Niacin (nicotinic acid) is one of the oldest cholesterol-lowering drugs. A member of the B vitamin family, it’s found in fruits, vegetables, meats, and grains, as well as in most multivitamins. At doses up to 35 milligrams per day, niacin is considered a supplement, but if you’re taking it at doses high enough to lower your cholesterol — more than 100 times the recommended daily intake of 16 milligrams for men and 14 milligrams for women — you need to be taking it under the supervision of your doctor (even though it’s sold over the counter).

Niacin works by reducing the production and release of LDL from the liver, lowering LDL 15 to 20 percent. It also reduces the release of free fatty acids stored in fat cells, which eventually become triglycerides. Thus, it’s an excellent drug for lowering triglycerides, resulting in decreases of 20 to 50 percent. It also raises HDL between 15 and 35 percent. In fact, the branded timed-release form, Niaspan, is one of only two drugs approved to increase HDL. (In case you’re wondering, the other is the fibrate gemfibrozil, brand name Lopid.)

Sound too good to be true? Well, there is a drawback to niacin that turns some people off: It can cause flushing and redness — an intense blush. This occurs because niacin relaxes blood vessels, enabling more blood flow. The blushing usually disappears within an hour or so after taking the drug. And taking aspirin beforehand can reduce this effect, as can gradually building up to the dose you need.

There are two types of nicotinic acid: immediate release and timed release. The timed-release version reduces the flushing, but be doubly sure you don’t take this form without your doctor’s supervision. If you take too much, the drug could cause liver damage and raise blood glucose levels dangerously high. It can also raise blood glucose and hemoglobin AIC levels in people with diabetes. That’s why most experts recommend starting with the immediate-release form. Also, make sure you’re taking nicotinic acid; another form of niacin called nicotinamide doesn’t lower cholesterol levels.

Side effects: In addition to flushing, other possible side effects of niacin include:

  • Liver enzyme abnormalities. About 5 percent of people who take more than 3 grams of nicotinic acid per day may learn they have elevated liver enzymes, an indication that their liver is under stress. If the elevation continues and your enzymes are more than three times normal levels, your doctor may want you to stop taking the drug.
  • Blood glucose control. In about 10 percent of people — particularly those with diabetes, insulin resistance, or metabolic syndrome — nicotinic acid may make it more difficult to control blood sugar levels.
  • Gout. About 5 to 10 percent of those people taking nicotinic acid find their production of uric acid increases. This can result in gout, a condition involving painful and inflamed joints.
  • Gastrointestinal symptoms. Infrequently a variety of gastrointestinal symptoms, including nausea, indigestion, gas, vomiting, diarrhea, and ulcers, may also occur.
  • Muscle toxicity. This is rare but may occur if you’re combining nicotinic acid with other drugs, such as statins or fibrates.

Warnings: Don’t take niacin if you have diabetes, liver disease, an active peptic ulcer, arterial bleeding, or unexplained liver enzyme elevations. And be careful if you’re also taking blood pressure medication. Niacin can increase the effect of some blood pressure drugs, so your doctor should closely monitor your blood pressure when you first start taking niacin.

Recommended dose: 1 to 3 grams daily, taken under a doctor’s supervision.

Fibric acid derivatives, or fibrates, affect the actions of key enzymes in the liver, enabling the liver to absorb more fatty acids, thus reducing production of triglycerides. These drugs also work well at increasing production of HDL. Although they can also lower LDL levels, they’re not considered first-line treatments for high LDL or total cholesterol. Overall, they tend to lower LDL levels between 10 and 15 percent, increase HDL levels between 5 and 20 percent, and lower triglycerides between 20 and 50 percent. Fibrates are often prescribed in conjunction with other cholesterol-lowering drugs, but they shouldn’t be taken with statins. They may be particularly helpful for people with insulin resistance syndrome, in which HDL tends to be low, LDL normal, and triglycerides high. Brands include Atromid-S (clofibrate), Lopid (gemfibrozil), and Tricor (fenofibrate).

Side effects: Fibrates have few side effects and most people can take them with no problem. The most common problems are gastrointestinal complaints, such as nausea and gas. The drug may also increase your likelihood of developing gallstones.

Warnings: Combining fibrates with statins could result in muscle damage. Fibrates are also not recommended if you have liver, kidney, or gallbladder disease.

Recommended dose: Fibrates are usually given in two daily doses totaling 1,200 milligrams, taken 30 minutes before morning and evening meals.

Bile Acid Sequestrants
This class of drug, in use for more than 40 years with no major problems, acts like super glue, binding with bile acids in the intestines so that the acids are removed with the stool. Bile acids (which help your body digest fatty foods) are made from cholesterol in the liver. Ordinarily, as they pass through the intestines they are reabsorbed into the bloodstream and carried back to the liver. This “recycles” the cholesterol component as well. But bile acid sequestrants interrupt this pathway, causing the bile acids to exit the body. This causes a loss of cholesterol as well. In response, the liver removes more LDL from the bloodstream. And — voilà — your blood cholesterol levels drop.

The most common drugs include cholestyramine, sold under the brand names Questran, Prevalite, and LoCholest, and colestipol (Colestid). These drugs generally lower LDL about 15 to 30 percent with relatively low doses while increasing HDL slightly (up to 5 percent). They may be prescribed with a statin if you already have heart disease. Together the two drugs can lower LDL more than 40 percent.

Side effects: These drugs may cause bloating, heartburn, constipation, and abdominal pain, and may increase triglycerides, particularly if levels are already high.

Warnings: Bile acid sequestrants may delay or reduce your ability to absorb oral medications and vitamins, so you shouldn’t take them along with other medications or supplements.

Recommended dose: Bile acid sequestrants generally come as tablets or as a powdered resin that you mix with liquids or foods. A typical dose is about 10 grams per day.

First the proviso: Aspirin won’t lower your cholesterol. But its effects on blood clotting and inflammation are so significant that anyone with known heart disease, diabetes, or two or more risk factors for heart disease (and no problems taking aspirin) should talk to their doctor about taking a daily baby aspirin. Aspirin acts like WD-40 on blood platelets, making them less likely to stick to plaque in blood vessels. It also reduces the inflammation that is a hallmark of heart disease and a part of the process that leads to the buildup of plaque.

Numerous studies have found that aspirin reduced the risk of another heart attack, stroke, or premature death in people with heart disease, and it also reduced the risk of heart attacks in healthy people. One analysis of four large studies conducted on people with no history of heart disease found a daily aspirin reduced the risk of a nonfatal heart attack 32 percent.

Side effects: Aspirin’s very strength is also its greatest weakness. Because it acts on the overall system that affects bleeding, aspirin increases the risk of gastrointestinal bleeding, either from an ulcer or gastritis (inflammation of the stomach lining), and the risk of a rare but dangerous form of stroke called hemorrhagic stroke, caused not by a blood clot but by bleeding in the brain. To learn whether the benefits of aspirin therapy outweigh the risk for you personally, take the simple test at You will need to know your blood pressure and cholesterol readings.

Warnings: If you’re taking blood-thinning medication such as Coumadin (warfarin), talk to your doctor before taking aspirin regularly. The combined effect can pose a serious hazard. And be aware that aspirin can boost the blood-thinning effects of certain supplements, such as vitamin E, ginkgo biloba, St. John’s wort, and others. (Fish oil also thins the blood, but the heart benefits of taking both fish oil and aspirin probably outweigh the risks.) Be sure to let your doctor know about any supplements you take when you discuss the pros and cons of aspirin therapy with him. Finally, don’t take aspirin if you’ve ever had any problems with the drug,
including stomach pain or allergies.

Recommended dose: One baby aspirin (81 milligrams) daily.

New drug ‘effective’ for those with intolerable statin side effects

“A breakthrough drug can slash levels of bad cholesterol by half without the side effects of statins,” the Daily Mail reports.

Statins are a class of drug used to reduce high cholesterol levels, they are often given to people thought to be at risk of heart disease or stroke.

A complaint from some people who take statins is that they seem to trigger muscle pains and spasms. In some cases, these side effects are so troublesome that a person stops taking the drug all together.

This study included almost 500 people who previously had muscle problems when they tried several types of statin.

They were randomised to take either low-dose atorvastatin or inactive placebo, and were unaware of which drug they were taking. The researchers found just under half reported muscle problems when taking the statin only.

These people were then randomised to take two alternative non-statin drugs – oral ezetimibe or the new injected drug evolocumab. Overall, researchers found the latter was better at reducing cholesterol.

One practical consideration regarding evolocumab is its cost. The drug is expensive: a year’s supply is reported to cost £4,450.

The National Institute for Health and Care Excellence (NICE) is reported to be making a final decision about whether evolocumab should be offered on the NHS and, if so, in what circumstances.

People should continue to take their statins as prescribed, but anyone with unexplained muscle aches and pains should report these to their doctor. Lowering the dose or trying a different type of statin may help relieve these symptoms.

Where did the story come from?

The study was carried out by researchers from the University of Amsterdam School of Medicine at Mount Sinai in the US and various other institutions worldwide.

Funding was provided by Amgen, which produces the cholesterol-lowering medication evolocumab, sold under the tradename Repatha™.

According to the researchers, Amgen was “involved in the design and conduct of the study, selected the investigators, monitored the trial, and collected and managed the trial data. The sponsor participated in the decision to publish the study and committed to publication of the results prior to unblinding the trial.”

The study was published in the peer-reviewed journal JAMA on an open-access basis, so you can read it for free online.

There is also an accompanying editorial (also free) written by independent experts, which provides a useful second opinion about the implications of the research.

The Daily Mail’s reporting of the study is accurate, but its claim that, “Breakthrough treatment could get NHS green light by end of the month” is possibly overoptimistic.

In contrast, The Daily’s Telegraph reporting of the study is somewhat confusing and misleading.

The Telegraph said: “Statins really do cause painful muscle cramps, scientists have found, vindicating hundreds of thousands of people who have repeatedly claimed to have suffered debilitating side effects” which seems to imply that doctors don’t recognise these types of side effects. This is simply not the case: these are known side effects that are highlighted in the product literature.

It remains a puzzle as to why people taking statins experience these types of side effects – as yet, no plausible biological explanation has been found.

What kind of research was this?

This randomised controlled trial was conducted in two phases. Researchers aimed to see whether statins do cause muscle symptoms and then compare the fat (lipid) lowering ability of two alternative non-statin medications.

Statins are well established to be effective drugs for lowering cholesterol, but muscle-related adverse effects such as pain and weakness have often been reported. This risk is recognised by the medical profession.

Subsequently, people who have experienced muscle-related effects need to look for alternative treatments. Approaches may include using very low-dose statins, giving statins intermittently, or alternatively giving non-statin treatments.

Non-statin options include ezetimibe, which limits the absorption of cholesterol, and a new group of drugs called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Evolocumab (given by injection) is a PCSK9 inhibitor that has recently been approved by medical regulators for use in the UK.

A randomised controlled trial is the best way of looking at the safety and effectiveness of treatments.

What did the research involve?

The trial was conducted in two phases. The first phase compared atorvastatin – usually the first-choice statin medication – with inactive placebo, looking at muscle-related side effects. The second phase compared the non-statin drugs ezetimibe and evolocumab for their cholesterol-lowering effects.

The trial specifically included people previously unable to tolerate a normal statin dose because of muscle pains.

They went through a four-week washout period in which they took no medication. They were then randomised to either inactive placebo or a “re-challenge” with atorvastatin (20mg) for 10 weeks.

During this time neither participants nor researchers knew which drug they were taking. The drugs were then stopped and they had another two-week washout period before they were switched to the alternative drug (placebo or atorvastatin).

After phase one, those who had experienced muscle-related effects using atorvastatin were eligible to enter phase two – the 24-week trial of oral ezetimibe versus injected evolocumab.

This trial was also double blind, and involved people either taking a dummy tablet or having a dummy injection, depending on which treatment they were assigned to.

In phase one the main study endpoint was therefore the incidence of muscle-related side effects. The main study endpoint at phase two was changes in low-density lipoprotein (LDL) – “bad” – cholesterol, though any side effects were also reported.

What were the basic results?

A total of 492 people entered phase one of the study, most of whom had been intolerant of at least three different statins in the past. Overall, 42.6% of these people experienced muscle-related side effects with atorvastatin, but not placebo.

Somewhat oddly, around a quarter reported muscle-related side effects while using the placebo but not atorvastatin. The remainder either had symptoms with both or neither.

A person had a significantly higher risk of developing muscle-related side effects while taking atorvastatin than placebo.

The main results relate to the effectiveness of the two alternatives. A total of 218 people entered phase two.

Overall, evolocumab lowered LDL cholesterol significantly more than ezetimibe – an absolute difference of 37%.

There was no significant difference in the muscle-related symptoms of these two drugs, which were reported by 29% of people taking ezetimibe and 21% of people taking evolocumab.

How did the researchers interpret the results?

The researchers concluded: “Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks.”


The main results of this study relate to the lipid-lowering effects of two alternative non-statin medications. However, it highlights the muscle-related adverse effects that can occur with statins.

The study is carefully designed and has many strengths, including:

  • a washout period between drugs to remove any residual effects
  • double-blind design throughout so people didn’t know what they were taking
  • sufficient duration for each phase of the study (10 and 24 weeks) to allow effects to develop
  • a good sample size – the researchers calculated beforehand how many people would need to be recruited to enable them to reliably detect differences between the groups

There are some points to keep in mind, however.

This study isn’t able to inform us of the overall incidence of muscle aches and pains when people take statins. A specific sample of people was recruited to the study, and they had already reported muscle problems when taking several statins previously.

It can then tell us that when these people took low-dose atorvastatin and placebo in a double-blinded manner, just under a half of them experienced these problems when taking the statin only. This suggests that these were effects definitely related to the statin.

However, that’s not to say the remaining half had previously imagined these effects – they could have had effects with other statins or with higher doses than the 20mg taken here.

The muscle-related side effects of statins are already well known. Product literature notes side effects of muscle aches, pains and weakness, and the potential risk of developing the serious condition rhabdomyolysis. This is where muscle fibres are broken down and released into the bloodstream, which can damage the kidneys. Doctors are advised to use statins with caution in people with a history of muscle weakness or rhabdomyolysis.

Statins are highly effective and relatively safe drugs, and are the medication of first choice for lowering cholesterol. Ezetimibe is currently only recommended by the regulatory body NICE for people who cannot take a statin.

Evolocumab has only recently been licensed for the treatment of people who cannot take statins, or in combination with a statin if a statin alone is ineffective at reducing cholesterol.

NICE issued draft guidance at the end of last year that did not recommend this drug if other lipid-lowering treatments could be taken. However, the final version of the guidance, which may say something different, is expected some time this year.

People should continue to take their statins as prescribed, but anyone with unexplained muscle aches and pains should report these to their doctor.

Often, lowering the dose or switching to an alternative type of statin can help prevent side effects. Lifestyle changes such as eating a healthy diet and taking regular exercise can also help lower your cholesterol.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Drug to beat cholesterol WITHOUT statin side effects: Breakthrough treatment could get NHS green light by end of the month

Daily Mail, 3 April 2016

Statins do cause muscle pain, scientists conclude

The Daily Telegraph, 3 April 2016

Links to the science

Nissen SE, Stroes E, Dent-Acosta R, et al.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance – The GAUSS-3 Randomized Clinical Trial

JAMA. Published online April 3 2016

Further reading

Waters DD, Hsue PY, Bangalore S.

PCSK9 Inhibitors for Statin Intolerance?

JAMA. Published online April 3 2016

National Institute for Health and Care Excellence (NICE).

NICE issues draft guidance on evolocumab for lipid disorder – Press Release

November 18 2015


Generic Name: ezetimibe (ez ET i mibe)
Brand Names: Zetia

Medically reviewed by Sanjai Sinha, MD Last updated on Apr 11, 2019.

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What is Zetia?

Zetia (ezetimibe) reduces the amount of cholesterol absorbed by the body.

Zetia is used to treat high cholesterol.

Zetia is sometimes given with other cholesterol-lowering medications.

Important information

Zetia is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Some cholesterol medications should not be taken at the same time. If you take Zetia with another cholesterol medicine, follow your doctor’s dosing instructions very carefully.

You should not use Zetia if you have moderate to severe liver disease. You should not use ezetimibe with a “statin” cholesterol medicine if you have active liver disease, or if you are pregnant or breast-feeding a baby.

Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Before taking this medicine

You should not use Zetia if you are allergic to ezetimibe, or if you have:

  • moderate to severe liver disease.

You should not use ezetimibe with a “statin” cholesterol medicine (Zocor, Lipitor, Crestor, and others) if:

  • you have active liver disease;

  • you are pregnant; or

  • you are breast-feeding a baby.

To make sure Zetia is safe for you, tell your doctor if you have:

  • kidney disease; or

  • a thyroid disorder.

Before you start taking Zetia, tell your doctor if you already take a statin cholesterol medicine.

Some cholesterol medications can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid).

You should not take ezetimibe with a statin medication if you are pregnant or breast-feeding.

It is not known whether Zetia alone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. Use effective birth control to prevent pregnancy while you are using ezetimibe with a statin medication.

It is not known whether ezetimibe alone passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby. You should not breast-feed if you take Zetia with a statin medication.

How should I take Zetia?

Take Zetia exactly as it was prescribed for you. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Zetia is usually taken once daily. Take the medicine at the same time each day.

You may take this medicine with or without food.

Zetia may be taken at the same time with fenofibrate, or with a statin medication such as atorvastatin, lovastatin, simvastatin, pravastatin, or fluvastatin.

Some cholesterol medications should not be taken at the same time.

  • If you also take cholestyramine, colestipol, or colesevelam: Wait at least 4 hours after taking any of these medicines before you take ezetimibe. You may also take ezetimibe 2 hours before taking any of these other medicines.

  • You should not take ezetimibe with gemfibrozil.

You may need frequent blood tests to check your liver function if you take ezetimibe with a statin medicine.

It may take up to 2 weeks before your cholesterol levels improve. Keep using your medication as directed. You will need frequent blood tests to measure your cholesterol levels.

Zetia is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Zetia?

Avoid eating foods that are high in fat or cholesterol. Zetia will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Zetia side effects

Get emergency medical help if you have signs of an allergic reaction to Zetia: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some cholesterol medications can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Side effects may be more likely in older adults.

Common Zetia side effects may include:

  • muscle or joint pain;

  • stuffy nose, sinus pain, sore throat;

  • diarrhea; or

  • pain in an arm or leg.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Zetia dosing information

Usual Adult Dose for Hyperlipidemia:

10 mg once a day with or without food.

Usual Adult Dose for Sitosterolemia:

10 mg once a day with or without food.

What other drugs will affect Zetia?

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • cyclosporine; or

  • a blood thinner (warfarin, Coumadin, Jantoven).

This list is not complete. Other drugs may interact with Zetia, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Zetia only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2020 Cerner Multum, Inc. Version: 5.01.

Medical Disclaimer

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New Cholesterol Drug Could Be Alternative for Those Unable to Take Statins, Study Says

Statins like Lipitor and Crestor are widely used as the first line of defense in treating high cholesterol, but not everyone can take them. Muscle pain is the most common side effect, and some patients can also experience inflammation in the liver, increased blood sugar levels that could lead to type 2 diabetes, and loss of memory.

A new drug that could become available soon, if approved in the United States and Europe, represents a potential alternative. Bempedoic acid is a novel oral drug that could be taken instead of statins or in conjunction with them, depending on the patient. It blocks a key enzyme made by the body to build cholesterol, and since it can’t leave the liver once it’s activated, it can’t cause muscle pain.

RELATED: What You Need to Know About High Cholesterol

Research Shows Lower LDL Levels With New Cholesterol Drug

In a study of 2,230 people drawn from the United States, Canada, and Europe, the drug lowered LDL cholesterol levels by 18 percent after three months. The research was published in March 2019 in The New England Journal of Medicine, and is the first to measure the safety and effectiveness of the drug when compared with placebo in patients with an increased risk of heart attack and stroke.

It can help both those who can’t take statins, and those who need additional intervention on top of statins or other drug regimens to lower their cholesterol.

New Drug Could Potentially Reduce Treatment Cost for Some

There’s also the cost factor — it’s expected to be in the middle ground between current options. Statins are now available as generics, which are less expensive. But for those who can’t take them, or have had heart attacks or stroke and need stronger intervention, the current alternatives are first eztemibe, which is available as a generic, or the expensive PCSK9 inhibitors for more severe cases.

“Bempedoic acid will help multiple groups of people,” says Kausik Ray, MD, study author and a cardiologist and professor of public health at the Imperial College London in England. “On top of statins, some patients are in no man’s land where cholesterol is not low enough but not high enough to get reimbursed (by insurance) for a PCSK9 inhibitor, so this is a huge new option.”

RELATED: New Cholesterol Guidelines Focus on Personalized Approach

An Additional Line of Treatment When Statins Aren’t Enough

When used in combination with Zetia (eztemibe), it can help bring down cholesterol levels by 50 percent, as opposed to using only eztemibe, which delivers a 20 to 25 percent reduction, says Dr. Ray.

He presented his research this past March at the American College of Cardiology conference in New Orleans. This study was funded by Esperion Therapeutics, a U.S.-based pharmaceutical company that developed bempedoic acid.

Not everyone will need the drug, especially if they don’t suffer adverse effects from statins. But when taking statins alone is not sufficient to lower cholesterol, it can be an additional line of treatment.

“It doesn’t matter how you lower your LDL, but how much and how long you keep it low,” Ray said. “Clinicians and patients like and need choice. One size does not fit all.”

There is a possibility of increased gout with bempedoic acid, but the study reports no major side effects.

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A new type of cholesterol-fighting drug was well-tolerated by patients and led to “significantly lower” levels of LDL — the harmful type of cholesterol — during a year-long trial, researchers reported Wednesday.

Bempedoic acid, taken as a daily pill, could be an option for people who can’t bring their LDL levels low enough with statin therapy alone, or who don’t tolerate statins because of side effects such as muscle pain.

After three months of taking the new drug on top of statins, patients saw their LDL levels drop by an average of 18 percent compared to people taking a placebo, according the study published in The New England Journal of Medicine.

The trial was funded by Esperion Therapeutics, a pharmaceutical company that’s seeking approval from the Food and Drug Administration to make the drug available in the U.S.

Bempedoic acid works in the same pathways as statins, but at a different site, said cardiologist Dr. Kausik Ray, the study’s lead author and a professor in the Imperial College London’s School of Public Health. It blocks a key enzyme the body uses to make cholesterol.

“We’ve got a number of different studies now that have shown that it looks to be yet another really good option. Doctors like options because patients don’t fit one size, so it gives us an option for people with an unmet need,” Ray told NBC News.

“I think it’s a great development.”

Study Finds Cholesterol-Lowering Statins Cut Heart Disease Risk

April 2, 201602:20

Low-density lipoprotein, or LDL, contributes to fatty buildups in the arteries, raising the risk of heart attack and stroke. About 71 million American adults have high LDL, according to the Centers for Disease Control and Prevention.

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Heart disease is the leading cause of death for both men and women in the U.S. and lowering LDL cholesterol has become a cornerstone of heart health. When diet and exercise don’t work, statins — drugs that interfere with the production of cholesterol — can be the simplest and cheapest treatment. Known under brand names such as Lipitor, Zocor and Crestor, they’ve become among the most widely prescribed drugs in the world.

But 10-15 percent of patients report side effects, most commonly muscle pain, weakness and cramps. Many people simply stop taking the pills.

The new drug — once converted into its active form in the liver — can’t leave the liver cells, so it can’t enter muscles, making muscle-related side effects less likely, Ray said.

A good candidate for this medication would be someone who has high risk for heart disease and still has high LDL despite taking the highest dose of a statin he or she can tolerate, noted Dr. Christie Mitchell Ballantyne, chief of cardiology at Baylor College of Medicine in Houston, Texas.

“This medicine could help a lot of people,” Ballantyne said. “We hope that we can help more people to get their LDL levels to a very safe and healthy level.”

Want to Reduce Your Cholesterol? Doctors Suggest Lowering Stress

Feb. 18, 201602:01

The trial involved 2,230 people — mostly white men — who were on average 66 years old and had a mean LDL cholesterol level of about 103 at the start. More than 97 percent had a history of atherosclerotic cardiovascular disease.

Two-thirds of the patients were assigned to receive bempedoic acid and the rest swallowed a placebo. All continued the highest intensity statin regimen they could tolerate.

“The main reason for doing this is that when you work through the same pathways, there’s always the question: If you’re going to add it on top of a statin, have you maxed the system out, or do you get any further incremental gain?” Ray noted.

The answer seems to be yes. Most people taking the new drug saw their LDL cholesterol level drop — by about 19 milligrams per deciliter on average — with the effects still apparent one year into the trial. The new drug was tolerated as well as the placebo, though there was a small increase in new cases of gout.

Jack Manley, 71, of Pearland, Texas, has been taking Lipitor for years for his high cholesterol, but he experienced severe leg cramps as a side effect from the statin.

“I needed a relief from the leg cramps because it was constant,” said Manley, a stroke survivor. His dosage of Lipitor was lowered, but it didn’t bring his cholesterol numbers down to where his doctors wanted them to be.

After trying the newest drug in the trial, his cholesterol dropped and he didn’t experience any side effects.

“Hopefully, it’ll be an affordable medicine that will keep my cholesterol in the range that it needs to be,” Manley said.

It’s not known how much bempedoic acid would cost if approved for the U.S. market, but it would likely be less expensive than PCSK9 inhibitors — injectable cholesterol-lowering drugs that are potent, but can cost thousands of dollars a year, Ray said.

Besides providing a boost to statins, bempedoic acid could be taken on its own or in combination with ezetimibe (known under the brand name Zetia), a medication that prevents the absorption of cholesterol in the intestine, he added.

An ongoing trial is testing even longer-term safety and whether the new drug has an effect on heart disease. Previous medicines have shown promise in improving cholesterol numbers only to fail at actually reducing the number of heart attacks and strokes.

Hate Statins? Studies Find New Drug May Help Lower Cholesterol

In the first study, the authors demonstrated the safety and efficacy of the drug in a large, placebo-controlled trial.

For one year, 2,230 patients with atherosclerosis, high cholesterol, or both took part in the trial, with two-thirds of them taking an oral dose of bempedoic acid and the remainder using a placebo.

Those using bempedoic acid lowered their average LDL cholesterol level by an average of 18 percent compared with the placebo group.

Researchers also found the drug to be safe and well-tolerated. During that time period, both groups had similar amounts of adverse health incidents — including heart attacks and death. That is, bempedoic acid did not increase the health risks for those taking it.

It is the first study to measure these outcomes.

“Bempedoic acid is an exciting new medication used to lower cholesterol,” said Dr. Guy L. Mintz, director of cardiovascular health and lipidology at Northwell Health’s Sandra Atlas Bass Heart Hospital in Manhasset, New York.

“Based on this study bempedoic acid can safely be added to statin therapy for those patients who require further LDL cholesterol reduction,” said Mintz, who is not affiliated with the study.

The second article published today demonstrates a biological proof of concept for how bempedoic acid works in the body. Using biologic data and biomarkers from over a half a million people, researchers modeled the likely effects of the treatment over a longer period of time. The study reinforced the conclusion that the effects of the drug would reduce cardiovascular disease without serious adverse health outcomes.

Bempedoic acid works by blocking the production of ATP citrate lyase, one of the key enzymes in the production of cholesterol.

Bempedoic acid actually works along the same chemical pathway as statins, just further “upstream” in the process. Statins work by inhibiting the body’s production of an enzyme called HMG-CoA reductase, another enzyme used to make cholesterol.

By inhibiting this enzyme, the liver produces less cholesterol, thereby lowering cholesterol levels.

“Many patients do not get enough LDL lowering for their level of risk… So this is a huge area of unmet need as the only alternative is to leave people at higher risk,” said Dr. Kausik K. Ray, professor of public health in the Ddartment of public health and primary care at Imperial College London, an author on both publications.

Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk

Release Date: September 28, 2018
Expiration Date: September 28, 2019
Media: Internet – based

Activity Overview

Statins have been the mainstream of hypercholesterolemia treatment for over 30 years, but clinicians now have effective nonstatin options when lipid-lowering goals are not met or when patients become statin intolerant. Besides bile acid binding resins and a cholesterol absorption inhibitor, 2 proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been available since 2015, alirocumab and evolocumab to provide a more aggressive approach to lipid-lowering.

In this Community Practice Connections™, 2 leading family-practice physicians will provide insight on statin intolerance and discuss nonstatin treatment options as well as compare and contrast indications for the PCSK9 inhibitors. Key points to incorporate PCSK9 inhibitors into clinical practice and tips to facilitate patient access will be included to readily broaden clinicians’ armamentarium of lipid-lowering treatments.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from by Amgen.

Target Audience

This continuing medical education (CME) activity is primarily intended for family physicians who treat patients with cardiovascular risk factors including hypercholesterolemia.

Educational Objectives

At the conclusion of this activity, you should be better prepared to:

  • Summarize the latest guidelines and recommendations on cholesterol management from major clinical organizations
  • Review potential cholesterol-lowering therapies beyond statins, and explain when these non-statin therapies should be considered
  • State the indications in detail for proprotein convertase subtilisin kexin type 9 inhibitor (PCSK9i) therapy

Faculty, Staff, and Planners’ Disclosures


Stephen A. Brunton, MD
Adjunct Clinical Professor
Department of Pharmacy Practice
Roseman University of Health Sciences
Salt Lake City, Utah

Disclosure: No relevant financial information to disclose

Michael Cobble, MD, FNLA
Canyons Medical Center
Sandy, Utah
Adjunct Faculty
University of Utah
Salt Lake City, Utah

Disclosure: Consultant: Kowa Pharmaceuticals America, Inc; Speakers Bureau: Amarin Corporation, Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc, Sanofi

The staff of Physicians’ Education Resource®, LLC, (PER®) have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.

PER Pulse™ Recaps

1 of 3
Insight from Stephen A. Brunton, MD—PER Pulse™ Recap:
Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk

The online continuing medical education activity Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk discusses various aspects of treating patients with hyperlipidemia with a focus on non-statin drugs. Clinical experts Stephen A. Brunton, MD, and Michael Cobble, MD, FNLA, discuss statin intolerance, familial hypercholesterolemia, cardiovascular outcomes with PCSK9 inhibitors, and issues with patient access to PCSK9 inhibitors, as well as other topics.

This first of 3 PER Pulse™ Recaps for Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk will focus on managing patients with statin intolerance.

Statin drugs are a mainstay of pharmacotherapy for hyperlipidemia. After lifestyle modifications, statins are the first option suggested by clinical guidelines for hyperlipidemia.1,2 For some patients, however, statins may not be a viable treatment option for various reasons. Statin intolerance is an often-used but often-misunderstood term associated with patient response to statins.3,4

Because statin intolerance is usually described as the inability to tolerate at least 2 statins,5 one common misconception is that statin intolerance equates to a patient who is unable to take any statin. On the contrary, per guideline recommendations, the approach should be to find the appropriate statin for each patient.6 Many patients who experience adverse events with one statin are likely to tolerate a different statin or a different dose of the original statin. Actual statin intolerance may occur in 10% to 15% of patients,3 and myalgia symptoms can occur in up to 29% of patients.7 Properly treating patients with statin intolerance as well as those experiencing statin-related adverse effects is critical for optimizing lipid-lowering goals. Clinicians should consider changing dosages (including via alternate-day dosing) and trying multiple courses of different statins before excluding the drug class entirely from treatment options.6 In addition, clinicians should rule out any drug–drug interactions that could increase statin exposure, thus leading to increased susceptibility to adverse events such as myalgia.

When statin intolerance is an issue or if low-density lipoprotein cholesterol (LDL-C) lowering is insufficient on the maximally tolerated dose of a statin, patients may benefit from any of the many non-statin lipid-lowering drugs available. These range from ezetimibe to bile acid sequestrants to PCSK9 inhibitors. When LCL-C lowering is not optimized on the maximally tolerated statin dose, combinations of these drugs can be used to achieve LDL-C lowering goals.

“We know that statins are very effective in lowering LDL for many patients. However, we sometimes hear that patients may be statin intolerant, and there’s a lot of confusion about what that means. There’s probably about 10% of patients have a problem with statins. The USAGE study , published in 2012, looked at some of the issues and found that about 30% of the patients might have some myalgia, and that may be responsible for some discontinuation. Plus, there’s a lot of nonadherence in this particular therapeutic area. Or it may be that some patients don’t achieve their goal.”
—Stephen A. Brunton, MD

2 of 3
Insight from Michael Cobble, MD, FNLA—PER Pulse™ Recap:
Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk

This second of 3 PER Pulse™ Recaps for Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk focuses on making sense of lipid target goals described by current clinical practice guidelines.

Published guidelines for the treatment of hyperlipidemia have a few key commonalities, including lifestyle changes as the cornerstone of treatment and statins as the first line of pharmacotherapy. Slight differences in how lipid target goals are described and recent changes to guidelines may lead to confusion on lipid targets. The 2013 American College of Cardiology/American Heart Association guidelines shifted to a focus on reducing atherosclerotic cardiovascular disease (ASCVD) risk, whereas the 2014 National Lipid Association guidelines used target levels of low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol.1,2

As Dr Cobble, director at Canyons Medical Center in Sandy, Utah, and adjunct faculty at the University of Utah in Salt Lake City explained, although guideline changes were made, the lipid target goals can be viewed as essentially the same, just described differently. He suggests thinking about lipid-lowering goals in terms of percentages based on the level of ASCVD risk of patients. In practice, the approach could be as follows: moderate-risk patients, lower their LDL-C by 30% to 50%; high-risk and very high-risk patients, lower their LDL-C by over 50%.

Reconciling differences between established guidelines and previous iterations of guidelines is important for proper management of hyperlipidemia. Confusion about the changes among both clinicians and patients may lead to suboptimal treatment. Confirming the patient’s starting LDL-C level is important, as well, to understand how much their level has changed from baseline.

“I think the key point is in your moderate-risk patients, you want to lower their LDL 30% to 50%. If their LDL is 150 and you lower it 30% to 50%, you’re going to get them down to around 80 or 90, under 100. If they’re very high-risk patients, that 150 needs to go over 50% down, close to 70%. If they’re diabetic, the LDL goal needs to be under 100. If you lower it 30%, it goes to 70. If you lower it 50%, it goes to 50. Some of the non-statin therapies in diabetic patients have shown benefit when you added them to a statin and got their LDL down to 50. Again, for most of your diabetic and high-risk patients, LDL reductions of 50% or more are extremely important. That’s one of the lipid goals.”
—Michael Cobble, MD, FNLA

3 of 3
Insight from Michael Cobble, MD, FNLA—PER Pulse™ Recap:
Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk

This third of 3 PER Pulse™ Recaps for the Community Practice Connections™: The Role of Non-Statin Therapies for LDL-C Lowering for Management of ASCVD Risk focuses on appropriate use of PCSK9 inhibitors.

With the introduction of alirocumab and evolocumab in 2015, a new class of hyperlipidemia drugs was established: PCSK9 inhibitors. Both drugs are monoclonal antibodies that can have profound effects on low-density lipoprotein cholesterol (LDL-C) levels. Recent clinical studies also suggest that the drugs can reduce the risks of certain atherosclerotic cardiovascular disease (ASCVD) outcomes.1,2 Updates to hyperlipidemia guidelines provide advice on appropriate use of PCSK9 inhibitors.3

In this Community Practice Connections™ segment, Dr Cobble, director at Canyons Medical Center in Sandy, Utah, and adjunct faculty at the University of Utah in Salt Lake City highlight several clinical scenarios in which PCSK9 inhibitors should be considered. Two groups of patients are prime candidates for PCSK9 inhibitors: those with homozygous familial hypercholesterolemia (HoFH) and those with heterozygous familial hypercholesterolemia (HeFH). It must be noted that both alirocumab and evolocumab are approved for use in HeFH, but only evolocumab is approved for HoFH. Patients with HeFH or HoFH are prime candidates for the drugs because these patients have exorbitantly high LDL-C levels that may be refractory to other pharmacotherapy. Other patient groups who could benefit from PCSK9 inhibitors are patients with diabetes and those with a history of ASCVD whose LDL-C is not controlled (ie, >100 mg/dL).

As biologics, the drugs have a high price tag that may affect patient access even with insurance coverage. Clinicians should be aware of strategies to ensure patient access. Prior authorization is often required, and proper documentation is critical to success with either an initial approval or an appeal.4,5 Recent changes to pricing for the PCSK9 inhibitors may aid in increasing patient access.6,7

“I think the patients are most appropriate for PCSK9 inhibitor therapy would really be your very highest-risk patients. Those are going to be people with homozygous familial hypercholesterolemia. Those people will have cholesterols in the 400 to 800 range. LDLs will be 300 to 500. I’ve seen them as high as 1200. Those patients are appropriate. The heterozygous familial hypercholesterolemia patients with genetic disease, as well—they usually have cholesterol in the 300 or 400 range, with LDLs above 200. Then I think any patient with diabetes or has had a vascular event—peripheral artery disease, cerebrovascular disease, cardiovascular disease—and their LDL is still above 100 despite optimal therapy need at least another 50% reduction in their LDL. Again, the PCSK9 drugs will additively or independently lower LDL at least 50%, oftentimes 60% to 70% in addition to current therapy they’re on.”
—Michael Cobble, MD, FNLA

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