When Statins Aren't for You

Content provided by the Faculty of the Harvard Medical School
Excerpted from a Harvard Special Health Report

Ezetimibe (Zetia, Vytorin)

Ezetimibe is a cholesterol-absorption inhibitor that blocks the intake of cholesterol from foods in your digestive tract. It can decrease LDL levels by 20%, and is often used in combination with a statin. The drug Vytorin combines ezetimibe with a statin.

Ezetimibe has an excellent safety record and is well tolerated—more so than other lipid-lowering agents (such as niacin, fibrates, and bile acid binders), and maybe even more than statins. However, its effectiveness has been called into question by a number of studies.

In one study, known as the ENHANCE trial, researchers compared Vytorin's effect on the thickness of carotid artery plaque to that of simvastatin alone. Participants included 720 people with a genetic defect that produces very high cholesterol levels. The outcome showed no difference in plaque reduction between the two drugs. This finding led some experts to question the study design, and others to question the usefulness of ezetimibe alone or combined with statins.

Another study—the SEAS trial—compared the effect of Vytorin versus a placebo on the progression of aortic valve narrowing in 1,900 subjects. The drug reduced the risk of coronary artery problems, but failed to slow the progression of aortic stenosis, the study's main endpoint. The SEAS trial also raised concerns about a link between ezetimibe and cancer, but further analysis of the data found that the increase in cancer most likely occurred by chance.

A third study, known as ARBITER-6 HALTS, was stopped early in 2009 when its safety panel concluded that niacin plus a statin was superior to ezetimibe plus a statin, causing a greater reduction in cholesterol-filled plaque in the carotid artery. In contrast, a 2011 study, known as SHARP, found a significant reduction in cardiovascular disease in patients with kidney disease who took Vytorin.

Experts are divided on the value of adding ezetimibe to statin therapy, as the data on its additional benefit are conflicting. Most believe that it should still be thought of as a safe way to lower LDL cholesterol when statins are not tolerated or do not lower LDL levels enough. Another very large study on Vytorin's effectiveness, IMPROVE-IT, is still under way, and this may clarify some of the issues around the drug's usefulness in patients with coronary disease.

Bile acid binders

Like ezetimibe, bile acid binder resins inhibit the body's absorption of dietary cholesterol, but they work via a different mechanism. Your liver uses cholesterol to make bile acids, a substance needed for digestion. Bile acid binders lower cholesterol indirectly by binding to these acids, prompting the liver to use additional cholesterol to make more bile acids. This reduces the level of cholesterol in your blood.

Medications in this class include cholestyramine (Prevalite, Questran), colesevelam (Welchol), and colestipol (Colestid). Typically, they lower LDL cholesterol by 15% to 30%, depending on the daily dose. Larger amounts produce greater reductions, but also heighten side effects.

Adverse effects of bile acid binders include constipation, heartburn, and a bloated feeling. They can bind with substances other than bile acids and may interfere with the body's ability to absorb some medications, particularly digitalis preparations, beta blockers, warfarin, thiazide diuretics, anticonvulsants, and thyroid hormone supplements. People with high triglyceride levels should not take bile acid binders because they tend to elevate triglycerides. For these reasons, these drugs have largely been replaced by ezetimibe.

Fibric acid derivatives (fibrates)

Fibrates decrease triglycerides by reducing your liver's production of VLDL cholesterol and speeding up its removal from your blood. The two most commonly prescribed fibric acid derivatives are gemfibrozil (Lopid) and fenofibrate (TriCor, Lofibra). Fibric acid derivatives reduce triglyceride levels by 20% to 50% and raise HDL levels by 10% to 15%, but they have only a modest effect on LDL levels. In general, they're prescribed for people with high triglyceride levels and are rarely used for those whose sole problem is high LDL cholesterol.

Gemfibrozil and fenofibrate are usually taken once (fenofibrate) or twice (gemfibrozil) a day with meals. Most people don't experience side effects, although a few develop dyspepsia (feelings of fullness, bloating, or heartburn after eating), dizziness, or changes in sensations, such as touch and taste. Gemfibrozil and fenofibrate can also increase the risk for gallbladder disease.

When used with a statin, fibric acid derivatives can cause rare cases of significant muscle breakdown. However, evidence suggests that this outcome might be less likely with fenofibrate than with gemfibrozil, when it is used with moderate doses of statins. Fibrates can also boost the action of blood thinners, such as warfarin (Coumadin). Because of these uncommon but significant side effects, everyone taking a fibric acid derivative should have liver function tests and blood cell counts before and during therapy. Those on blood-thinning medications should also have their prothrombin time (a measure of clotting ability) monitored closely.

Reference: Cholesterol section on Better Medicine

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