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A Review of Ezetimibe (ZETIA) and Ezetimibe with Simvastatin (VYTORIN) For Cholesterol Lowering

Worst Pills, Best Pills Newsletter article December, 2004

 The Health Research Group’s Seven Year Rule

You should wait at least seven years from the date of release to take any new drug unless it is one of those rare “breakthrough” drugs that offers you a documented therapeutic advantage over older proven drugs. New drugs are tested in a relatively small number of people before being released, and serious adverse effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people. A number of new drugs have been withdrawn within their first seven years after release. Also, warnings about serious new adverse reactions have been added to the labeling of a number of drugs, or new drug interactions have been detected, usually within the first seven years after a drug’s release.

Any person with elevated LDL cholesterol or other form of elevated blood fats (hyperlipidemia) should undergo medical evaluation to rule out other causes before drug treatment is begun.

Secondary causes are:

  • Diabetes
  • Hypothyroidism (low thyroid)
  • Chronic kidney failure
  • Drugs that increase LDL cholesterol and decrease HDL cholesterol are progestins, anabolic steroids, and corticosteroids.

The Food and Drug Administration (FDA) approved Zetia (ezetimibe) in October 2002 to manage high cholesterol. It was approved to be used either alone or in combination with the widely used family of cholesterol lowering agents known as “statins.” More recently, in July of 2004, FDA approved a single combination pill of Vytorin (ezetimibe and simvastatin). Zetia alone has rapidly moved on to the list of top-selling drugs with more than 4.2 million prescriptions being dispensed in 2003 in U.S. pharmacies.

Zetia works to lower cholesterol in a new way different from the statins: it inhibits the absorption of cholesterol in the small intestine, whereas the statins work by blocking cholesterol production in the liver. Drugs that work in new ways are always a cause for concern because they have the potential to cause adverse drug reactions in unexpected new ways. That is a particular worry in this case, since clinical trials were so short (only 3 months vs. the more usual 6 to 12 months, or longer).

The statins on the market in the U.S. which can be combined with Zetia, are Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor (lovastatin), Pravachol (pravastatin), Crestor (rosuvastatin), and Zocor (simvastatin). Baycol (cerivastatin) was withdrawn from the market in August 2001 because it produced rhabdomyolysis, a condition causing rapid muscle breakdown that can result in kidney failure and death (see Worst Pills, Best Pills News October 2001 ). The Health Research Group has asked the FDA to remove Crestor from the market.

Both Zetia and the fixed combination with simvastatin are co-promoted by Schering-Plough and Merck. The companies’ principle marketing claim for Zetia has been improved safety over other cholesterol lowering drugs, particularly the statins, but with no actual proof that safety is, in fact, improved. Indeed, there is already evidence from the FDA Adverse Events Reports System (AERS) that Zetia may, on its own, cause rhabdomyolysis, a serious and potentially fatal disease involving destruction or degeneration of skeletal muscle.

Much of this article is based on publicly available FDA reviews of clinical trials and pharmacology studies that ezetimibe’s manufacturer submitted to support the approval of the drug. We find these reviews invaluable as the analyses are independent of company influence, unlike so much of the peer reviewed medical literature. These reviews can be found on FDA’s website for approved products: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

We are concerned about any new drug but are particularly concerned about the use of Zetia together with statins. The FDA subsequently approved the fixed combination pill of Vytorin (ezetimibe and simvastatin). This approval occurred despite the fact that the FDA Pharmacology Reviewer sounded a warning of serious safety concerns about the combination, and recommended against approval. She observed that no matter how small the amount of the two drugs administered together to laboratory animals, toxicity was still seen; that is, there was no “no-observed-adverse-effect-level” or NOAEL. The technical definition of NOAEL is that it is the highest concentration of a substance which causes no detectable adverse change in morphology, functional capacity, growth, development, or life span (of laboratory animals, in this case).

Specifically, the FDA Reviewer wrote:

Pharmacology recommends approval of this drug [ezetimibe] for monotherapy for the proposed indication [use], but preclinical studies do not support safety of ezetimibe in combination with statins. Generally, a NOAEL could not be established. The toxicity profile appears to be that associated with statins. . . . However the toxicity appears at lower duration and exposure than in statin monotherapy.

She further noted that toxicity seen when Zetia was used alone occurred in the heart, lymph nodes, kidneys and bone marrow in laboratory animals; an earlier pharmacology review found lung and liver toxicity as well. When Zetia was combined with a statin, toxicity was seen in even more organs: liver, stomach, skeletal muscle, spleen, heart, lungs, testes, and prostate.

Adverse Reactions Seen in Clinical Trials

Muscle: A major safety concern with cholesterol lowering drugs, particularly the statins, is the possibility of rhabdomyolysis, a breakdown of muscle. This potentially fatal adverse effect led to the withdrawal of cerivastatin in 2001. The FDA Medical Officer conducting the Zetia safety review of clinical trials noted that patients taking Zetia were more likely to have elevations of a blood enzyme known as creatinine phosphokinase (CPK), an early signal of muscle toxicity and a risk factor for the possible development of rhabdomyolysis.

In the clinical trials, 2.1 percent of Zetia patients and 1.3 percent of placebo patients had CPK levels greater than three times the upper limit of the normal value. An even greater CPK increase (greater than ten times the upper limit of normal) was seen in 0.2 percent of the patients receiving Zetia and 0.1 percent given the placebo. Moreover, when Zetia was added to a statin, the incidence of muscle pain jumped from 2.6 percent to 4.5 percent.

Liver: There was an elevation of a liver enzyme that was greater than three times the upper limit of normal levels (a warning signal for liver damage) in 0.0 percent of patients receiving placebo, 0.8 percent of patients taking Zetia alone (10 milligrams per day), 1.0 percent of patients taking a statin alone, and 2.1 percent of patients taking both Zetia (10 milligrams) plus a statin.

Post-marketing adverse reactions of combination therapy (medical literature)

Two case reports published in the April 20, 2004 Annals of Internal Medicine suggest that Zetia may trigger muscle and tendon pain when it is added to statin treatment. Unexpected muscle pain can be another early signal for rhabdomyolysis.

Post-marketing adverse reactions Zetia and combination (FDA reports)

We examined the FDA’s adverse drug reaction database from late 2002, when Zetia was approved, through September 2003, to see what kinds of adverse reactions were being voluntarily reported. Since as few as one-in-ten serious adverse drug reactions are reported to the FDA, the numbers of cases we found can probably be multiplied by ten.

Muscle: Twenty cases of rhabdomyolysis were reported in patients taking ezetimibe by itself (without a statin or a fibrate, another class of lipid lowering drugs), one with kidney failure. There was one additional report of rhabdomyolysis when Zetia was used in combination with a statin. Although no patient developed rhabdomyolysis in pre-approval clinical trials, those trials were only 3 months long, and patients were carefully monitored to catch any problems early, before they could develop into anything more serious. In addition to the rhabdomyolysis, we found 83 reports of increased CPK blood levels in patients taking Zetia alone with only two cases of elevations in patients taking the combination Zetia with a statin. Now that Vytorin is approved, the incidence will undoubtedly increase.

Liver: Liver toxicity is also a concern. The statin drugs are known to cause elevations in the blood levels of liver enzymes, an early signal of more serious liver toxicity, and this information is carried in the professional product labeling or package inserts for the statins (see Worst Pills, Best Pills News January 2001). We have found that Zetia can also cause elevations of liver enzymes, with 106 cases being reported for patients taking Zetia without a statin. There have been two reports of liver failure, one in a patient taking Zetia alone and one in a patient taking both Zetia and a statin.

Zetia’s professional product labeling cautions that when the drug is used in combination with a statin, liver function tests should be performed at the initiation of treatment and according to the recommendations for the statin drug being used. Whether those taking Zetia alone also need monitoring is not yet known, but Zetia does appear to have liver toxicity on its own.

Other target organs: FDA has received multiple adverse reaction reports of patients taking Zetia where other organ systems (besides muscle and liver) have been harmed: these included the heart, gastrointestinal tract, and skin. Eleven deaths had also been reported (as of September 30, 2003), 8 of which were related to the heart (chest pain, angina, or heart attack); there was also one death due to liver failure, and one to pancreatitis.

In July and September 2004, FDA added new warnings to the list of adverse events associated with the use of Zetia in the drug’s professional product labeling. These warnings followed reports coming into the FDA of hypersensitivity reactions, angioedema, inflammation of the gallbladder, gallstones, pancreatitis and nausea. Angioedema is a serious allergic skin condition characterized by patches of circumscribed swelling involving the skin and its subcutaneous layers, the mucous membranes, and sometimes the heart, liver, or intestine.

Alternate treatments for high cholesterol

It is our view that Zetia and Vytorin (Zetia combined with simvastatin) are not first-choice drugs for treating high cholesterol: they have not been shown to have any health benefits, e.g., to reduce the risk of a first or second heart attack or stroke in people with high cholesterol, as have some of the other cholesterol lowering drugs (the FDA does allow the statin drugs on their own, lovastatin, pravastatin, and simvastatin, to make such claims). We have further concerns about Vytorin, since both animal toxicology studies and clinical trials indicate an increase in adverse effects compared with either drug alone.

The FDA recently approved Lipitor’s (atorvastatin’s) claim that in adults with multiple risk factors for coronary heart disease (such as age 55 years or greater, smoking, high blood pressure, low levels of good cholesterol (HDL), or a family history of early coronary heart disease), but without clinically evident coronary heart disease, atorvastatin can reduce the risk of a heart attack.

Niacin extended-release tablets are also approved by the FDA to reduce cholesterol and to reduce the risk of recurrent nonfatal heart attack in patients with a history of a previous heart attack and elevated cholesterol levels. This applies only to the brand name product Niaspan.

What You Can Do

There is no medical reason for you to be taking Zetia alone (ezetimibe) or Vytorin (Zetia in combination with simvastatin) when there are safer and more effective drugs, in terms of reducing cardiovascular events, on the market.

A life style consisting of a healthy diet, adequate rest, exercise, and no smoking is the best prevention of cardiovascular disease.