Drug Profile

Atorvastatin (LIPITOR), lovastatin (MEVACOR), pravastatin (PRAVACHOL) and simvastatin (ZOCOR) are members of the statin family of cholesterol-lowering drugs. Statin drugs work by inhibiting an enzyme that is responsible for the production of cholesterol in the body. These drugs should be used only when there has been an inadequate response to nondrug treatment measures, including exercise and dietary changes.

Like all cholesterol-lowering drugs, statins should always be used in addition to a diet restricted in saturated fat and cholesterol.

The consumer’s gold standard for learning about the health benefits, if any, of a prescription drug is the Food and Drug Administration (FDA)-approved product label for that drug. It is clear from the FDA-approved label for statin drugs that use of lovastatin, pravastatin, simvastatin and atorvastatin is preferred over use of rosuvastatin (CRESTOR) or fluvastatin (LESCOL) because use of the former four drugs is supported by acceptable scientific evidence that these drugs confer additional health benefits for people with elevated cholesterol levels, as opposed to solely lowering cholesterol (as is the case with rosuvastatin and fluvastatin).

Lovastatin

The major FDA-approved uses for lovastatin are to reduce the risk of heart attack, reduce the risk of unstable angina (chest pain) and minimize the need for coronary revascularization procedures (procedures to open blocked heart arteries) such as angioplasty and stent placement or heart bypass surgery in individuals without symptomatic cardiovascular disease and individuals with moderately elevated cholesterol levels.[2]

Pravastatin

Pravastatin was approved by the FDA as the primary drug to reduce the risks of heart attack, revascularization procedures such as angioplasty and heart bypass surgery, and cardiovascular mortality for individuals who do not have clinically evident coronary heart disease — without increasing their risk of death from noncardiovascular causes.[3]

Pravastatin also is approved for the secondary prevention of cardiovascular events. Secondary prevention refers to reducing the risk of a serious outcome in individuals who already have clinically evident coronary heart disease. Pravastatin is approved to reduce the risk of coronary death, heart attack, coronary revascularization procedures, stroke and stroke/transient ischemic attack. It also is approved to slow the progression of coronary atherosclerosis (buildup of fatty deposits in the inner walls of arteries).[3]

Simvastatin

The FDA has approved simvastatin for use in individuals at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. In this group of patients, simvastatin is approved to reduce the risk of coronary heart disease, death, nonfatal heart attack and stroke, as well as coronary and noncoronary revascularization procedures.[4]

Atorvastatin

Atorvastatin has been approved to reduce the risk of heart attack, stroke, angina (chest pain) and the need for revascularization procedures, such as angioplasty or bypass surgery, for adult patients who have either clinically evident coronary heart disease or multiple risk factors for coronary heart disease. In addition, for patients who have coronary heart disease, the drug is approved to reduce the risk of hospitalization for congestive heart failure.[5]

A Patient Package Insert was added to the atorvastatin product label to provide patients with information about taking this drug.

Adverse effects

Psychiatric risks

Statin drugs appear to share psychiatric risks with other cholesterol-lowering drugs. Aggressive behavior; memory impairment; mood changes; and cognitive, sleep and perception disorders, such as nightmares, have been reported with the use of many drugs used to treat high cholesterol. These include statins, fenofibrate (TRICOR, TRILIPIX), gemfibrozil (LOPID), ezetimibe (ZETIA) and clofibrate (ATROMID-S).[6],[7]

Researchers have not yet established a direct link between these risks and the use of the aforementioned cholesterol-lowering drugs, although in the October 2005 issue of the Canadian Adverse Reaction Newsletter, 19 cases of memory loss or impairment associated with the use of a cholesterol-lowering statin drug were reported.

Patients should be alert to the possibility of psychiatric risks and report unexpected changes to their doctors. Statin-induced memory impairment could be mistaken for other conditions, such as early Alzheimer’s disease. This could result in the prescribing of a drug to treat Alzheimer’s disease when it is not needed.[8]

Liver toxicity

Liver toxicity is another potential problem with statin drugs. The current labels for these drugs state that elevations in liver function test results, an early indication of possible liver toxicity, have been seen with the use of statins. The label also warns, “It is recommended that liver function tests be performed prior to and at 12 weeks following initiation of therapy or the elevation of dose.” No mention is made of possible liver failure.

The FDA undertook an evaluation of reports of potential liver failure associated with the use of statin drugs in May 2000. A total of 90 cases of liver failure had been reported to the FDA for the six statin drugs on the market at the time. Of the 90 cases, 62 were consistent with the FDA’s definition of liver failure, and more than half of these 62 patients died.[9]

Rhabdomyolysis

Drug-induced muscle injury, or rhabdomyolysis, is another known adverse effect of all statin cholesterol-lowering drugs. Rhabdomyolysis usually is accompanied by pain, tenderness and weakness in the affected muscles.

The most important consequences of rhabdomyolysis, however, are not those on the muscles themselves. As muscle cells break down, they release substances that can cause permanent injury to the kidneys. Even when the condition is reversible, it sometimes requires temporary kidney dialysis (mechanical filtering of the blood). If muscle cells break down rapidly enough, released potassium can cause lethal heart rhythm disturbances. A number of drugs can interact with statins and increase the likelihood of drug-induced muscle injury. (See the "Interactions With Other Drugs" section.)

A large number of cases of fatal rhabdomyolysis led to the withdrawal of the statin drug cerivastatin (BAYCOL) in August 2001.[10] Rosuvastatin (CRESTOR) is listed as a Do Not Use drug because of cases of rhabdomyolysis and direct kidney toxicity (not just from rhabdomyolysis) seen in randomized clinical trials before the drug was approved. In addition, there is no evidence that rosuvastatin prevents heart attacks or strokes in people with elevated cholesterol levels.

Neuropathy

In addition to the adverse effects listed above, there also is an association between the long-term use of statins and an increased, although rare, risk of neuropathy (damage to the nervous system). This can take the form of decreased or increased sensation, abnormal sensation (pins and needles) or muscle weakness. In most cases, the symptoms improved upon cessation of the drug.[11]

Tendinitis and tendon rupture

In 2010, the Netherlands Pharmacovigilance Centre Lareb received 11 reports of tendinitis and 10 reports of tendon rupture associated with statin drug therapy. Tendinitis occurs when the tendon — fiber that joins the muscles to the bones — becomes inflamed. Tendon rupture occurs when the tendon is torn.[12]

Interstitial lung disease

The Canadian Adverse Reactions Newsletter published an article in its October 2011 issue concerning the use of statin drug therapy and the occurrence of interstitial lung disease (ILD), a group of lung disorders that affect breathing. The article stated that “[a]s of Mar. 31, 2010, Health Canada received 8 adverse reaction (AR) reports of ILD, or pathologies associated with ILD.” These cases were suspected to be associated with statin drug use.[13]

Risk of increased blood sugar levels and diabetes

In January 2013, Health Canada (an agency similar to the FDA) issued a communication to the public concerning the use of statins and the risk of increased blood sugar levels in patients with a pre-existing risk of diabetes. Close monitoring for diabetes is recommended in these patients when using statins.[14]

In May 2017, Nutrition, Metabolism & Cardiovascular Diseases published a study showing that statin drugs are associated with an increased risk of new-onset diabetes.[15]

Risk with 80-mg dose

The Medical Letter on Drugs and Therapeutics published an article in August 2011 examining the use of simvastatin in the highest approved dose (80 milligrams [mg]). The article highlighted the changes made by the FDA to the simvastatin drug label concerning the use of the 80-mg dose and the risk of myopathy. The authors of the article advised against using the 80-mg dose. The FDA found that there was an increased risk of muscle injury for patients taking the 80-mg dose of simvastatin.[16]

Despite these findings, the FDA has not banned the 80-mg dose. The agency issued an advisory in 2010 noting the results of a large clinical trial that showed the risk involved with the 80-mg dose. However, in 2011, the FDA advised health care providers to limit the 80-mg dose to patients who have taken that dose for a year or more. It also stated that new patients and those already taking lower doses should not be started on an 80-mg dose.

Interactions with other drugs

The December 2010 Worst Pills, Best Pills News highlighted information on an interaction between simvastatin and danazol (DANOCRINE). Danazol most likely increases simvastatin blood levels by inhibiting the enzyme that metabolizes simvastatin and helps the body get rid of the drug. In severe cases, this can cause rhabdomyolysis.

In December 2011, the FDA restricted the dose of simvastatin from 20 mg to 10 mg when used with amiodarone (CORDARONE, PACERONE). The combination of these two drugs also can cause rhabdomyolysis, which can lead to kidney disease or death. In March 2012, the FDA warned of the interaction of statins with drugs used to treat human immunodeficiency virus (HIV) or hepatitis C virus (HCV). When these two types of drugs are taken together, they increase statin levels and, thus, the risk of muscle injury.

The product labeling for simvastatin also indicates that the drug should never be taken by patients who are being treated with itraconazole (ONMEL, SPORANOX), ketoconazole, posaconazole (NOXAFIL), voriconazole (VFEND), erythromycin (E.E.S., E.E.S. 200, E.E.S. 400, ERYC, ERYPED, ERY-TAB, ERYTHROCIN STEARATE, PCE, PEDIAMYCIN, PEDIAMYCIN 400), clarithromycin (BIAXIN), nefazodone, gemfibrozil (LOPID) or cyclosporine (NEORAL, GENGRAF, SANDIMMUNE).

Studies show …

In early 2003, a highly publicized study comparing a high dose of atorvastatin with a standard dose of pravastatin found that atorvastatin was better in reducing a combination of adverse cardiovascular events in people who had recently been hospitalized with a heart attack or angina. Although this combination of subsequent events was reduced by atorvastatin (compared with pravastatin), there was no significant reduction in the incidence of heart attacks alone or in strokes alone.[17]

In June 2012, the Archives of Internal Medicine published an article concerning the use of statins in women. The article was about a meta-analysis of previously published studies on the use of statins in women. The meta-analysis revealed two major findings: First, the benefits of statins were significant for all outcomes in men, a result consistent with previously published results; second, although there was a statistically significant reduction in risk of coronary mortality, heart attack (fatal and nonfatal) and cardiac intervention in both men and women, there was “no statistically significant risk reduction for women taking statins compared with women taking placebo for the reduction of all-cause mortality [death from any cause] and any type of stroke.”[18]

In 2012, a study was conducted to review muscle and tendon adverse events associated with statin drug use that were reported to the FDA Adverse Event Reporting System. The data studied in these post-marketing case reports showed that the adverse events reported varied for the different drugs in the statin drug class. The drugs reviewed in the study were atorvastatin, simvastatin, lovastatin, pravastatin, rosuvastatin and fluvastatin. The study data examined the relative potency of each drug to muscle-related adverse events risk. The results of the study found that rosuvastatin had the highest relative risk of adverse events, atorvastatin and simvastatin had an intermediate risk, pravastatin and lovastatin had the lowest risk and fluvastatin was “an apparent exception.” (For a detailed description of adverse events reported for each drug, see the referenced article.)[19]

In 2013, the Annals of Internal Medicine published an article on the co-administration of statins (atorvastatin, lovastatin and simvastatin) with macrolide antibiotics (clarithromycin, erythromycin and azithromycin) in patients older than 65 years. The data reviewed showed that patients using atorvastatin, lovastatin or simvastatin experienced statin drug toxicity with co-administration of clarithromycin or erythromycin.[20]

The British Medical Journal published a study in May 2013 that examined the risk of new-onset diabetes in patients treated with statin drugs. The study analyzed the risk in patients treated with atorvastatin, simvastatin or rosuvastatin compared with patients treated with pravastatin. The results of the study indicated that patients treated with atorvastatin, simvastatin or rosuvastatin had a higher risk of new-onset diabetes. The study also stated that patients treated with lovastatin and fluvastatin did not show this increased risk.[21]

An article published in 2015 in Diabetologia showed that patients using statins had a 46% increase in the risk of type 2 diabetes.[22]

In 2016, the American Journal of Cardiovascular Drugs published an article warning that use of statin drugs was associated with an increased risk of developing diabetes.[23]

In 2018, Journal of the American Medical Association Internal Medicine (JAMA Internal Medicine) published an article warning that statins are associated with a rare but potentially disabling autoimmune muscle disorder known as idiopathic inflammatory myositis.[24]

With more than 200 million prescriptions each year in the United States, statins are one of the most prescribed drug categories here and in much of the world (at least in so-called developed countries). About two-thirds of statins are prescribed not for secondary prevention but for primary prevention — that is, to prevent heart attacks, strokes or other cardiovascular disease from developing in people who have not previously had such conditions. Over the past decade, and especially in the past several years, a number of published studies and reviews have documented the overprescribing of statins for primary prevention, especially for those whose combination of age, medical history, cholesterol levels and other cardiovascular risk factors place them at the lower end of the scale of risk for first-time cardiovascular events. This research has raised serious questions regarding the need for any pharmacological intervention in these lower-risk people. Unfortunately, statin users are subjected to the risks of these drugs without benefits.

Before advertising a drug for any use, drug manufacturers must submit clinical trial data to the FDA to show that the drug is effective and safe when used to treat or prevent the indicated disease or condition. Below is a chart that describes which statin drugs are approved for which uses and can therefore be promoted as such. Use of a statin for primary prevention indicates that the drug is approved in a patient with high cholesterol before they have a heart attack or stroke in order to reduce the risk of such an event. Secondary prevention indicates that a patient has already suffered a heart attack or stroke and is trying to prevent a second event by lowering cholesterol levels.

*WorstPills.org has listed rosuvastatin as a Do Not Use drug since the drug's approval, and Public Citizen's Health Research Group has petitioned the FDA to ban it.

In 2023, Journal of the American Heart Association published an article indicating there was a small increase in the risk of hemorrhagic stroke with use of statin drugs.[25]

Regulatory actions surrounding statins

2005: On March 4, the FDA denied two citizens' petitions that would have required the product label for statins to recommend that the dietary supplement coenzyme Q10 be added to statins to reduce the risk of muscle damage, heart damage and congestive heart failure. The FDA found that there was not significant evidence to suggest that coenzyme Q10 levels are responsible for the adverse effects associated with statin use or to suggest that supplementation with coenzyme Q10 has any impact on preventing or lessening any of the potential adverse effects of statin drugs.[26]

2006: The FDA revised the product label of atorvastatin to include information from a large study that examined the effects of statin drugs on patients who recently had a stroke. The study showed that patients who took atorvastatin and had suffered a hemorrhagic stroke within the six months preceding the study appeared to be at an increased risk of hemorrhagic stroke compared with patients who were given a placebo.[5]

The FDA required the manufacturer of lovastatin to update information in its product label about drug interactions that can increase the risk of severe muscle damage. For more detailed information on this update, see the April 2006 Worst Pills, Best Pills News.[2]

2008: The FDA issued an advisory warning on the risks of using dosages of simvastatin greater than 20 mg per day with amiodarone. This combination can lead to muscle injury (rhabdomyolysis), which can lead to kidney failure or death. This risk was added to the simvastatin label in 2002, but the FDA continues to receive reports of it. Dosages of simvastatin greater than 20 mg per day should be avoided in patients taking amiodarone.[27]

2010: The FDA issued an advisory that data from a large clinical trial (and other sources) showed that there was an increased risk of muscle injury for patients taking the highest approved dose of simvastatin (80 mg). According to the advisory, the data included patients taking lower doses of simvastatin “or possibly other drugs in the ‘statin’ class.”[28]

2011: The FDA issued another advisory concerning the use of simvastatin in 80-mg doses and the risk of myopathy (muscle injury). The FDA advises limiting the use of the 80-mg dose to patients who have been taking this dose for 12 months or more without evidence of myopathy. The FDA recommends that new patients and patients already taking lower doses of simvastatin not be started on the 80-mg dose.[29]

In December, the FDA announced new restrictions for the dose of simvastatin when administered with amiodarone. Similar to the agency’s 2008 warning, the revision limits the dose of simvastatin to 20 mg when it is co-administered with amiodarone.

2012: In February, the FDA issued information concerning safety changes for statins. These changes include the removal of routine monitoring of liver enzymes from the drug product information and the addition of information about potential, generally nonserious and reversible cognitive adverse effects, as well as reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels.

Safety changes also were added for lovastatin concerning contraindications and dose limitations when lovastatin is taken with certain medicines that can increase the risk of muscle injury.[30]

In March, the FDA issued an advisory that addressed interactions between protease inhibitors and certain statin drugs. HIV or HCV protease inhibitors, when used with statins, may raise the levels of statins in the blood and increase the risk of muscle injury (myopathy).[31]

2013: The FDA updated the drug product label for statins to include information on rare reports of an autoimmune myopathy associated with use of such drugs. Immune-mediated necrotizing myopathy presents with proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of treatment with statins.[32]

2023: The FDA updated the drug product label for simvastatin to include information on rare reports of new or worsening myasthenia gravis (a disease causing muscle weakness).[33],[34]

2024: The FDA updated the drug product label for atorvastatin to include information on rare reports of new or worsening myasthenia gravis (a disease that causes muscle weakness).[35]