Dean A. Seehusen, MD, MPH, FAAFP; Chad A. Asplund, MD; Dawn R. Johnson, DO; Kevin Horde, A. DO 

South Med J.  2006;99(3):250-254.  ?2006 Lippincott Williams & Wilkins

Abstract and Introduction

Introduction

HMG-CoA reductase inhibitors (statins) have become one of the most commonly prescribed classes of medications in the United States. While serious adverse events are rare, less serious events are frequently seen. Published guidelines recommend initial screening labs as well as ongoing monitoring of liver enzymes during therapy. Up to 5% of patients will have some muscle complaints while taking statins. Therefore, primary care clinicians will often be faced with real or potential complications of statin therapy. There are well established risk factors for development of these complications. Being aware of a patient's risk and using the lowest effective dose minimizes the occurrence of adverse events. The great majority of these abnormalities either do not require discontinuation of therapy or require only brief interruption of therapy. Judicious and systematic use of laboratory testing will minimize needless evaluation and premature discontinuation of statin therapy.

Introduction

Statins (3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) have become the mainstay of therapy for controlling lipid disorders. The future promises more patients will be taking these medications as goals for cholesterol therapy are dropped and new indications for statin therapy are introduced. While serious adverse events are rare with statin therapy, less serious side effects and minor laboratory abnormalities are relatively common. Most of the common issues encountered during statin therapy are either self-limited or can be easily addressed without permanently discontinuing statin therapy. A thoughtful approach to monitoring and evaluating statin side effects will allow most patients to continue to reap the benefits of this valuable class of lipid lowering agents. This review covers the two most commonly encountered clinical situations that represent potential adverse effects of statin therapy: myopathy and elevated transaminases.

Statin-induced Myopathies

Muscle symptoms are a relatively common, and the most potentially hazardous, complaint of patients taking statin medications.^[1] These include a range of conditions from muscle pain or weakness through frank rhabdomyolysis. In August of 2001, cervastatin was taken off the US market because of a fatal rhabdomyolysis rate of greater than 3 patients per one million prescriptions.^[2]

The underlying pathophysiology of statin-induced muscle disorders is not well understood and is the subject of much debate in the medical literature.^[2,3] It is clear, however, that these complications are dose related and have several predisposing factors associated with them.^[4]

Spectrum of Disease

The American College of Cardiology (ACC), the American Heart Association (AHA) and the National Heart, Lung and Blood Institute (NHLBI) have defined myopathy as any disease of muscles. They further defined three types of muscle disorders associated with statins: myalgia-muscle pain or weakness without CK elevation, myositis-pain or weakness with CK elevation, and rhabdomyolysis-muscle symptoms with CK elevation greater than 10 times the upper limit of normal, usually associated with myoglobinuria.^[5] These complications of statin therapy may happen soon after initiating therapy or may occur many months later. It has been pointed out elsewhere that these definitions leave out asymptomatic CK elevations and that the cutoff for rhabdomyolysis at 10 times the upper limit of normal CK levels is somewhat arbitrary.^[3]

In most randomized controlled trials, between 1 and 5% of patients in both the study and placebo groups had muscle complaints.^[3,4,6] Pooled analyses of clinical trials involving pravastatin^[7] and atorvastatin concluded that serious myopathies were rare in clinical trials and that study subjects experienced myopathy at no greater rate than placebo subjects.^[8] Pfeffer found no cases of severe myopathy in over 112,000 patient years of treatment during clinical trials of pravastatin.^[7] It should be kept in mind, however, that many of these studies used highly selected study populations that may not reflect the groups that are prescribed statins in practice.^[9,10] In a population-based study, Graham et al^[11] found an incidence of hospitalized rhabdomyolysis of 0.44 per 10,000 for monotherapy with atorvastatin, pravastatin, or simvastatin. Based on available data, the incidence of serious myopathy appears to be less than one tenth of 1% and the rate of fatal rhabdomyolysis is less than 1 per million prescriptions with the currently available statin preparations.^[3]

Initiating Therapy

There are well established risk factors for developing myopathy with statin therapy. Among these are older age, alcohol abuse, small stature, chronic renal insufficiency, hepatic disease, diabetes and hypothyroidism.^[6,8] Unfortunately, some of these risk factors contribute to the indications for prescribing cholesterol-lowering medications. Several of these conditions occur more frequently in elderly women, making them a group to pay particular attention to when initiating therapy.^[6] Statin therapy should be started at a low dose in patients at increased risk and should be maintained at the lowest dose needed to achieve therapeutic goals in all patients.^[3]

There are several medications that, when used in combination, increase the risk of statin-induced myopathy. These include niacin, verapamil, diltiazem, amiodarone, cyclosporine, azoles, macrolides and, notably, fibric acids. Of these, gemfibrozil is the most clinically important (see below). In addition, the consumption of large amounts of grapefruit juice is considered a risk factor for developing statin-induced myopathy.^[3,4]

All patients in whom statin therapy is initiated should be warned about the possibility of muscular symptoms. Patients should be told to immediately report any muscle pain or weakness. They should also be told to stop the medication immediately and seek medical attention for severe muscle pain or brown urine.

The third report of the Adult Treatment Panel III (ATP III)^[12] recommends that baseline creatine kinase (CK) levels be checked upon initiating statin therapy, the rationale being that asymptomatic CK elevations are relatively common. Determining the patient's pretreatment CK levels will prevent inappropriately attributing CK elevation to statin therapy in the event of muscle complaints later. It is not clear what should be done in the event that CK levels are elevated at baseline. In practice, it appears that this recommendation is not widely followed. Drawing a TSH before initiating statin therapy is also recommended since untreated hypothyroidism not only predisposes to statin-induced myopathy but can itself elevate cholesterol levels.^[2,13]

Patients should be questioned about muscle symptoms 6 to 12 weeks after initiating therapy and at each follow-up visit.^[14] Some authorities recommend discontinuation of statin therapy in preparation for major surgery or before expected strenuous activity, such as marathon running.^[3,5]

Monitoring CK Levels

Despite a lack of evidence for utility,^[15,16] many physicians choose to periodically monitor CK levels. Smith et al^[17] evaluated the practice at the primary care center of Beth Israel Deaconess Medical Center during 1998 and found that over half of the patients receiving statin therapy had their CK levels monitored. Less than 1% of these patients were found to have significantly elevated CK levels and in none of the patients was it felt to be attributable to statin therapy. CK levels rise suddenly in severe myopathy, not gradually, so screening is unlikely to be beneficial.^[1] The ACC, AHA and NHLBI,^[5] in their combined clinical advisory on the use and safety of statins, do not endorse routine monitoring of CK levels in patients taking statin medications. Sniderman6^[1] has also argued saliently that such monitoring is potentially harmful by leading physicians to discontinue statins in patients at high risk for cardiovascular events.

It has also been shown that some patients can have normal CK levels and still have histologic evidence of myopathy. Phillips et al8^[1] reported a study of four patients without CK elevations who had pathologic changes consistent with myopathy on muscle biopsy. These patients had muscle complaints while taking statins which resolved when switched to placebo in a blinded manner and recurred with reinstitution of therapy. The histologic changes resembled abnormalities previously reported in metabolic abnormalities and coenzyme Q10 deficiency.

Evaluation of Complaints

When a patient on statin therapy complains of muscle pain or weakness, a thorough history to evaluate for predisposition to myopathy and a physical examination focusing on tenderness to palpation and findings consistent with other causes of myopathy should be conducted. Other causes, such as strenuous exercise, should be ruled out. Initially, a creatine kinase level and a TSH should be drawn.^[5] If the patient complains of brown urine or if CK levels are markedly elevated, renal function and urine myoglobin should be evaluated. If CK levels are elevated, a workup for other possible causes of myopathy should be initiated, including an ANA and CBC.^[2] Figure 1 suggests a decision tree for evaluation and classification of muscle complaints.

Figure 1. 

Diagnostic decision tree for patients on statins presenting with muscular complaints.

     

Therapeutic Options

In patients with myalgias without CK elevations, continuing therapy at the same or lower dose, with increased frequency of monitoring is a reasonable option as long as their symptoms are tolerable and not progressive. This may be the wisest alternative in patients at high risk for vascular events.^[19] Alternatively, the current statin can be stopped and restarted after resolution of symptoms.^[5] Some providers may choose to try an alternative statin or another class of medications altogether.^[3] These same options exist for those patients with mild or moderate elevations in CK levels. If therapy is continued despite CK elevation, patients should be warned to stop their medication if they develop brown urine or if their symptoms suddenly worsen.

Statin-induced muscle abnormalities generally resolve in a few days to a few weeks after discontinuation of the drug.^[13] There have been isolated cases of persistent CK elevations for months to years.^[6] With myalgia or myositis, many patients will tolerate reintroducing the same statin after symptoms resolve.^[5] Reintroduction should be at a lower dose if possible.

In patients with marked elevation of CK levels or myoglobinuria, statin therapy should be discontinued at once and the patient should be evaluated for evidence of renal failure. Patients with rhabdomyolysis and renal failure should be admitted to the hospital for further management. In patients without renal failure, it is reasonable to follow them as outpatients until resolution. It is unclear if these patients should be restarted on statin therapy. This decision should be made on an individualized basis, carefully weighing risks and benefits of further statin therapy.^[3,5]

The Role of Coenzyme Q10

While the cause of statin-associated myopathy is controversial, a central role for coenzyme Q10 (CoQ10 or ubiquinone) is slowly gaining acceptance. Statins have been shown to create an acquired CoQ10 deficiency.^[20,21] This enzyme is essential to mitochondrial ATP generation and antioxidant function in lipid and mitochondrial membranes.^[2,20] This acquired deficiency may lead to myopathy by inhibiting the biosynthesis of cholesterol.^[22,23] Statin-induced CoQ10 deficiency is more prevalent in patients with a pre-existing deficiency such as the elderly,^[24,25] as CoQ10 decreases with age, congestive heart failure,^[25] or those with unmasked mitochondrial defects.^[2]

CoQ10 deficiency can be corrected with exogenous supplementation, as dietary sources are insufficient.^[25] Prophylactic therapy may be considered with CoQ10 (60 mg/d to 120 mg/d)^[2,20,25] at the initiation of statin therapy. For treatment of statin-associated myalgias, temporarily discontinue the drug and institute a CoQ10 trial before statin reintroduction. If the symptoms are due to CoQ10 deficiency, repletion may improve symptoms in as little as 3 days, or may take up to 8 weeks.^[2,20,25]

CoQ10 supplementation is generally well tolerated. Although CoQ10 may cause gastrointestinal side effects in less than 1% of patients, no significant adverse effects have been reported in clinical studies. Case reports have documented interference with warfarin anticoagulation and CoQ10 may enhance the blood pressure-lowering effects of antihypertensive medication.^[26]

Cotherapy with Fibric Acids

The most recent ATP III goals for triglyceride levels make combination therapy very appealing.^[5,27] However, adding fibric acid therapy, in particular gemfibrozil, to statin therapy may increase the incidence of significant muscle toxicity. Although some studies have found minimal risk,^[8,28] others have found rates of significant myopathy as high as 5% with fibrate-statin combination therapy.^[4] Graham et al1^[1] found greater than a 10-fold increase in the incidence of hospitalized rhabdomyolysis when a fibrate was added to statin therapy. Manufacturer package inserts have started indicating that statins should be used at a low dose when combined with gemfibrozil.^[3] Patients on combination therapy need to be counseled more extensively and should be monitored more closely for signs and symptoms of muscle problems.^[4]

Although the reason for the increased rate of adverse effects with combination therapy is not clear, one possible explanation is that gemfibrozil increases serum concentrations of active statin acids.^[29] In comparison, fenofibrate does not seem to increase serum statin concentrations, and may therefore pose a less significant risk than gemfibrozil when combined with a statin. An evaluation using the United States Food and Drug Administration's Adverse Event Reporting System revealed a 15-fold lower rate of reported cases of rhabdomyolysis in patients using fenofibrate combined with a statin compared with those taking gemfibrozil and a statin.^[30]

Liver Toxicity

Due to concerns about liver toxicity, it has been recommended that liver enzymes be checked in patients beginning statin therapy and periodically thereafter. In clinical trials, mild transaminase elevations have been common both in patients on statins and in control groups. Serious liver toxicity from statins is rare. It remains controversial to what extent, if any, the recommended screening for underlying liver disease or statin-induced hepatotoxicity is beneficial.

Monitoring Transaminases

Early clinical trials on lovastatin showed frequent elevations of transaminases. High dose lovastatin has previously been shown to cause hepatitic necrosis in laboratory animals.^[19] Because of concerns regarding the risk of hepatitis in humans, the Food and Drug Administration and drug manufacturers have recommended screening transaminase values before starting, at 12 weeks following initiation of therapy, at any elevation in dose, and periodically thereafter. Most physicians follow these recommendations.^[15,17] In the Scandinavian Simvastatin Survival Study (S4),^[10] minor elevations of ALT were almost always greater than AST and were unrelated to alkaline phosphatase or bilirubin. Therefore, some authors have recommended that monitoring ALT is all that is required for documenting possible hepatotoxicity because of the relative nonspecificity of AST levels, which can occur with either muscle or liver injury.^[31]

No data to date has shown that elevated liver enzymes are predictive of liver injury or acute hepatocellular reactions with statin therapy, thus questioning the necessity of routine monitoring.^[32] The presentation of early symptoms consistent with toxic effects, such as pruritus or jaundice, may be the best way to prompt further laboratory testing. In a retrospective review of over 1,000 patients, Smith et al found that routine monitoring of transaminases revealed no significantly or moderately abnormal values attributable to statins.^[17] In a meta-analysis of 3 major trials of pravastatin, assessing over 112,000 person-years of exposure, only 1.4% showed significant transaminase elevations, which was the same as placebo.^[7] A separate large meta-analysis, involving almost 50,000 patients from 13 clinical trials, showed that statins at low to moderate doses are not associated with a risk of significant liver abnormalities.^[33]

Even in patients with elevated baseline transaminases, there is little objective evidence that statins increase the risk of significant elevations. In the Prospective Pravastatin Pooling Project, 5% of patients with baseline transaminase elevations of 1.5 to 3 times the upper limit of normal went on to have elevations of greater than 3 times the upper limit of normal. In comparison, 7.3% of similar patients on placebo developed similar elevations.^[7] In a study by Chalasani, patients with a history of elevated baseline liver enzymes had a higher incidence of mild-moderate but not severe elevations in liver biochemistries. The frequency of mild-moderate or severe elevations in patients with existing elevated transaminases was not significantly different from those not prescribed a statin. This suggests that individuals with elevated baseline liver enzymes are not at higher risk for hepatotoxicity from statins.^[34] Although there is no strong evidence, two areas where more frequent monitoring may be warranted are in the presence of pre-existing liver disease and in patients on multiple medications for which hepatitis is a known side effect.^[35]

Transaminase Elevations

The term "transaminitis" represents liver enzyme leakage without hepatotoxic consequences in patients receiving drug therapy of any kind.^[32] Asymptomatic increases in transaminases to greater than 3 times normal occur in about 1 to 3% of patients and appear to be dose-dependent.^[32,36] These elevations are felt to be most common during the first 3 months of therapy but can happen at any time.^[6,29] Hepatic failure rarely occurs with statin therapy and is an idiopathic event.^[16] Asymptomatic transaminitis is not considered a harbinger of hepatitic failure and it is unlikely that impending liver failure would be caught with screening labs.^[16,19]

Transaminitis is not unique to statin therapy; it can occur with any class of lipid lowering agent, suggesting that the elevations may be secondary to changes in lipid metabolism induced by the drugs, and not to toxic effects of the medications themselves. It is possible that specific effects of serum lipid lowering on the cellular membranes allows for more leakage of cellular enzymes leading to transaminitis.^[37] The fact that histologic injury does not appear to occur with elevations of ALT suggests that hepatic adaptation or tolerance occurs rapidly.^[10,37]

Therapeutic Options

In patients found to have elevated transaminase levels on routine screening, the appropriate response will depend on the level of increase, the patient's symptoms and the need for lipid statin therapy. The first step in the evaluation of transaminase elevation is to repeat the test.^[38] The level of abnormality dictates how soon levels should be re-evaluated. Mild elevations could be rechecked in 3 months while larger elevations should be rechecked within the week.^[39] About half of the time, these abnormalities will resolve with repeat testing done within one week without stopping the medication.^[6] Transient increases are common and not clinically important.

If the elevation remains and the level of increase is less than 3 times the upper limit of normal, there is no need to interrupt therapy, although more frequent monitoring might be justified. Patients with persistent elevations should be questioned about symptoms, risks of underlying hepatic disease should be assessed and further evaluation for viral, alcoholic or other liver disease should be pursued as indicated.^[6,38]

For persistent elevations greater than 3 times the upper limit of normal, a decrease in dose or discontinuation of therapy is warranted. Transaminase elevations due to statin therapy will almost always resolve within 6 weeks of discontinuation. The decision to reinstitute therapy should be based on an individualized risk versus benefit analysis.^[38] Signs and symptoms of hepatic failure should prompt immediate discontinuation of therapy and referral to a specialist.^[6]

Other Possible Adverse Effects

Early observational studies and meta-analyses seemed to show an association of statin therapy and depression, aggression and suicidal behavior^[40] More recent studies have failed to confirm the association.^[41] In a nested case-control study, Yang et al2^[4] found a decreased risk of depression among those taking statins. The authors were quick to point out that they did not believe there was a causal relationship, however.

Concerns have been raised about the potential carcinogenicity of long term statin use. However, both randomized trials and meta-analyses of statin exposure have shown no association with increased risk of fatal or nonfatal cancer over a 4- to 6-year period of use.^[7,19,43] Prospective studies that look at longer exposure remain to be done. One Danish population study^[44] found a slight decreased risk of all cancers in statin users over a 13-year period. Atorvastatin and fluvastatin have been shown to inhibit the growth of breast cancer cells in vitro^[45] although no clinical trials have examined the potential antitumor effects of statins.

There is conflicting data on the impact of statins on cognition. Numerous case reports have raised the possibility of cognitive decline after initiation of statin therapy.^[46] A meta-analysis done by Etminan et al^[47] showed a lower risk of cognitive decline in patients taking statins. A randomized study designed to evaluate cognitive effects of statins is currently underway.^[48]

There may be an adverse association between statin therapy and diastolic heart failure. Statin therapy in patients with congestive heart failure has not been well studied because these patients have been excluded from many major trials.^[49] Some studies have shown lower serum cholesterol to be independently associated with a worse prognosis in patients with congestive heart failure.^[50] In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), more heart failure admissions were seen in patients randomized to 10 mg of atorvastatin than those taking placebo.^[51] Whether or not statins actually worsen heart failure remains controversial and currently, several large prospective, randomized trials are being conducted to evaluate the effects of statins in patients with congestive heart failure.^[52]

Silver et al^[51] recently published a small study confirming with Doppler echocardiography that many patients' left ventricular diastolic function declined with atorvastatin treatment, and improved with supplemental CoQ10 administration. Although not all studies have found coenzyme Q10 to be beneficial, many have reported significant subjective and objective outcome improvements and none have shown CoQ10 to be harmful.^[53-59] Until further studies are available, providers may want to discuss the risks and benefits of such therapy with their congestive heart failure patients on statins.^[60]

Statin Therapy in Children

Treatment of hypercholesterolemia in children is becoming more common. It appears that statin therapy is both safe and effective for patients over the age of 10 with familial hypercholesterolemia.^[61-63] A recent 2-year study of 214 children with familial hyperlipidemia found no significant differences in height, weight, endocrine function, or Tanner staging between children on pravastatin and those on placebo. Similarly, levels of AST, ALT, and CK showed no difference between the groups and no appreciable changes from baseline.^[64]

Conclusion

Statins are among the most widely prescribed medications in the United States and are likely to become even more popular. While there are well recognized adverse effects related to statin therapy, overall, these drugs have a very good safety record. Unfortunately, the patients in whom statin therapy is most useful also tend to be most at risk for serious side effects. Being aware of a patient's risk and using the lowest effective dose minimizes the occurrence of adverse events. Judicious and systematic use of laboratory testing will minimize needless evaluation and premature discontinuation of statin therapy.

The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of Defense.

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Sidebar: Key Points

Reprint Address

Dean A. Seehusen, MD, MPH, FAAFP, Dwight D. Eisenhower Army Medical Center, Fort Gordon, GA 30509. Email: dseehusen@msn.com