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1 Dr Jacobson has served as a consultant and speaker for Abbott, AstraZeneca, Merck, Merck/Schering-Plough, Novartis, Pfizer, Reliant, and Schering-Plough.
Terry A. Jacobson
Correspondence
Individual reprints of this article are not available. Address correspondence to Terry A. Jacobson, MD, Office of Health Promotion and Disease Prevention, Emory University, Faculty Office Building, 49 Jessie Hill Jr Dr SE, Atlanta, GA 30303
1 Dr Jacobson has served as a consultant and speaker for Abbott, AstraZeneca, Merck, Merck/Schering-Plough, Novartis, Pfizer, Reliant, and Schering-Plough.
Affiliations
Office of Health Promotion and Disease Prevention, Emory University School of Medicine, Atlanta, GA
1 Dr Jacobson has served as a consultant and speaker for Abbott, AstraZeneca, Merck, Merck/Schering-Plough, Novartis, Pfizer, Reliant, and Schering-Plough.
Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and postmarketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.
Despite reducing relative risks of coronary events and mortality from coronary events and all causes in several landmark clinical trials, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are underused.
The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: findings from the National Health and Nutrition Examination Survey, 1999 to 2000.
Circulation.2003 May 6; 107 (Epub 2003 Apr 28.): 2185-2189
Many health care professionals have expressed concern about potential adverse events (AEs), particularly severe muscle toxicity, which has been recognized as an impediment to appropriate statin use.
Given these perceptions, an AE, such as myalgia, can assume an important role in a patient's decision to discontinue a much-needed lipid-modifying medication. Indeed, several studies document a significant decrease in adherence to lipid-lowering treatments over time among outpatients, and some indicate that patients' perception of AEs is a primary reason for discontinuation.
A more collaborative physician-patient relationship, which might include asking the patient about statin tolerance, has been recommended to foster adherence.
In light of these considerations, several clinical issues arise. What is the magnitude of statin-associated myalgia? How does it affect patient acceptance of and adherence to statin therapy? Are there clinically meaningful differences among the statins that might affect the risks of myalgia, myopathy, and rhabdomyolysis? How can the risk and severity of statin-associated myopathy be minimized? How can statin-associated muscle symptoms be managed?
This review delineates the scope of statin-related myalgia, myopathy, and rhabdomyolysis on the basis of findings from recent meta-analyses, cohort trials, and clinical trials and of analyses of Food and Drug Administration (FDA) data; explores the clinical effects of statin-associated muscle symptoms; and outlines diagnostic and management strategies for muscle symptoms.
METHODS
Data Sources and Extraction
Consensus guidelines concerning statin safety issues were reviewed, and certain articles cited in their bibliographies were included. An English-language PubMed search spanning the past 30 years (January 1, 1977-December 31, 2007) was conducted. Search terms included adherence, compliance, creatine kinase, hydroxymethylglutaryl coenzyme A reductase inhibitors, human, hypercholesterolemia, muscle, myalgia, myopathy, myositis, pain, rhabdomyolysis, safety, tolerability, toxicity, treatment discontinuation, treatment outcome, and weakness. Only prospective studies were included. Although case series, case reports, and open-label studies were excluded, observational studies and retrospective analyses, including analyses of postmarketing surveillance databases, were eligible for inclusion.
Definitions of Terms
Muscle symptoms, signs (creatine kinase [CK] elevations), or a combination thereof (myositis or rhabdomyolysis) are the most prevalent and important AEs associated with statin therapy.
However, for the purposes of the current review, symptoms of myalgia include cramping, pain, aches, tenderness, soreness, stiffness, heaviness, and weakness, either at rest or during physical exertion (eg, loss of strength). In some patients, weakness is the only symptom and develops insidiously. Many patients experience myalgia, including a loss of strength, only during physical exertion. Myositis is defined as elevated CK in the presence of muscle symptoms. Rhabdomyolysis is defined as pronounced CK elevation, 10 times the upper limit of normal (ULN), with serum creatinine elevation, in the presence of muscle symptoms.
Consensus guidelines from the American College of Cardiology, American Heart Association, and National Heart, Lung, and Blood Institute define myopathy generally as any disease of muscles—either congenital or acquired.
commented on the limitations of these definitions, including their imprecision. It should also be noted that CK can be increased by factors other than lipid-modifying treatment, including immunoglobulin-bound CK (macro CK), which has been documented since 1979
and could be responsible for (largely artifactual) CK elevations in approximately 3% of patients.
The exact mechanism for statin-associated myopathy, including myalgia, has yet to be elucidated. The pharmacodynamic basis of this problem might involve depletion of mevalonate derivatives distal to the rate-limiting enzyme blocked by statins (HMG-CoA reductase). These derivatives mediate certain processes critical to the integrity of the skeletal myocyte. One such metabolite is ubiquinone (also termed coenzyme Q10 [CoQ10]), a constituent of the mitochondrial electron transport chain.
Other proposed mechanisms of myopathy include depletion of cholesterol, leading to alterations in myocyte membrane cholesterol, or statin depletion of key isoprenoids that control myofiber-apoptosis.
Isoprenoids, lipids that are a product of the HMG-CoA reductase pathway, are linked to proteins by either farnesylation or geranylgeranylation. A reduction in the farnesylation or geranylgeranylation of proteins is thought to increase levels of cytosolic calcium, which activates a cascade of events leading to the activation of caspase-3, a proteolytic enzyme that has a central role in cell death.
Variation in definitions, the failure to carefully characterize AEs reported in the literature, and potential limitations of the FDA Adverse Event Reporting System (AERS) all hamper the determination of the absolute risks of muscle-related AEs with statins.
These limitations not-withstanding, serious muscle toxicity with marketed statins is rare: myopathy occurs in 5 patients per 100,000 person-years and rhabdomyolysis in 1.6 patients per 100,000 person-years.
The incidence of myalgia, which is not as well defined as that of more serious myotoxicities, is reported in randomized controlled trials (RCTs) as ranging from 1.5% to 3.0%.
The higher rate in clinical practice reflects the tendency to exclude from RCTs potentially statin-intolerant patients and those with risk factors for muscle toxicity (eg, elderly patients, those receiving polypharmacy, individuals with renal or hepatic impairment).
The frequency of mild muscle-related symptoms in primary care could be underestimated because physicians might overlook, and patients might fail to report, such symptoms.
For these reasons, observational studies that include an unselected patient population or use more liberal eligibility criteria can impart more meaningful information to clinicians administering statins than RCTs and are hence the focus of the following section on the clinical effect of statin-related myalgia.
FREQUENCY AND CLINICAL EFFECTS OF STATIN MYALGIAS
Examination of recent systematic reviews and meta-analyses, FDA postmarketing surveillance data analyses, clinical and observational trials, and claims database reviews sheds light on the scope of statin-associated myotoxicity and potential differences among statins. However, as already stated, muscle-related symptoms in clinical trials, which involve highly selected patient populations with high treatmentadherence and statin tolerance, do not reflect the true prevalence of myalgia in the clinic, as reflected by findings in observational studies.
Statin-associated myalgia can compromise patients' quality of life, medication adherence, and, consequently, treatment outcome.
Statin-associated myalgia was the most common reason for discontinuing rosuvastatin (13.6% of all reasons specified) in an observational cohort study of 11,680 patients.
In a systematic review of RCTs, the mean difference between active-treatment and placebo groups in the incidence of muscle pain, tenderness, or weakness sufficient to consult a physician or stop taking treatment was 5 per 100,000 person-years (confidence interval [CI], -17 to 27).
Seven (16%; our computation) of 45 patients experiencing myalgia in a 2-year study of simvastatin (80 mg/d; N=508) discontinued treatment because of this AE.
Two-year efficacy and safety of simvastatin 80 mg in familial hypercholesterolemia (the Examination of Probands and Relatives in Statin Studies With Familial Hypercholesterolemia [ExPRESS FH]).
Among 165 patients reporting muscle symptoms attributed to lipid-lowering therapy on a self-administered questionnaire, 48.1% experienced moderate discomfort and 9.8% experienced discomfort severe enough to confine them to bed or to cause them to stop working.
The PRIMO study enrolled an unselected population of 7924 French adult outpatients aged 18 to 75 years (mean ± SD, 58.4±10.8 years) who had hypercholesterolemia and received high-dose statins for 3 or more months before the study. These daily statin regimens included atorvastatin (40 or 80 mg), fluvastatin (80 mg) (chiefly fluvastatin extended-release [XL]), pravastatin (40 mg), or simvastatin (40 or 80 mg). Patients were eligible provided that they were not receiving statins under the auspices of a clinical trial and were not participating in any study during the 12-month observation period. Men outnumbered women by about 2:1 in groups with and without muscle-related symptoms. The 2 groups were similar across other demographic and baseline characteristics, with the exception of a significantly lower fat mass in those with muscle-related symptoms (29.7%) than in those without muscle-related symptoms (28.8%; P=.004).
A total of 832 patients (10.5%) reported muscle-related symptoms. This proportion was at least 2 times higher than has been observed in clinical trials involving statins (1%-5%).
Among the high-dose statins examined, the proportion of patients reporting muscle-related symptoms was lowest in those receiving fluvastatin XL (5.1% vs 10.9% for high-dose pravastatin, 14.9% for atorvastatin, and 18.2% for simvastatin) (Table 1).
All data are reported as number (percentage) unless otherwise indicated. Table excludes 31 patients for whom data on individual statin were missing. AE = adverse event; PRIMO = Prediction of Muscular Risk in Observational Conditions; XL = extended release.
Statin
No. of patients
Personal history of muscular or tendonitis-associated AEs during lipid-lowering therapy
Significant differences (P<.05) as determined by Pearson χ2 test. From Cardiovasc Drugs Ther,34 with permission of Springer Science and Business Media.
83 (4.5)
32 (1.8)
274 (33.1)
1570 (22.2)
14.9
Simvastatin
1027
100 (9.8)
55 (5.4)
13 (1.3)
187 (22.6)
840 (11.9)
18.2
Fluvastatin XL
3121
274 (8.8)
115 (3.7)
47 (1.6)
159 (19.2)
2962 (41.9)
5.1
a All data are reported as number (percentage) unless otherwise indicated. Table excludes 31 patients for whom data on individual statin were missing. AE = adverse event; PRIMO = Prediction of Muscular Risk in Observational Conditions; XL = extended release.
b Percentage of patients with symptoms relative to total number of patients (with or without muscular symptoms).
c Significant differences (P<.05) as determined by Pearson χ
The clinical presentation of myalgia was heterogeneous, with diverse symptoms that, in the aggregate, tended to occur soon after initiation of high-dose statin regimens or intensification of statin doses (Figure 1). The median time to onset of muscle-related symptoms was 1 month after treatment initiation or intensification. The finding that the time to onset of muscle-related symptoms was unimodal (on logarithmic transformation of data) after either initiation or intensification of statin doses is consistent with an association between increased statin doses and the onset of muscle-related symptoms.
In addition, about 15% of patients reporting muscle-related symptoms had symptoms that appeared more than 6 months after treatment initiation.
FIGURE 1Distribution of the time of onset of muscular symptoms after initiation of statin therapy (left) or titration to higher doses (right). The median time to onset was 1 month after either initiation of statin therapy or titration to a higher dosage of statin. From Cardiovasc Drugs Ther,
Most patients (58.7%) could not identify any particular trigger for their muscle-related symptoms (Table 2). Of the triggers reported, most involved undergoing unusual physical exertion or taking a new medication. Discomfort was widespread in 60.1% of patients, with 24.2% reporting pain “all over.” Pain was more common in the lower extremities, including the thighs and calves, than in the upper extremities or trunk. Most patients (71%) reported muscle-relatedsymptoms as heaviness, stiffness, or cramps. Nearly 28% of patients experienced myalgia during physical exertion, including weakness or loss of strength with or without other symptoms (eg, heaviness, stiffness, cramps).
Some patients reported multiple triggering factors; hence the number of patients reporting individual factors exceeds the total number of patients reporting a possible triggering factor.
Yes
334 (40.1)
Unusual physical exertion
178
New medication
101
Resting or lying down
44
Cold
30
Legionella infection
1
Unknown
9
No
488 (58.7)
Unknown
10
Type of pain
Heaviness/stiffness/cramps
482 (57.9)
Weakness or loss of strength during exertion. with or without other symptoms
221 (26.6)
Stiffness/cramps
109 (13.1)
Weakness/heaviness/loss of strength during exertion/stiffness/cramps
8 (1.0)
Unknown
12 (1.4)
Widespread pains
Yes
500 (60.1)
No
233 (28.0)
Unknown
99 (11.9)
Predominant site of pain
Thighs/calves
215 (25.9)
All over
201 (24.2)
Calves
138 (16.6)
Thighs
80 (9.6)
Trunk
68 (8.2)
Arm/forearm
66 (7.9)
No predominant site
47 (5.7)
Unknown
17 (2.0)
Tendonitis-associated pain
Yes
203 (24.4)
Multiple tendons
109
Single tendon
75
Unknown number of tendons
19
No
614 (73.8)
Unknown association
15 (1.8)
Similar symptoms experienced before statin treatment
Yes
110 (13.2)
No
700 (84.1)
Unknown similarity
22 (2.6)
a PRIMO = Prediction of Muscular Risk in Observational Conditions.
b Some patients reported multiple triggering factors; hence the number of patients reporting individual factors exceeds the total number of patients reporting a possible triggering factor.
Among affected patients, approximately 25% experienced continuous and 73% intermittent muscle pain. In most patients, duration of discomfort was several minutes or several hours with or without exertion. Nearly 40% of patients used analgesics for pain relief. Myalgia disrupted daily life for many patients. Although such discomfort resulted in bed rest or missed work in only about 4% of patients, in another 64% myalgia interfered with moderate (38%) or strenuous exertion (26%). In response to myalgia, approximately 57% of patients received an alternative lipid-modifying therapy (chiefly another statin or fibrate), about 20% of patients discontinued statin treatment, and 17% underwent a decrease in dose.
A history of muscle pain in the course of lipid-lowering therapy was the strongest independent risk factor for muscle symptoms (odds ratio [OR], 10.12; 95% CI, 8.23-12.54; P<.001). In addition, both high-dose atorvastatin (P=.04) and simvastatin (P<.001) were associated with significantly higher frequencies of reported muscle symptoms compared with high-dose pravastatin. In contrast, fluvastatin XL was associated with a significantly lower risk of muscle symptoms than pravastatin (P<.001).
Other independent predictors of muscle symptoms with high-dose statin therapy included current hypothyroidism, a history of CK elevations or unexplained cramps, and a family history of muscle symptoms.
The PRIMO investigators drew several important conclusions about these findings. First, both the frequency and the disruptiveness of muscle-related symptoms of high-dose statin therapy might have been underappreciated on the basis of clinical trials before the PRIMO study. Second, identifying strong predictors of statin myalgia should inform clinical practice and help to optimize treatment, including dosing and patient adherence. Although few patients in the PRIMO study had a family history of muscle pain during lipid-altering therapy, this risk factor nearly doubled the risk of muscle-related symptoms. This finding opens the prospect of identifying particular genes or single-nucleotide polymorphisms that increase the risk of myopathy (or reduce the maximal tolerated dose) during lipid-modifying therapy, and such information might ultimately inform treatment decisions including dosing. A personal history of elevated CK concentrations (“subclinical myopathy”) also predicted muscle-related symptoms in patients receiving high-dose statin regimens, although the PRIMO investigators stopped short of advocating routine CK assays in each candidate for such treatment.
Patients who tended to be more physically active were more likely to experience myalgia, potentially because low-level muscle injury might be augmented by statin treatment.
including advanced age (>70 years) and renal insufficiency, did not significantly predict reports of muscle-related symptoms in the PRIMO population. Alcohol consumption (light to moderate), a well-documented risk factor for the frequently fatal rhabdomyolysis, did not significantly increase the risk of muscle-related symptoms in the PRIMO study.
Among potential limitations of the PRIMO study was the reliance on chronological occurrence rather than on more comprehensive systems (eg, Naranjo algorithm) to establish causality between statin treatment and myalgia. In addition, it is not at all clear that the risk factors for myalgia established in the PRIMO study are similar for the development of the rare but frequently fatal rhabdomyolysis. The pathobiology of myalgia and rhabdomyolysis can have some discontinuities, and rhabdomyolysis can occur in the absence of muscle-related symptoms.
The effect of AEs on adherence to lipid-lowering therapy has been documented in several other studies. In an open-label study of 3845 hyperlipidemic patients receiving statin therapy, the incidence of AEs in general (23.3% vs 18.2%; P=.001), and of muscle symptoms specifically (6.9% vs 5.2%; P=.05), was significantly higher in nonadherent than in adherent patients.
Another study of 193 patients treated with at least 1 antihyperlipidemic agent demonstrated an inverse correlation between perception of frequent AEs and adherence to lipid-lowering therapy.
In several cohort studies, the reported rate of adherence to statin therapy at 1 year ranged from 26% to 85%, with a rapid decline in adherence rates typically observed within the first few months.
This is not surprising, given that many patients do not appreciate the long-term benefits of therapy for a chronic, asymptomatic condition such as hyperlipidemia. Consequently, they perceive the short-term disadvantages (eg, AEs) to outweigh any benefits, resulting in nonadherence to therapy.
Irrespective of its causes, suboptimal adherence to lipid-lowering medications results in excess morbidity and mortality. In the West of Scotland Coronary Prevention Study of men without a history of coronary artery disease, the risk of all-cause mortality was reduced 33% more among those who took 75% or more of their prescribed medication compared with those taking less than 75%. The risk of myocardial infarction or death from coronary events was reduced by 38% in those with 75% or more adherence compared with 31% among those with less than 75% adherence to statin therapy.
In the Lipid Research Clinics Coronary Primary Prevention Trial, the reduction in risk of coronary events was 39.3% among patients fully adherent to lipid-lowering therapy, compared with risk reductions of 10.9% and 26.1% among patients with approximately 25.0% and 50.0% adherence, respectively.
The Lipid Research Clinics Coronary Primary Prevention Trial Results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
According to a systematic review of 21 clinical trials providing 180,000 person-years of follow-up in patients treated with statins or placebo, myalgia (defined as minor muscle pain) affected 190 patients per 100,000 person-years; myopathy (defined as muscle pain, tenderness, or weakness sufficient to consult a physician or stop taking a statin), 5 patients per 100,000 person-years; and rhabdomyolysis, 1.6 patients per 100,000 person-years (all figures were placebo corrected).
suggested that myalgia (reported in 21 studies including 48,138 patients) was not significantly more common among those treated with available statins than among those receiving placebo (relative risk, 0.99; 95% CI, 0.96-1.03). Among individual statins, only atorvastatin had a significantly higher risk difference (RD) compared with placebo (5.1% vs 1.6%; P=.04; RD, 1.9%; 95% CI, 2.1%-61.6%) in myalgia incidence. No cases of myalgia were reported with fluvastatinin any of the studies evaluated, compared with 4 events among matching placebo groups (0% vs 0.6%; RD, -6.4%; 95% CI, -73.1% to 60.2%). Neither CK elevation nor rhabdomyolysis was more common in the statin class compared with placebo or with any individual statin compared with placebo. Rosuvastatin had higher incidences of myalgia and CK elevation compared with placebo, but the low numbers of patients in rosuvastatin trials reduced the power to detect a statistically significant change.
Another recent meta-analysis helped to delineate the risk-benefit ratio of statin treatment according to absolute risks (Table 3).
This analysis, which encompassed 18 trials (N=71,108; 301,374 person-years), yielded 316 myopathy-related events (myalgia, myopathy, asthenia) in the statin group compared with 253 in the placebo group (P<.001), and 81 cases of CK elevation in the statin group compared with 64 in the placebo group (P=.001).
Rhabdomyolysis was reported in 9 patients receiving simvastatin, 1 patient receiving lovastatin, and 5 patients receiving placebo. These data indicate that 3400 was the number needed to treat in order to harm; that is, 3400 patients had to be treated with a statin rather than placebo to observe a single case of statin-related rhabdomyolysis or CK elevation of 10 × ULN or more. The number needed to treat to benefit, or the number of patients who had to be treated with a statin in order to prevent 1 occurrence of myocardial infarction, revascularization, stroke, cardiovascular death, or all-cause mortality, was 27. The absolute risk-benefit ratio was hence approximately 126:1.
TABLE 3Adverse Events and Myotoxic Adverse Events With Statin Use: Meta-analysis of 18 Trials Including 301,374 Person-Years of Follow-Up
One case of rhabdomyolysis was reported with lovastatin in the Air Force/Texas Coronary Atherosclerosis Prevention Study, and 9 cases of rhabdomyolysis were reported in the Heart Protection Study.
One case of rhabdomyolysis was reported with lovastatin in the Air Force/Texas Coronary Atherosclerosis Prevention Study, and 9 cases of rhabdomyolysis were reported in the Heart Protection Study.
Fluvastatin
17
3666
216
NR
NR
Placebo
806
146,112
181
48
3044
a CK = cre atine kinase; NR = not reported; ULN = upper limit of normal.
b Person-years per event represents number of years of statin therapy expected to observe any adverse event reported in major trials.
c One case of rhabdomyolysis was reported with lovastatin in the Air Force/Texas Coronary Atherosclerosis Prevention Study, and 9 cases of rhabdomyolysis were reported in the Heart Protection Study.
Fluvastatin, pravastatin, and simvastatin were all associated with significantly fewer occurrences of myalgia than atorvastatin (OR, 0.28; 95% CI, 0.18-0.44; P<.001 for fluvastatin vs atorvastatin; OR, 0.43; 95% CI, 0.36-0.51; P<.001 for pravastatin vs atorvastatin; OR, 0.23; 95% CI, 0.19-0.28; P<.001 for simvastatin vs atorvastatin). Pravastatin was also associated with fewer occurrences of myalgia than simvastatin (OR, 0.53; 95% CI, 0.44-0.65; P<.001).
However, the meta-analysis included a highly selected sample, and the findings could be skewed for statin use by the trials reviewed.
Postmarketing Surveillance Data
The FDA AERS database yields a reporting rate of 0.3 case to 2.2 cases of myopathy and 0.3 case to 13.5 cases of rhabdomyolysis per 1 million statin prescriptions.
From each drug's launch date through May 2001, there was 1 reported case of fatal rhabdomyolysis per 23.4 million prescriptions with atorvastatin, 27.1 million prescriptions with pravastatin, and 8.3 million prescriptions with simvastatin.
Notably, no cases of fatal rhabdomyolysis associated with fluvastatin have been reported in the literature or to the FDA from the launch of this statin in 1993 through May 2001, a period covering more than 37 million prescriptions.
The FDA AERS is potentially limited by being a voluntary system, resulting in possible underreporting of events, and by being subject to reporting biases, such as the effects of publicity, the “new drug” reporting effect, or secular trends in AE reporting.
This includes using the lowest statin dose required to achieve therapeutic goals and avoiding, when possible, concomitant therapy with drugs known to increase systemic exposure and the risk of myopathy.
One way to minimize the risk of statin-related myopathy is to use caution in prescribing these agents to patients with predisposing risk factors for myopathy. For instance, findings from the multivariate analysis of the PRIMO study
indicate patients at significantly elevated risk of statin myalgia include those with a personal or family history of such discomfort while using lipid-modifying therapy, with a personal history of CK elevations, and with hypothyroidism. Therefore, it might be possible to reduce the risk of myalgia by exercising caution in prescribing statins to such patients (or not prescribing them at all).
Patient-related risk factors for statin-induced myotoxicity include female sex; frailty or low body mass index; hypothyroidism; concomitant treatment with certain cytochrome P (CYP) 450 inhibitors; polypharmacy, which is especially common in the elderly; and changes related to increasing age (ie, declines in hepatic and renal function; changes in albumin and α-1 acid glycoprotein levels with consequent changes in free concentrations of statins; and changes in lean body mass vs body fat ratio with attendant changes in the distribution of hydrophilic and lipophilic drugs).
In addition, statin treatment should be temporarily suspended a few days before elective surgery or if supervening events require immediate medical care or surgery.
Statin myopathy is thought to be a dose-related phenomenon: as the statin dose and statin systemic exposure increase, the risk of CK elevation increases to a threshold level, above which myotoxicity begins to accelerate to levels beyond acceptable risk-benefit ratios.
Given this relationship, a lower dose of a more potent statin might be less likely to cause myopathy than a higher dose of a less potent statin. However, increases in CK concentrations do not seem to be related to the milligram-to-milligram potency of statins in lowering low-density lipoprotein cholesterol (LDL-C).
Nor does there appear to be an association between the rate of rhabdomyolysis and either the relative or absolute LDL-C reduction achieved with statins.
For marketed statins, threshold concentrations for myopathy among patients receiving monotherapy appear to be above approved doses, but patients' risk factors or statin factors (eg, potential for drug interactions) that can increase systemic exposure can elevate statin concentrations to myotoxic levels and increase the possibility of developing statin-associated myopathy.
Statin properties that increase the risk of statin-induced myopathy include high systemic exposure, bioavailability and lipophilia, limited protein binding, and potential for drug interactions via CYP450 isoenzymes (especiallyCYP3A4) or glucuronidation pathways (eg, simvastatin and lovastatin with gemfibrozil).
Most clinically important drug interactions that occur with statins are attributable to the concurrent use of statins metabolized by the CYP3A4 isoenzyme (ie, atorvastatin, lovastatin, simvastatin) and other agents that are substrates or potent inhibitors of this enzyme (eg, macrolide antibiotics, azole antifungals, nondihydropyridine calcium channel blockers, protease inhibitors, cyclosporine, amiodarone, and large quantities of grapefruit juice [>1 L/d]).
Pravastatin is not metabolized by CYP enzymes; rosuvastatin is metabolized minimally by CYP enzymes (chiefly by CYP2C9 and CYP2C19); and fluvastatin is metabolized chiefly by CYP2C9, resulting in potential drug interaction with warfarin, among other agents. Alcohol abuse also seems to predispose patients to develop myopathy. More than half of statin-associated rhabdomyolysis cases involve interactions with concomitant medications affecting statin metabolism (Table 4).
The combination of statins and fibrate therapy could be beneficial in certain patients with metabolic syndrome, diabetic dyslipidemia, and other forms of dyslipidemia characterized by low levels of high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and small, dense LDL-C particles.
found more than a 10-fold increase in incidence of hospitalizations due to rhabdomyolysis in a recent inception-cohort analysis, from 0.44 per 10,000 person-years for atorvastatin, pravastatin, or simvastatin monotherapy to 5.98 per 10,000 person-years when fibrates were added to thestatin regimen.
A review of statin-induced rhabdomyolysis cases submitted to the FDA between November 1997 and March 2000 indicated that 38% were associated with concomitant fibrate administration.
However, according to a separate analysis of the FDA AERS database, the rhabdomyolysis reporting rate per million prescriptions for the fenofibrate-statin combination was 0.58, approximately one-fifteenth that of the gemfibrozil-statin combination (8.6).
Gemfibrozil inhibits glucuronidation of certain statins and their acid metabolites by competing for uridine diphosphate glucuronosyltransferase, an enzyme that promotes statin clearance or lactonization to inactive forms.
This competition can result in increased systemic levels of active forms of these statins, particularly atorvastatin and simvastatin.
Certain pharmacologic factors are associated with an overall lower risk of such AEs, including (1) low bioavailability and systemic exposure; (2) high protein binding; (3) hydrophilia, which is less consistent with passive diffusion of statins across skeletal myocyte cell membranes (in the absence of an active transporter in skeletal myocytes vs hepatocytes); (4) non-CYP3A4 metabolism; (5) nonglucuronidation substrate; and (6) absence of circulating metabolites.
fluvastatin is a synthetic statin with high first-pass hepatic extraction, low bioavailability, short plasma residence, and high protein binding that is not a CYP3A4 (ie, CYP2C9) or glucuronidation substrate. Rosuvastatin is relatively hydrophilic and is neither a CYP3A4 nor glucuronidation substrate but is relatively long-lived (half-life 19 hours). Pravastatin is also relatively hydrophilic and is not metabolized by CYP enzymes. In a pharmacokinetic study, pravastatin had a neutral drug-interaction profile with CYP3A4 inhibitors, whereas these agents significantly increased the systemic exposure or half-life of simvastatin and atorvastatin (Table 5). In contrast, pravastatin did interact with cyclosporine, which might compete with pravastatin for egress from skeletal myocytes via the multidrug resistance protein 2 transporter.
Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (rapamycin).
In contrast, the Assessment of Lescol in Renal Transplantation study confirmed the safety and tolerance of fluvastatin in patients undergoing renal transplants, many of whom receive cyclosporine, and there is no clinically meaningful interaction between fluvastatin and cyclosporine.
Results are based on 40-mg oral doses, with the exception of fluvastatin XL (80 mg). C = maximum concentration of drug; CYP = cytochrome P; logP = log partition coefficient (octanol/water); NR = not reported; Tmax = time of occurrence for maximum drug concentration; T1/2 = half-life; XL = extended release.
a Results are based on 40-mg oral doses, with the exception of fluvastatin XL (80 mg). C = maximum concentration of drug; CYP = cytochrome P; logP = log partition coefficient (octanol/water); NR = not reported; Tmax = time of occurrence for maximum drug concentration; T1/2 = half-life; XL = extended release.
The systemic exposure of fluvastatin is limited by certain pharmacokinetic characteristics, including high hepatic first-pass extraction (40%-70%), avid protein binding (>98%), low volume of distribution at steady state (0.35 L/kg), and short half-life (0.5-2.3 hours for immediate-release formulations).
have shown that fluvastatin contributed the smallest number (percentage) of cases of rhabdomyolysis among the statins: 55 (1.6%) of 3339 cases. In addition, because fluvastatin is not an appreciable substrate for either CYP3A4 metabolism or its glucuronidation, the drug has been safely administered with fibrates.
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone and the combination of fluvastatin XL 80 mg with ezetimibe, in patients with a history of muscle-related side effects with other statins.
Am J Cardiol.2008 Feb 15; 101 (Epub 2007 Dec 20.): 490-496
studied the effects of fluvastatin in patients with a history of statin-induced myalgia; on the basis of these findings (Figure 2), fluvastatin is recommended for statin-intolerant patients in our clinical algorithm (Figure 3).
FIGURE 2Kaplan-Meier curve of time to first muscle-related adverse event (MRAE) by treatment group among patients with history of MRAE.* = versus ezetimibe monotherapy; CI = confidence interval; HR = hazard ratio. From Am J Cardiol,
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone and the combination of fluvastatin XL 80 mg with ezetimibe, in patients with a history of muscle-related side effects with other statins.
Am J Cardiol.2008 Feb 15; 101 (Epub 2007 Dec 20.): 490-496
a Risk factors for muscle toxicity include advanced age and frailty, small body frame, deteriorating renal function, infection, untreated hypothyroidism, interacting drugs, perioperative periods, alcohol abuse.
b Causes for elevated CK levels/muscle toxicity are as follows: increased physical activity, trauma, falls, accidents, seizure, shaking chills, hypothyroidism, infections, carbon monoxide poisoning, polymyositis, dermatomyositis, alcohol abuse, and drug abuse (cocaine, amphetamines, heroin, or PCP).
c Patient counseling regarding intensification of therapeutic lifestyle changes (reduced intake of saturated fats and cholesterol, increased physical activity, and weight control) should be an integral part of management in all patients with statin-associated intolerable muscle symptoms.
The original clinical algorithm depicted in Figure 3 incorporates some of these recommendations but builds on and extends them. Measuring baseline CK levels is not routinely necessary but can be considered in high-risk patients, such as those who are older, who are receiving concomitant medications known to increase myotoxicity, or who have renal or hepatic dysfunction. Likewise, routine CK measurements in asymptomatic patients are unnecessary because marked, clinically important CK elevations are rare and are usually related to physical exertion or other causes. Patients should be advised to report muscle symptoms to a health care professional.
In patients with muscle symptoms, CK measurements should be obtained to help assess the severity of muscle damage and inform decisions regarding continuation of therapy or dose changes. Statin therapy can be continued at the same or reduced doses in patients who develop tolerable muscle symptoms or are asymptomatic with a CK level of less than 10 × ULN, and symptoms can be used as a clinical guide to stop or continue therapy (Figure 3). Statins should be discontinued if patients develop intolerable muscle-related symptoms with or without CK elevation or if other causes for the symptoms have been ruled out. Biopsies could be warranted in patients with persistent myopathy after statin withdrawal, provided that they are performed in consultation with experts in muscle diseases.
Several treatments, supported by varying degrees of clinical evidence, could be considered for hyperlipidemia in patients who develop intolerance to a statin because of muscle symptoms (Figure 3). Once the patient's muscle symptoms have resolved, statin therapy (with the same or different agents) can be restarted (ie, rechallenge), either at the same dose to test reproducibility of symptoms or at a lower dose (Figure 3).
If a patient is able to tolerate a lower dose of statin but is not at LDL-C goal, ezetimibe can be added to statin therapy to reduce the risk of recurrent muscle symptoms but retain efficacy. In a retrospective study of 12 patients who experienced intolerable AEs when their statin doses were increased, 10 patients (83%) tolerated the addition of ezetimibe (10 mg/d) to their original, lower statin dose and had lower levels of total cholesterol (TC) (-10%; P=.005) and LDL-C (-20%; P<.001), as well as an improved LDL-C:HDL-C ratio (-23%; P<.001).
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone and the combination of fluvastatin XL 80 mg with ezetimibe, in patients with a history of muscle-related side effects with other statins.
Am J Cardiol.2008 Feb 15; 101 (Epub 2007 Dec 20.): 490-496
Rosuvastatin 5 and 10 mg/d: A pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies.
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone and the combination of fluvastatin XL 80 mg with ezetimibe, in patients with a history of muscle-related side effects with other statins.
Am J Cardiol.2008 Feb 15; 101 (Epub 2007 Dec 20.): 490-496
In this study, 199 hyperlipidemic patients with a history of statin-induced muscle-related AEs (MRAEs) were randomized to fluvastatin XL (80 mg) alone, ezetimibe alone, or a combination of both. Meanreductions in LDL-C levels after 12 weeks were 15% with ezetimibe alone, 32% with fluvastatin XL alone, and 46% with combination therapy. Myalgia developed in 12.6% of patients in the trial (16.7%, ezetimibe monotherapy; 13.0%, fluvastatin XL monotherapy; 7.8%, combination therapy). Cases of MRAE and MRAE leading to discontinuation were less common with fluvastatin XL monotherapy (17.4% vs 4.3%) or combination therapy (14.1% vs 3.1%) than with ezetimibe monotherapy (24.2% vs 7.6%) (Figure 2). No clinically relevant elevation in CK level occurred in the fluvastatin monotherapy or combination treatment arm. Levels of LDL-C were reduced in 32.9% of cases with fluvastatin XL and in 46.1% with combination fluvastatin XL and ezetimibe. To my knowledge, this is the only published prospective RCT evaluating the safety of a statin in patients with a history of statin myalgia. Given its low risk of myotoxicity, particularly of serious events (such as myopathy or rhabdomyolysis), fluvastatin should be offered to any patient who experiences muscle signs or symptoms using another statin. This recommendation is supported by the only RCT to date that has studied statins in patients with myalgia.
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone and the combination of fluvastatin XL 80 mg with ezetimibe, in patients with a history of muscle-related side effects with other statins.
Am J Cardiol.2008 Feb 15; 101 (Epub 2007 Dec 20.): 490-496
If a trial of fluvastatin XL (80 mg) is unsuccessful, another option is to switch to otherwise low-dose rosuvastatin regimens (5-10 mg/d) or to alternate-day or weekly rosuvastatin (Figure 3). In an open-label pilot study of 61 patients with hypercholesterolemia who were unable to tolerate other statins because of myalgia, rosuvastatin (5 mg/d or 10 mg/d) (dose stratified by patients' National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] risk category) reduced LDL-C by a mean of 42% vs baseline (P<.001).
Rosuvastatin 5 and 10 mg/d: A pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies.
Median duration of treatment was 16 weeks with rosuvastatin (5 mg/d) and 44 weeks with rosuvastatin (10 mg/d), and all patients were instructed at baseline on the NCEP ATP III therapeutic lifestyle changes diet. Therapy was well tolerated; of the 61 patients, 1 receiving rosuvastatin (10 mg/d) discontinued treatment because of muscle pain after 4 weeks.
In a retrospective review of 27 patients with prior statin intolerance (including myalgia) who then received alternate-day dosing of either rosuvastatin (n=12; mean, 4.8 mg on alternate days), atorvastatin (n=3; mean, 10 mg on alternate days), or pravastatin (n=1; mean, 10 mg on alternate days), 16 (59%) patients tolerated therapy (11 of the 16 had a history of myalgia).
Favorable lipid profile changes from baseline to follow-up (mean, 3.9 months) included reductions in TC (-27%; P<.001), LDL-C (-37%; P<.001), and the LDL-C:HDL-C ratio (-43%; P<.001). The same investigators reported a case series of 8 patients, 6 of whom had statin intolerance due to myalgia, who then tolerated once-weekly rosuvastatin (5 to 20 mg) and experienced a mean LDL-C reduction of 29% after 4 months.
If muscle symptoms recur with trials of multiple statins and doses, then initiation of non-statin lipid-lowering therapy must be considered. Agents that have been studied in statin-intolerant patients include ezetimibe monotherapy and ezetimibe in conjunction with colesevelam.
Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance.
In a retrospective study of 27 patients who received ezetimibe monotherapy (10 mg/d) after discontinuing statin therapy because of intolerable AEs, 25 (93%) completed the 2- to 3-month study and experienced favorable changes in the lipid profile: TC was reduced by 18% and LDL-C by 26% (P<.001 for both). The LDL-C:HDL-C ratio decreased by a median of 22% (P<.001).
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
In a retrospective review of 16 patients with diabetes mellitus or metabolic syndrome with a documented history of statin intolerance (myalgia [n=9], myopathy [n=1], or elevated liver function test results [n=6]), the combination of ezetimibe (10 mg/d) plus colesevelam (1.875 g twice daily), a bile acid resin, achieved significant reductions from baseline in TC (-27.5%), LDL-C (-42.2%), and non-HDL-C (-37.1%).
Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
At baseline, 10 patients had been prescribed colesevelam (1.875 g twice daily), and 6 initially received ezetimibe (10 mg/d). After at least 3 months of monotherapy, a minimum of 3 months of combination therapy ensued (ezetimibe plus colesevelam).
A key aspect of hyperlipidemia management is the institution of therapeutic lifestyle changes as outlined in the NCEP ATP III guidelines: reduced intake of saturated fats and cholesterol, increased physical activity, and weight control.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
These lifestyle changes take on even greater importance in the management of hyperlipidemia in patients who are intolerant of statins. Therefore, patient counseling on intensification of therapeutic lifestyle changes should be an integral part of management in all patients with statin-associated intolerable muscle symptoms. Therapeutic dietary options include plant stanols and sterols and soluble fiber.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
Another possible treatment for some patients is the addition of CoQ10 to statin therapy to mitigate symptoms of statin-associated myalgia. However, studies of adjunctive CoQ10 treatment have yielded equivocal results in well-designed randomized trials addressing this issue.
Although investigators have recommended the use of CoQ10 to prevent statin myalgia because such treatment has no known risks, the clinical algorithm in the current article does not recommend such treatment (Figure 3).
CONCLUSION
The spectrum of statin-associated myotoxicity ranges from the more common but less severe myalgia (5%-10%) to the less common but more severe myopathy (0.1%) and its potentially fatal complication, rhabdomyolysis (0.01%). A risk-benefit assessment to inform decisions regarding statin therapy must consider statin-associated myopathy and rhabdomyolysis in the context of the cardioprotective benefits of statins.
The estimated mortality risk from rhabdomyolysis is 0.3 case per 100,000 person-years of statin therapy on the basis of a systematic review of clinical trial and cohort data.
The survival benefit of statins in patients with coronary artery disease far exceeds this risk, yielding 360 lives saved per 100,000 person-years on the basis of reductions in cardiovascular mortality in a meta-analysis of 17 placebo-controlled, secondary prevention trials.
Although less severe than other myotoxicity, statin-associated myalgia is more frequent, and its potential clinical effect should not be underestimated; mild MRAEs of statins can reduce quality of life, reduce treatment adherence, and impair cardiovascular outcomes. Meta-analyses and several clinical trials suggest that various statins are associated with differing forms of myotoxicity, with possible advantages for fluvastatin (particularly in patients with risk factors for myopathy or existing myalgia). The risk and severity of statin-associated myopathy can be minimized by following the recently promulgated National Lipid Association guidelines for prevention and management of statin-associated myopathy, along with treatment options for those who develop intolerable muscle symptoms while receiving statin therapy.
Acknowledgments
Assistance in manuscript preparation was provided by Stephen W. Gutkin, BA, Rete Biomedical Communications Corp (Ridgewood, NJ), and Angela Cimmino, PharmD.
The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group
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The Lipid Research Clinics Coronary Primary Prevention Trial Results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (rapamycin).
Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone and the combination of fluvastatin XL 80 mg with ezetimibe, in patients with a history of muscle-related side effects with other statins.
Am J Cardiol.2008 Feb 15; 101 (Epub 2007 Dec 20.): 490-496
Rosuvastatin 5 and 10 mg/d: A pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies.
Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
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