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Basic Information ⬇

AUTHORS: Lisa Cohen, PharmD and Anne L. Hume, PharmD

Definition

Statin-induced muscle syndromes (SIMS) include myopathy, myalgia, myositis, and rhabdomyolysis. Definitions for these syndromes are inconsistent in the medical literature.

  • Myopathy: A general term defined as any disease of muscles
  • Myalgia: Muscle weakness or pain without serum creatinine kinase elevation
  • Myositis: Muscle weakness or pain with an increased serum creatinine kinase level
  • Rhabdomyolysis: Muscle weakness or pain and a marked serum creatinine kinase level usually greater than 10× the upper limit of normal and serum creatinine elevation as well as signs of brown urine and elevated urine myoglobin. A rare immune-mediated necrotizing myopathy (IMNM), also known as statin-associated autoimmune myopathy, has also been associated with the use of statins with symptoms persisting after discontinuation of the drug. This condition presents with symmetric proximal arm and leg weakness and severe elevations of muscle enzymes
Synonyms

SIMS

Statin-induced myopathies

Statin-induced myositis

Statin-induced myalgias

Statin-induced rhabdomyolysis

Statin-associated autoimmune myopathy

ICD-10CM CODES
M60.9Myositis, unspecified
M62.82Rhabdomyolysis
G72.2Myopathy due to other toxic agents
G72.9Myopathy, unspecified
G72.81Critical illness myopathy
G72.89Other specified myopathies
M60.89Other myositis, multiple sites
Epidemiology & Demographics
Incidence

Risk of statin-induced rhabdomyolysis is 1.2 per 10,000 persons/yr. Rhabdomyolysis risk of death is 0.15 deaths per 1 million prescriptions. SIMS most commonly occur in people aged 51 to 75, which may reflect the pattern of statin use. Statin-associated autoimmune myopathy occurs in an estimated 2 or 3 of every 100,000 patients treated with statins.

Prevalence

The prevalence of statin-induced myalgias is about 1% to 5%, similar to placebo in clinical trials, although observational studies have suggested a prevalence of 10% or higher. Statins may cause elevated transaminases (ALT, AST) at a prevalence of 0.5% to 2.0% and rhabdomyolysis ∼0.08%.

Predominant Sex & Age

The mean age of hospitalized patients with statin-induced myopathy or rhabdomyolysis was 64 yr old and was slightly more common in women (56%).

Peak Incidence

Patients on high-dose statins have a 0.9% incidence of statin-induced rhabdomyolysis.

Risk Factors

Small body frame; age over 80 yr; women, particularly frail elderly women; patients taking multiple drugs, especially gemfibrozil, niacin, cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, verapamil, amiodarone; renal or liver impairment; pharmacogenetic variability; hypothyroidism; excessive alcohol intake; vigorous exercise; severe infections; excessive grapefruit juice ingestion; low vitamin D levels; inherited defects of muscle metabolism such as carnitine palmityl transferase II deficiency, McArdle disease, and myoadenylate deaminase deficiency; acquired myopathies such as postpoliomyelitis syndrome; lipophilic statins (simvastatin, atorvastatin, lovastatin); multiple conditions such as diabetes; renal impairment, and prior elevated CK; and drugs of abuse (amphetamines, heroin, cocaine, phencyclidine).

Genetics

Interpatient variability exists in the activity of the CYP3A4 gene for the metabolism of simvastatin, atorvastatin, and lovastatin. Homozygous carriers of CYP2D6 (poor metabolizers) had a higher rate of discontinuation of simvastatin due to muscle syndromes compared with the CYP2D6 wild-type genotype; patients taking atorvastatin and having a muscle event were more likely to have the CYP2D6∗4 allele. SLCO1B1 polymorphisms encode for the organic anion transport of statins into the liver cells. The variant C allele may increase the risk of the SLCO1B1 statin-induced myopathy in patients taking simvastatin and atorvastatin. Simvastatin-induced myopathy is more likely to be associated with SLO1B1 genotype and not ABCB1 genotype. However, a statin-associated autoimmune myopathy has shown a link to class II HLA allele DRB1∗11:01 in the development of anti-HMG CoA reductase antibodies, leading to an increase in expression of the antibodies in the muscles of patients exposed to statins. Deficiencies in ubiquinone (coenzyme Q10) may exist in patients with a mutation in the COQ2 gene. The EYS gene can affect neuromuscular tissue and may have a role. In addition, RYR1 and CACNA1S genetic variants may be associated with statin-induced muscle syndromes and elevated CK levels.

Physical Findings & Clinical Presentation

  • Myopathy can occur at any time, although it is more common within the first 4 wk of therapy; statin-associated necrotizing myopathy may occur after months of using statins
  • Proximal generalized muscle aches, body aches, and pains, and may be mild or severe
  • Dark-colored urine
  • Muscle cramps, spasms, tenderness, or stiffness
  • Unusually tired or weak
  • Nocturnal cramping
  • Tendon pain
Etiology

  • History of current statin use.
  • May be explained by one of three deficiencies of end products of the 3-hydroxy-3-methyl-glutaryl-coA reductase pathway: Cell signaling and apoptosis, mitochondrial function and ubiquinone concentrations, and cholesterol concentrations and cell membrane integrity.
  • The risk may be enhanced by drug interactions that interfere with hepatic metabolism and gut wall transport of interacting medications and by pharmacodynamic effects.
  • Underlying metabolic muscle disorder may predispose a patient to develop myopathy.
  • Patients with statin-associated autoimmune myopathy have been found to have anti-HMG-CoA reductase antibodies even prior to exposure to statin therapy.

Diagnosis ⬆ ⬇

Differential Diagnosis

Bursitis, tendinitis, radiculopathy, osteoarthritis, muscle strain, myofascial pain, hypothyroidism, proton pump inhibitor-induced polymyositis, viral illness, polymyositis, idiopathic inflammatory myositis, and polymyalgia rheumatica

Workup

Workup consists of a thorough history, including exercise history, urine color, medication history, and physical exam to palpate tenderness and obtain blood tests to evaluate muscle and kidney damage.

Laboratory Tests

If severe myopathy or rhabdomyolysis is suspected:

  • Elevated CPK, positive serum myoglobin, elevated BUN, serum creatinine, AST, ALT, LDH, and potassium
  • Urine creatinine, positive casts, and hemoglobin in urine with absence of red blood cells
  • Anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMG-CoA) antibody
  • Consider electrocardiogram and assessment of calcium, phosphate, and uric acid

If mild to moderate myopathy is suspected:

  • Monitor TSH and CPK levels; CPK may only be elevated when sudden severe myopathy occurs.
  • If the patient has brown or dark urine or elevated CPK, monitor BUN and serum creatinine.
  • In statin-associated autoimmune myopathy, the creatine kinase level is usually ≥10 times the upper limit of normal. In these patients, muscle biopsy specimens will be positive for autoantibodies against HMG-CoA reductase and may have necrosis.
Imaging Studies

  • Not recommended.
  • In statin-associated autoimmune myopathy, electromyography shows small-amplitude motor-unit potentials with increased spontaneous activity characteristic of an active myopathic process. Muscle edema is evident on MRI.
  • Statin Intolerance Tool:
    1. The American College of Cardiology has created a tool to assess statin muscle symptoms and to guide clinicians that can be of value: http://tools.acc.org/statinintolerance/#!/

Treatment ⬆ ⬇

Nonpharmacologic Therapy

Treatment of rhabdomyolysis is generally supportive in nature (see “Rhabdomyolysis” topic).

Acute General Rx

  • Stop statin therapy immediately if muscle symptoms occur. Check history, potential drug-drug interactions, CPK, TSH, renal function, hepatic function, and urinalysis.
  • If patients have suspected rhabdomyolysis, they should be hospitalized and treated with supportive therapy and monitoring of complications.
  • If CPK <10× the upper limit of normal without symptoms, continue statin therapy at the same or lower dosage.
  • If CPK <10× the upper limit of normal with intolerable symptoms, discontinue statin.
  • If CPK >10× the upper limit of normal, discontinue statin.

Box E1 describes recommendations of the National Lipid Association Statin Safety Assessment Task Force regarding statin and muscle safety.

BOX E1 Recommendations to Health Care Professionals Regarding Statin and Muscle Safety

  • Whenever muscle symptoms or an increased CK level is encountered in patients receiving statin therapy, health professionals should attempt to rule out other causes, because these are most likely to explain the findings. Other common causes include 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).
  • Obtaining a pretreatment, baseline CK level can be considered in patients who are at high risk of experiencing muscle toxicity (e.g., older patients or those combining a statin with an agent known to increase myotoxicity), but this is not routinely necessary in other patients.
  • It is unnecessary to measure CK levels in asymptomatic patients during the course of statin therapy, because marked, clinically important CK elevations are rare and are usually related to physical exertion or other causes.
  • Patients receiving statin therapy should be counseled about the increased risk of muscle symptoms, particularly if initiation of vigorous, sustained endurance exercise or a surgical operation is being contemplated; they should be advised to report such muscle symptoms to a health professional.
  • Creatine kinase measurements should be obtained in symptomatic patients to help gauge the severity of muscle damage and facilitate decision of whether to continue therapy or alter doses.
  • In patients who develop intolerable muscle symptoms with or without CK elevation and for whom other etiologies have been ruled out, the statin should be discontinued. Once symptoms disappear, the same or a different statin at the same or a lower dose can be restarted to test the reproducibility of symptoms. Recurrence of symptoms with multiple statins and doses requires initiation of other lipid-altering therapy.
  • In patients who develop tolerable muscle symptoms or have no symptoms but have a CK level <10× ULN, statin therapy may be continued at the same or reduced doses and symptoms may be used as the clinical guide to stop or continue therapy.
  • In patients who have positive anti-HMG-CoA antibodies and statin-associated necrotizing autoimmune myopathy, more aggressive immunosuppressant treatments may be necessary.
  • In patients who develop rhabdomyolysis (CK >10,000 IU/L or >10× ULN with an elevation in serum creatinine or need for intravenous hydration therapy), statin therapy should be stopped. Intravenous hydration therapy in a hospital should be instituted if indicated for patients experiencing rhabdomyolysis. Once patients recover, risk versus benefit of statin therapy should be carefully reconsidered.

From McKenney JM et al: Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force, Am J Cardiol 97(suppl 8A):89C-94C, 2006.

Chronic Rx

  • After stopping the statin and symptom or CPK resolution, which may take up to 4 mo, consider the same statin at a lower dosage or a different statin at an equivalent or lower dosage.
  • When restarting therapy, consider statins such as low-dose rosuvastatin; pravastatin; and alternate-day dosing of rosuvastatin or atorvastatin.
  • If patient had rhabdomyolysis secondary to statin therapy, consider nonstatin treatments.
  • If the patient develops myopathy after a second trial of therapy, statin treatment should be permanently discontinued and nonstatin cholesterol-lowering therapy initiated.
  • A nocebo effect of statin-induced myopathy has been demonstrated in some patients.
  • Bempedoic acid may offer a safe and effective lipid-lowering therapeutic option for patients unable to tolerate statins.
  • For IMNM (statin-associated autoimmune myopathy and idiopathic inflammatory myositis), immunosuppressive therapy with prednisone (1 mg per kg of body weight per day) and at least one agent (methotrexate, azathioprine, or mycophenolate mofetil) have been used. In resistant cases, IV immune globulin or another agent such as rituximab may be added.
Integrative Medicine

  • The effect of coenzyme Q10 on reducing or preventing SIMS remains controversial; although it may be effective in reducing muscle pain, weakness, cramps, and tiredness, it has no effect on lowering CK levels. Given its safety, coenzyme Q10 can be recommended if the actions listed under “Chronic Rx” are insufficient to continue the use of the statin and if the muscle symptoms have been limited to myalgias. Use coenzyme Q10 with caution in patients taking warfarin, as its anticoagulant effect may be decreased.
  • A 2015 meta-analysis of observational studies reported that vitamin D levels were lower in patients with statin-induced myalgias than in individuals who did not have these symptoms.
  • A more recent trial1 comparing statin users who took vitamin D supplements to those who took placebo revealed that both had the same incidence of muscle symptoms. The mean 25 hydroxyvitamin D level at baseline was 30 mg/mL. Vitamin D did not prevent symptoms in subgroups with baseline levels less than 30 mg/mL or <20 mg/mL.
Disposition

  • Usually resolves within 1 wk up to 4 mo after discontinuing statin therapy.
  • Once the patient has a full recovery, an alternative statin can be tried.
  • Statins should not be restarted in IMNM or idiopathic inflammatory myositis.
Referral

If rhabdomyolysis is suspected, immediate referral for hospitalization is suggested.

Pearls & Considerations ⬆ ⬇

Comments

  • SIMS are usually mild and will resolve within a few wk after discontinuing statin therapy. However, such syndromes may progress to rhabdomyolysis.
  • A recent meta-analysis2 revealed that among participants taking statins 27.1% reported muscle symptoms compared with 26.6% in the placebo group for a 3% small increase during a median of 4 yr which is considered barely significant. All excess risk occurred in the first year of therapy.
Prevention

  • Follow the 2013 AHA/ACC treatment guidelines and the 2017 ACC focused update on nonstatin therapies for LDL cholesterol and limit the concomitant use of fibrates with statins.
  • Discontinue statin therapy prior to and during surgical procedures.
  • If patient requires a short-term therapy with an interacting medication such as an azole antifungal, temporarily discontinue statin until interacting therapy is completed.
  • If statin-fibric acid therapy is warranted, fenofibrate is preferred over gemfibrozil to decrease risk of myopathy.
  • Baseline liver function testing before initiation of statin therapy and only if clinically indicated thereafter.
Patient & Family Education

  • Inform patients to promptly report muscle weakness, unexpected muscle pain, or brownish urine.
  • Providers should be cautious of the impact of media coverage of statin-induced side effects, which may include the nocebo effect.
  • Ensure that the pharmacist and/or primary care physician checks for drug-drug interactions with every new prescription, including those from dentists and physicians from other specialties.
  • Coenzyme Q10 may lessen milder muscle symptoms from statins, but patients should inform their physician and pharmacist if they decide to use this supplement.
  • A recent clinical trial comparing lipid-lowering efficacy for two nonstatin therapies, ezetimibe and evolocumab, among patients with statin intolerance revealed that evolocumab resulted in a significantly greater reduction in LDL-C levels after 24 wk. Further studies are needed to assess long-term efficacy and safety.
Related Content

Rhabdomyolysis (Related Key Topic)

Suggested Readings ⬆ ⬇

  1. Caughey G.E. : Association of statin exposure with histologically confirmed idiopathic inflammatory myositis in an Australian populationJAMA Intern Med. ;178:1224-1229, 2018.
  2. Hou Q. : Association between SLCO1B1 gene T521C polymorphism and statin-related myopathy risk: a meta-analysis of case-control studiesMedicine (Baltim). ;94(37), 2015.
  3. Jetty V. : Safety of 50,000-100,000 units of vitamin D3/week in vitamin D-deficient, hypercholesterolemic patients with reversible statin intoleranceN Am J Med Sci. ;8(3):156-162, 2016.
  4. Mammen A.L. : Statin-associated autoimmune myopathyN Engl J Med. ;374:664-669, 2016.
  5. Michalska-Kasiczak M. : Analysis of vitamin D levels in patients with and without statin-associated myalgia-a systematic review and meta-analysis of 7 studies with 2420 patientsInt J Cardiol. ;178:111-116, 2015.
  6. Nazir S. : Statin-associated autoimmune myopathy: a systematic review of 100 casesJ Clin Rheumatol. ;23(3):149-154, 2017.
  7. Newman C.B. : Statin safety and associated adverse events: a scientific statement from the American Heart AssociationArterioscler Thromb Vasc Biol. ;39(2):e38-e81, 2019.
  8. Nissen S.E. : Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial 158001590 JAMA. ;315(15), 2016.
  9. Qu H. : Effects of coenzyme Q10 on statin-induced myopathy: an updated meta-analysis of randomized controlled trialsJ Am Heart Assoc. ;7(19), 2018.

Related Content ⬆

    1. Hlatky MA et al: Statin-associated muscle symptoms among new statin users randomly assigned to vitamin D or placebo, JAMA Cardiol 8(1):74-80, 2023.
    2. Cholesterol Treatment Trialists’ Collaboration: Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials, Lancet 400(10355):832-845, 2022.