Statin myopathy 4/5 (7)

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Statin-induced myopathy (statin myopathy)

Definition

Statins (HMG-CoA reductase inhibitors) are cholesterol-lowering drugs. It is well documented that statins lower LDL cholesterol and thus the risk of heart attack, stroke and other cardiovascular diseases. More or less serious side effects are not uncommon, of which muscle side effects are among the most common. The related muscle problems can be divided into two main types:

Occurrence

  • Toxic statin myopathy
    • 5-20% of patients using statins discontinue treatment due to muscle symptoms (reference: Mohassel p, 2013). However, muscular pain is so common in the population that a placebo-controlled study (with dummy treatment showed similar muscle aches among those who received placebo (dummy treatment) (reference: Walk HV, 2014). Adding a CK increase of 10 times over the reference range, toxic statin myopathy is likely to occur in fewer than 1 / 10.000 / statin users and rhabdomyolysis with CK 10-20.000 is assumed under 1 / 100.000 (reference Dalakas MC, 2009; Armitage J, 2007)
  • Statin-associated autoimmune myopathy / immune mediated myopathy
    • Very rare with incidence of 2-3 / 100.000 / year (reference: Mammen AL, 2016). Among patients with myositis, this form is assumed to constitute 6% (in a selected American material) (reference: Watad A, 2015)

Symptoms

  • Toxic statin myopathy
  • Statin-associated autoimmune myopathy
    • As with classic myositis
    • Muscle pain
    • Muscle weakness, most in proximal muscle groups (thighs, upper arms)

Medical investigations

  • Toxic statin myopathy
    • Clinical examination: Rare detectable loss of muscle strength, but rhabdomyolysis (CK 10-20.000 or higher) is also described (reference: De Schryver, 2015)
    • Blood tests: Creatine kinase (CK), LD and AST are often normal or slightly increased
    • Antibodies: Absent
    • Genetic Outline: rs4363657 SNP in the SLCO1B1 gene on chromosome 12 (non-routine study)
    • EMG: Often normal finds
    • MRI of the thigh muscles: Often normal findings (edema detected by rhabdomyolysis)
    • Biopsy:
      • Mild cases: Cytochrome oxidase negative fibers and vacuoles
      • Severe affection: Muscular fiber necrosis and regeneration with indicated inflammation
  • Statin-associated autoimmune myopathy
    • Clinical examination: Gradually weakness develops into proximal muscles
      • Problems getting up from squatting and from the chair
      • Muscular atrophy (symmetrical)
    • Blood tests: Creatine kinase (CK) is elevated (1.000-50.000). AST and LD elevated
    • Antibody against HMGCR (3-Hydroxy-3-Methyl Glutaryl Coenzyme A Reductase) which is the pharmacological attack point of treatment with statins. The analysis is carried out at Immunological laboratory, Oslo University Hospital. HMGCR is detected in most and can help distinguish from toxic statin myopathy. However, HMGCR is not completely specific and can be seen by myopathy without prior statin use as well
    • Genetic Outline: HLA-DRB1 * 11: 01 (Non-Routine Examination)
    • EMG: Myopathy pattern
    • MRI examination of thigh muscles (T2 or STIR): Muscle and facial edema, muscle atrophy and fat in the muscles
    • Biopsy (tissue test)
      • Muscular fiber necrosis and regeneration with little inflammation
      • MHC Class I is up-regulated
      • Membrane Attack Complex (MAC) on non-necrotic fibers

Risk factors for toxic statin myopathy

  • Genetic disposition (see above)
  • Ciclosporin (Sandimmun Neoral) which is used against certain rheumatic diseases
  • Other medicines that interact with statins (atorvastatin, lovastatin, simvastatin) via CYP3A4 isoenzyme.
    • Paravchol (pravastatin), fluvastatin (Lescol) uses other enzyme systems. (interaksjoner.no)
  • Females
  • Alcoholism
  • hypothyroidism
  • Kidney failure
  • Low body weight (BMI)

Diagnosis and disease progression

  • Typical medical history of muscle symptoms after statin treatment was started
    • Most people get symptoms about 4 weeks after treatment start but with a spread from 4 weeks to 4 years
  • Symptoms of muscle pain
  • Toxic statin myopathy
    • Symptoms progress gradually after the statin treatment is stopped
    • Some get better at lower doses
    • The symptoms usually go completely absent after 2-3 months, but up to 14 months of symptoms are also described
  • Statin-associated autoimmune myopathy
    • Progresses despite the end of statin treatment
    • Investigation according to the above mentioned symptoms and examination findings

Incorrect diagnosis? (Similar diseases / differential diagnoses)

Treatment

Treatment goals are normal or almost normal CK levels in blood tests and gradual normalization of muscle strength

  • Toxic statin myopathy
    • Discontinuation of statin treatment.
    • Lower statin dose or Ezetrol (ezetimibe) can be considered.
    • If no clear improvement (CK values, muscle power) after 3 months, new investigation (CK, MRI of thigh muscles, biopsy)
  • Statin-associated autoimmune myopathy
  • Switch to other cholesterol lowering treatment (lower dose, ezetimibe / Ezetrol, PCSK-9 inhibitors / Pralvent / Repatha)
  • Intensified lifestyle change and diet

Medical prognosis

  • Two out of the three have almost the full recovery of the disease
  • In statin-associated autoimmune myopathy, relapse should be expected if the anti-rheumatic treatment is terminated

Literature

Myositis, BINDEVEVSSYKDOMMER.no


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