Statin induced myopathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby

Statin induced myopathy is a common entity that presents as a spectrum of symptoms ranging from complete absence of symptoms to myalgia, myositis and rhabdomyolysis. Myopathy, which is a general term that describes any pathology of the muscle, occurs in around 10 to 15% of patients taking statins. The pathophysiology of statin induced myopathy is complex. As for the treatment, it is guided by the severity of the symptoms and the degree of increase in creatine kinase levels.

N-of-1 trials have examined this:

• StatinWISE^[1][2]
• TaSINI^[3]
• Wood^[4]

Statin induced myopathy is a spectrum of muscular problems caused by the intake of statins. Myopathy is, by definition, any pathology of the muscle. The spectrum of statin induced myopathy can be classified into: myalgia, asymptomatic increase in creatine kinase, myositis and rhabdomyolysis. Myalgia is defined as one or combination of symptoms of muscle weakness, tenderness or pain in the context of normal or minimally elevated creatinine kinase. Myositis is defined as the presence of symptoms of muscle weakness, tenderness or pain in the setting of an elevated creatine kinase up to ten folds the normal level. Rhabdomyolysis is a potentially lethal acute degeneration of the skeletal muscle.^[5][6]

Statin induced myopathy has a complex poorly understood multifactorial pathophysiology. It is postulated that statin induced myopathy is caused by apoptosis of the skeletal muscle cells due to disrupted intracellular calcium signaling and mitochondrial dysfunction secondary to the depletion of mevalonate metabolism products, particularly coenzyme Q10.^[7]

The prevalence of statin induced myopathy, described as a spectrum of clinical conditions ranging from myalgia to myositis and rhabdomyolysis, is almost 10-15%.^[8]

Several risk factors predispose to statin induced myopathy. Some of the intrinsic risk factors are advanced age, genetic predisposition, diabetes, hypertension, hypothyroidism and renal diseases. Other extrinsic factors play a role in statin induced myopathy, including alcohol consumption, vitamin D deficiency, excessive exercise, trauma or concomitant use of other drugs like fibrates, mainly gemfibrosil, protease inhibitors and macrolide antibiotics.^[9][8][10]

Screening by measuring the creatine kinase level is not recommended by the national lipid association for statin induced myopathy unless the patient has significant predisposing factors like renal diseases, thyroid problems, metabolic diseases or pre-existing muscular diseases.^[8]

Myalgia is a common complaint and should not be attributed directly to the use of statins. The patient should be evaluated for any thyroid problems, inflammatory processes, alcohol use, excessive exercise, electrolyte disturbances, side effects of other medications or vitamin deficiencies.^[11]

The symptoms of statin induced myopathy belong to a spectrum ranging from being mild and asymptomatic to severe and lethal. The time of onset of symptoms varies among people, but the median time of onset of symptoms is four weeks since the beginning of the treatment. Similarly, the time for the resolution of symptoms after appropriate management also varies among individuals.^[12]The history of the patient should provide a description of the characteristics of the muscle pain as well as details about medications, history of trauma, exercise or excessive alcohol use.

When a patient presents with symptoms suggestive of statin induced myopathy, the diagnostic evaluation should include measuring the level of creatine kinase. It is useful to obtain the levels of TSH, ESR and vitamin D levels as well in order to rule out other diseases that can cause myalgia.^[8][11]

When symptoms of myopathy or elevation of creatine kinase occur in the setting of a patient taking statins, the majority of patients may safely continue the treatment with statins. The decision on whether the patient can discontinue or continue statins depends on two factors: the severity of the symptoms and the severity of the increase in the creatine kinase level. Statins can be safely continued when the symptoms are tolerable and the creatine kinase is elevated less than 5 times the upper limits of normal. Otherwise, if the creatine kinase level is higher than five times the upper limit of normal or if the symptoms are intolerable regardless of the level of creatine kinase, statins should be stopped for a certain period of time and restarted again with lower doses or with different types of statins. The role of vitamin D and coenzyme Q10 is still controversial in the management of statin induced myopathy as no studies support their use yet.^[8][13][14]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby

Statin induced myopathy is a spectrum of muscular problems caused by the intake of statins. Myopathy is, by definition, any pathology of the muscle. The spectrum of statin induced myopathy can be classified into: myalgia, asymptomatic increase in creatine kinase, myositis and rhabdomyolysis.^[1][2]

• Myalgia is defined as one or combination of symptoms of muscle weakness, tenderness or pain in the context of a normal or minimally elevated creatinine kinase level.
• Patients usually complain of cramping feeling in the muscles.

• Myositis is the inflammation of the muscle.
• Myositis is defined as the presence of symptoms of muscle weakness, tenderness or pain in the setting of an elevated creatine kinase up to ten folds the upper limits of normal.

• Rhabdomyolysis is the acute degeneration of the skeletal muscle.
• It is a potentially lethal condition due to its associated nephrotoxicity caused by myoglobinuria and myoglobinemia.
• Creatine kinase is elevated in rhabdomyolysis more than ten folds the upper limits of normal.
• The complications of rhabdomyolysis are acute tubular necrosis, hypocalcemia, hyperkalemia, metabolic acidosis, hyperuricemia, DIC and cardiomyopathy.^[3]

• Elevated creatine kinase after statin withdrawal.^[1]
• Autoimmune myopathy requiring immunosuppressive therapy.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby

Statin induced myopathy has a complex poorly understood multifactorial pathophysiology. It is postulated that statin induced myopathy is caused by apoptosis of the skeletal muscle cells due to disrupted intracellular calcium signaling and mitochondrial dysfunction secondary to depletion of mevalonate metabolism products, particularly coenzyme Q10.^[1]

The following changes are caused by statins:

• Changes in cholesterol content and alteration of the membrane fluidity of the skeletal muscle cells which disrupts their normal function
• Changes in skeletal muscle cells membrane electrical properties
• Changes in Na+/K+ pump density resulting in decreased production of ATP
• Changes in the excitation-contraction coupling
• Changes in the cell surface receptor transduction cascades
• Decreased synthesis of ubiquinone (coenzyme Q10), a component of the mitochondrial electron transport chain, leading to decreased ATP production and decreased free radical scavenging
• Increased intracellular calcium causing apoptosis of the skeletal muscle cells^[2]
• Decreased mevalonate metabolism products, particularly isoprenoids, leading to a chain of events that culminate in the apoptosis of skeletal muscle cells^[1]

In addition, muscle biopsies of patients suffering from statin induced rhabdomyolysis show a ragged red fibers appearance.^[3]

Shown below is an image depicting the mechanism of statin induced myopathy through increasing the intracellular calcium concentration.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby

The prevalence of statin induced myopathy is around 10 to 15%.^[1]

The prevalence of statin induced myopathy, described as a spectrum of clinical conditions ranging from myalgia to myositis and rhabdomyolysis, is around 10 to 15%.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby

The prevalence of statin induced myopathy is around 10 to 15%.^[1]

The prevalence of statin induced myopathy, described as a spectrum of clinical conditions ranging from myalgia to myositis and rhabdomyolysis, is around 10 to 15%.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby

Screening by the measurement of the creatine kinase level is not recommended by the national lipid association for statin induced myopathy unless the patient has significant predisposing factors like renal diseases, thyroid problems, metabolic diseases or pre-existing muscular diseases.^[1]

• The American Heart Association and the National Heart, Lung, and. Blood Institute (AHA/NHLBI) statin clinical advisory panel recommends the measurement of the creatine kinase level before the initiation of statin therapy.
• The national lipid association does not recommend the measurement of the creatine kinase level before the initiation of statin therapy for all patients. It is useful to check the creatine level in patients with high risk factors for statin induced myopathy as for example patient with kidney diseases.
• Otherwise, the level of creatine kinase should be measured only in the presence of symptoms of muscle pain, tenderness or pain^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby

Myalgia is a common complaint and should not be attributed directly to the use of statins. The patient should be evaluated for any thyroid problems, inflammatory processes, alcohol use, excessive exercise, electrolyte disturbances, side effects of other medications or vitamin deficiencies.^[1]

• Alcohol-related myopathy
• Arthritis
  • Degenerative arthritis
  • Inflammatory arthritis
• Connective tissue diseases
  • Polymyalgia rheumatica
  • Rheumatoid arthritis
  • Systemic lupus erythematosis
  • Sjögren syndrome
• Electrolyte abnormalities
  • Hypokalemia
  • Hypomagnesemia secondary to diuretic use
• Endocrine abnormalities
  • Addison disease
  • Acromegaly
  • Cushing syndrome
  • Hypoparathyroidism, hyperparathyroidism
  • Hypothyroidism, hyperthyroidism
• Fibromyalgia
• Guillain-Barré syndrome
• Metabolic myopathies
  • Carnitine palmitoyltransferase II (CPT II) deficiency
  • McArdle disease
  • Mitochondrial myopathies
• Muscle pain and myopathy from non-statin drugs
  • Bisphosphonates
  • Zidovudine (Retrovir)
  • Vitamin E
• Myelopathy, spinal stenosis
• Myositis
  • Dermatomyositis
  • Inclusion body myositis
  • Polymyositis
• Peripheral neuropathy
  • Diabetes
  • Idiopathic
  • Spinal stenosis
  • Vitamin B12 deficiency
• Peripheral vascular disease
• Progressive neuromuscular atrophy
  • Amyotrophic lateral sclerosis
  • Charcot-Marie-Tooth disease
  • Multiple sclerosis
  • Spinal muscular atrophy
• Vitamin D deficiency^[1]