Table 1.

Classification and spectrum of statin-associated muscle adverse events1,4,12,18–25

Type	Clinical presentation	Incidence/prevalence	Long-term outcome
Myalgia	Unexplained muscle discomfort without CK elevation, including muscle aches, soreness, stiffness, tenderness and exercise-related cramps.4 The pain is dull, aching, widespread and involves the trunk and proximal muscles. Calf and forearm pain is less common and is usually bilateral.	1–5% in controlled trials and 11–29% in observational studies4	Myalgias are generally tolerable but can become debilitating, requiring statin withdrawal. The long-term outcome is favourable. Symptoms improve or full recovery occurs in the majority of patients on cessation of statin therapy; however, the condition can continue beyond 14 months.22
Myopathy	Muscle weakness (not due to pain and/or CK elevation). A diagnosis is made by the detection of proximal weakness of grade ≤4/5 and standardised muscle testing with confirmation by electromyography and/or muscle biopsy.4 Other causes of muscle weakness should be excluded.	≈3%25	An annual assessment of muscle strength is indicated in patients with minimal symptoms without >3 x ULN CK elevations who elect to remain on statin therapy. Serial assessment in asymptomatic patients is unnecessary.4 Among patients with persistent symptoms after statin withdrawal, 10% have underlying neuromuscular disease.23
Myositis	Muscle inflammation (determined by skeletal muscle biopsy and/or magnetic resonance imaging), commonly associated with muscle pain and tenderness.4	Unknown as it is no longer diagnosed by clinical and CPK criteria	Can be toxic or autoimmune. The former improves with statin discontinuation, whereas in the latter only a few patients improve with drug discontinuation; for the remaining patients, the disease is persistent or progressive despite statin discontinuation.21,23,24 The autoimmune type is associated with anti-HMGCR antibodies and requires immunosuppressive therapy (steroids and/or intravenous immunoglobulin).20
Myonecrosis	Elevated muscle enzymes or consistently increased serum CK levels. Muscle injury is graded as mild (>3 x baseline untreated CK levels or age-, race- and gender-adjusted ULN), moderate (≥10 x baseline untreated CK levels or age-, race- and gender-adjusted ULN) or severe (≥50-fold above baseline CK levels or age-, race- and gender-adjusted ULN; consistent with an absolute CK concentration of 10,000 IU/L).4	Incidence is not well defined as CK levels are not routinely measured	No data available for this pathological entity in its full spectrum.
Clinical rhabdomyolysis	Severe myonecrosis, with myoglobinuria and/or acute renal failure*.4	Rare (0.1–8.4/100,000 patients/year)21	Carries a 7.6% risk of death with 19.8% of patients developing acute renal failure and 17% developing renal dysfunction. There is a 5.2% risk of dialysis in affected patients.19

CK = creatine kinase; ULN = upper limit of normal; CPK = creatine phosphokinase; HMGCR = 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

^*Increased serum creatinine levels of >0.5 mg/dL.4