From the Guidelines
Statins should be stopped when creatine phosphokinase (CPK) levels exceed 10 times the upper limit of normal (ULN), especially if accompanied by muscle symptoms, as recommended by the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1. For asymptomatic patients with CPK elevations between 3-10 times ULN, close monitoring may be appropriate while continuing the statin at the same or reduced dose. If a patient develops muscle symptoms with any CPK elevation, temporary discontinuation is recommended. After stopping the statin, CPK levels should be monitored until they normalize, and symptoms should resolve before considering rechallenge. When reintroducing statin therapy, options include using a lower dose of the same statin, switching to an alternative statin (such as rosuvastatin or pravastatin which may have lower myopathy risk), or implementing alternate-day dosing regimens. The mechanism behind statin-induced muscle injury involves disruption of muscle cell membranes and mitochondrial function, leading to CPK release into the bloodstream. Risk factors for statin-induced myopathy include advanced age, female gender, small body frame, kidney or liver disease, hypothyroidism, and certain medications that interact with statins. It is also important to note that routine measurements of creatine kinase and transaminase levels are not useful in patients treated with statins, unless there are symptoms suggesting hepatotoxicity or severe statin-associated muscle symptoms 1. In patients with increased diabetes mellitus risk or new-onset diabetes mellitus, it is recommended to continue statin therapy, with added emphasis on adherence, net clinical benefit, and the core principles of regular moderate-intensity physical activity, maintaining a healthy dietary pattern, and sustaining modest weight loss 1. Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of statin-associated muscle symptoms (SAMS) 1. In patients at increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver disease) when appropriately indicated, it is reasonable to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks 1. In patients at increased ASCVD risk with severe statin-associated muscle symptoms or recurrent statin-associated muscle symptoms despite appropriate statin rechallenge, it is reasonable to use RCT proven nonstatin therapy that is likely to provide net clinical benefit 1. The 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults also provides recommendations for the management of muscle symptoms in statin-treated patients, including the evaluation and treatment of muscle symptoms, and the consideration of other conditions that might increase the risk for muscle symptoms 1. However, the most recent and highest quality study, the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol, should be prioritized when making a definitive recommendation 1.
From the Research
CPK Elevation and Statin Therapy
- The decision to stop statins due to CPK elevation is complex and depends on various factors, including the level of elevation and the presence of symptoms 2, 3, 4.
- A study published in 2009 found that patients with asymptomatic high CK (>or=250 but <2500 IU/L) tolerated statins well without developing myalgia-myositis 2.
- Another study published in 2021 found that PCSK9 inhibitors were safe and effective in patients with markedly elevated CPK levels (>1,000 U/L), with 92% of patients demonstrating a reduction in CPK of >50% 3.
- A 2014 study found that the frequencies of substantive CPK increases and rhabdomyolysis during statin treatment were low, with highest risks seen in those on large daily doses or interacting drugs and on rosuvastatin 4.
Guidelines for Stopping Statins
- There is no clear consensus on the exact level of CPK elevation at which statins should be stopped.
- However, a CPK level >10 times the upper limit of normal (ULN) is generally considered a threshold for concern 2, 4.
- The presence of symptoms such as myalgia or rhabdomyolysis is also an important consideration in deciding whether to stop statins 3, 4.
- A study published in 1994 found that patients with CK levels exceeding 15,000 U/L had a higher incidence of acute renal failure and electrolyte disturbances 5.
Alternative Treatments
- For patients who cannot tolerate statins due to high CPK levels, alternative treatments such as PCSK9 inhibitors or ezetimibe may be considered 3, 6.
- A 2014 study found that the association of ezetimibe and simvastatin was an effective alternative to high-dose rosuvastatin, with a lower incidence of muscular pain 6.