|Recommendations||NHLBI Grade||NHLBI Evidence Statements||ACC/AHA COR||ACC/AHA LOE|
|1. To maximize the safety of statins, selection of the appropriate statin and dose in men and nonpregnant/nonnursing women should be based on patient characteristics, level of ASCVD∗ risk, and potential for adverse effects. Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present.|
Characteristics predisposing individuals to statin adverse effects include but are not limited to:
|2a. CK should not be routinely measured in individuals receiving statin therapy.||A (Strong)||45,49–51,54,55||III: No Benefit||A|
|2b. Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events because of a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk of myopathy.||E (Expert Opinion)||—||IIa||C (88)|
|2c. During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue.||E (Expert Opinion)||—||IIa||C (88)|
|3a. Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiation of statin therapy.||B (Moderate)||46,52,53||I†||B|
|3b. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera).||E (Expert Opinion)||—||IIa||C (89)|
|4. Decreasing the statin dose may be considered when 2 consecutive values of LDL-C levels are <40 mg/dL.||C (Weak)||45||IIb||C|
|5. It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of simvastatin to 80 mg daily.||B (Moderate)||6,54||III: Harm||A (67,90)|
|6. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines (91). Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events.||B (Moderate)||44||I‡||B|
|7. For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals who are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for HIV). A review of the manufacturer’s prescribing information may be useful before initiation of any cholesterol-lowering drug.||E (Expert Opinion)||—||IIa||C (16,64–70,89,92–94)|
|8. It is reasonable to evaluate and treat muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm:||E (Expert Opinion)||—||IIa||B (15,88,96–98)|
|9. For individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy.||E (Expert Opinion)||—||IIb||C (38,89,99,100)|
ACC indicates American College of Cardiology; AHA, American Heart Association; ALT, alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CK, creatine kinase; COR, Class of Recommendation; NHLBI, National Heart, Lung, and Blood Institute; LDL-C, low-density lipoprotein cholesterol; LOE, Level of Evidence; RCTs, randomized controlled trials; ULN, upper limit of normal; and —, not applicable.
↵∗ Based on the presence of clinical ASCVD, diabetes, LDL-C ≥190 mg/dL, or level of estimated 10-year ASCVD risk.
↵† Individuals with elevated ALT levels (usually >1.5 or 2 times ULN) were excluded from RCT participation. Unexplained ALT ≥3 times ULN is a contraindication to statin therapy as listed in manufacturer’s prescribing information.
↵‡ Statin use is associated with a very modest excess risk of new-onset diabetes in RCTs and meta-analyses of RCTs (i.e., ∼0.1 excess cases per 100 individuals treated for 1 year with moderate-intensity statin therapy and ∼0.3 excess cases per 100 individuals treated for 1 year with high-intensity statin therapy. The increased risk of new-onset diabetes appears to be confined to those with risk factors for diabetes. These individuals are also at higher risk of ASCVD because of these risk factors. Therefore, if a statin-treated individual develops diabetes as detected by current diabetes screening guidelines, he or she should be counseled to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of ASCVD events.