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Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 June 18/25, 2019 e1117 CLINICAL STATEMENTS AND GUIDELINES

triglycerides should preferentially be measured in the fasting state. 3.	 Patients with RA who are untreated or who have high disease activity generally have decreased levels of TC, triglycerides, HDL-C, and LDL-C.S4.5.5-21 These lower lipid levels are likely attributable in part to increased inflammation and may lead to functional proatherogenic changes, such as decreased cholesterol efflux capacity of HDL-C.S4.5.5-22 Treatment with anti-inflammatory medications, such as tumor necrosis factor alpha inhibitors or methotrexate, is associated with an increase in and normalization of lipid levels and a reduction in the ratio of TC to HDL-C.S4.5.5-23 Thus, to produce a more accurate risk estimate, ASCVD risk estimation should be repeated when the patient has a stable and low disease activity with normalization of their lipid levels; lower lipid levels measured during high disease activity may lead to a significant underestimation of ASCVD risk for patients with RA.

5. STATIN SAFETY AND STATIN- ASSOCIATED SIDE EFFECTS

Recommendations for Statin Safety and Statin-Associated Side Effects Referenced studies that support recommendations are summarized in Online Data Supplements 40 and 41.

COR LOE Recommendations

I A 1.  A clinician–patient risk discussion is recommended before initiation of statin therapy to review net clinical benefit, weighing the potential for ASCVD risk reduction against the potential for statin-associated side effects, statin–drug interactions, and safety, while emphasizing that side effects can be addressed successfully.S5-1–S5-7

I A 2.  In patients with statin-associated muscle symptoms (SAMS), a thorough assessment of symptoms is recommended, in addition to an evaluation for nonstatin causes and predisposing factors.S5-3–S5-7

I B-R 3.  In patients with indication for statin therapy, identification of potential predisposing factors for statin-associated side effects, including new-onset diabetes mellitus and SAMS, is recommended before initiation of treatment.S5-3–S5-7

I B-R 4.  In patients with statin-associated side effects that are not severe, it is recommended to reassess and to rechallenge to achieve a maximal LDL-C lowering by modified dosing regimen, an alternate statin or in combination with nonstatin therapy.S5-3–S5-8

I B-R 5.  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.S5-8–S5-12 I C-LD 6.  In patients treated with statins, it is recommended to measure creatine kinase levels in individuals with severe statinassociated muscle symptoms, objective muscle weakness, and to measure liver transaminases (aspartate aminotransferase, alanine aminotransferase) as well as total bilirubin and alkaline phosphatase (hepatic panel) if there are symptoms suggesting hepatotoxicity.S5-13–S5-15

I B-R 7.  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.S5-16–S5-18

IIa B-R 8.  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.S5-5,S5-6,S5-19

III: No Benefit B-R 9.  Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of SAMS.S5-20,S5-21

III: No Benefit C-LD 10.  In patients treated with statins, routine measurements of creatine kinase and transaminase levels are not useful.S5-13–S5-15

Synopsis Statin therapy is usually well tolerated and safe.S5-1,S5-14, S5-22–S5-24 As with other classes of medications, associated side effects are seen. Instead of the label statin intolerance, the present guideline prefers statin-associated side effects because the large majority of patients are able to tolerate statin rechallenge with an alternative statin or alternative regimen, such as reduced dose or in combination with nonstatins. Although infrequent or rare in clinical trials, statin-associated side effects can be challenging to assess and manage.S5-25,S5-26 The most frequent are SAMS. SAMS usually are subjective myalgia, reported observationally in 5% to 20% of patients.S5-11–S5-14 SAMS often result in nonadherence and can adversely impact ASCVD outcomes.S5-27–S5-29 Statins modestly increase risk of incident diabetes mellitus in susceptible individuals,S5-8–S5-11 but this should not be cause for discontinuation (Table 11). The present guideline recommends a comprehensive approach to statin-associated symptoms. The clinician should reassess, rediscuss, and encourage rechallenge as the initial approach unless side effects are severe. Ongoing communication is integral to patient care, as is regular monitoring to check for adherence, adequacy of response, new associated symptoms, and reaffirmation of benefit.S5-2

Recommendations for Statin Safety and Statin-Associated Side Effects (Continued)

COR LOE Recommendations

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