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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 April 1, 2025 e799

by 13% in statin-intolerant patients when started >90 days after ACS.10

3 Statin intolerance is frequent in clinical practice

and the most commonly reported cause is statinassociated muscle symptoms.27 To consider a patient as having statin intolerance, a minimum of 2 statins should be attempted, including at least 1 at the lowest approved daily dose.28 Currently available options for patients with complete or partial intolerance to statin therapy include ezetimibe, PCSK9 inhibitor monoclonal antibodies, inclisiran, and bempedoic acid. Ezetimibe and PCSK9 inhibitors have been demonstrated to be safe and well tolerated and improve lipid parameters in statin-intolerant patients.8,9 However, outcomes studies using these agents as monotherapy or in combination in statin-intolerant patients are not available. Bempedoic acid is an ATP citrate lyase inhibitor that reduces LDL-C levels by 15% to 25% with low rates of musclerelated adverse effects.29,30 A combination product that combines bempedoic acid with ezetimibe lowered LDL-C levels by approximately 35%.31 In the CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial, bempedoic acid was compared with placebo in statin-intolerant patients with or at high risk for ASCVD. Patients with ACS within 90 days prior to randomization were excluded from this trial. Mean LDL-C level was 139 mg/dL at enrollment and was reduced by 29 mg/dL with bempedoic acid compared with placebo. MACE was reduced by 13% in the bempedoic acid arm. Bempedoic acid raised uric acid levels in a small subset of patients, and rates of abnormal liver function tests, gout, and gallstones were increased with its use in the trial.10 4 IMPROVE IT randomized patients post-ACS

with LDL-C levels of ≥50 mg/dL and ≤125 mg/ dL (≤100 mg/dL if on lipid-lowering therapy) to the combination of simvastatin (40 mg) and ezetimibe (10 mg) or simvastatin (40 mg) and placebo (simvastatin monotherapy), with median LDL-C level at enrollment of 69.5 mg/dL. The addition of ezetimibe reduced the relative risk of MACE by 6.4% compared with placebo.5 Benefit was similar among patients with baseline LDL-C 50 to 70 mg/dL versus ≥70 mg/dL.32 FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) enrolled patients with LDL-C ≥70 mg/dL and thus did not specifically assess outcomes associated with adding PCSK9 inhibitor therapy among patients with LDL-C levels 55 to 70 mg/dL.6,7 However, secondary analyses of both trials demonstrated better outcomes in patients with achieved LDL-C <50 mg/dL versus those with achieved LDL-C levels ≥50 mg/dL, with monotonic relationships, suggesting better outcomes with progressively lower LDL-C even well below 50 mg/dL.11,12 Rates of neurocognitive and muscle events, including hemorrhagic stroke, were not increased among patients who achieved very low LDL-C levels with PCSK9 inhibition.11,12 Longer term follow-up studies support continued benefit and safety associated with achieving and maintaining very low LDL-C levels in secondary prevention with a PCSK9 inhibitor over several years.33 The benefits of ezetimibe and PCSK9 inhibitors appear to be greater among higher risk patients with prior ACS and diabetes or more advanced coronary or polyvascular disease or elevated biomarkers.20,34–41

5 Ezetimibe reduces LDL-C levels by 15% to 25%

by blocking its absorption from the gastrointestinal tract via the Niemann-Pick C1-Like 1 protein (NPC1L1). The IMPROVE IT trial studied the combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) to simvastatin (40 mg) and placebo (simvastatin monotherapy) in patients hospitalized with an ACS in the past 10 days. The median time from ACS to randomization was 5 days, and 34% of patients were already on a statin at the time of the ACS event. The addition of ezetimibe reduced the relative risk of MACE by 6.4% compared with placebo (hazard ratio, 0.936 [95% CI, 0.89-0.99]) over a median of 6 years’ follow-up. Ezetimibe was well-tolerated without any clear imbalances in adverse events compared with placebo.5

Table 12.  Statin Classification Statin Classification by Expected LDL-C Reduction High-Intensity Therapy* Moderate-Intensity Therapy† Low-Intensity Therapy‡ Atorvastatin 40-80 mg Rosuvastatin 20-40 mg Atorvastatin 10-20 mg

Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 1-4 mg Simvastatin 10 mg

Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg

Modified with permission from Grundy et al.42 Copyright 2018 American Heart Association, Inc., and American College of Cardiology Foundation.

*Expected LDL-C reduction ≥50%. †Expected LDL-C reduction ≥30% to 49%. ‡Expected LDL-C reduction <30%. BID indicates twice daily; LDL-C, low-density lipoprotein cholesterol.

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