The following are key points to remember about the 2022 American College of Cardiology (ACC) expert consensus decision pathway (ECDP) on the role of nonstatin therapies for low-density lipoprotein cholesterol (LDL-C) lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk:

1. ACC ECDPs use 'solution sets' that address key questions that provide clinical guidance for very common to rare diseases. The 2022 ACC ECDP provides guidance for use of nonstatin lipid-altering drugs prior to completion of cardiovascular outcome trials. The three Food and Drug Administration (FDA) approved nonstatin therapies not available in the 2018 American Heart Association (AHA)/ACC cholesterol guideline are bempedoic acid, evinacumab, and inclisiran.
2. For persons with persistent or severe hypertriglyceridemia, refer to the 2021 ACC ECDP on management of hypertriglyceridemia (Virani SS, et al. J Am Coll Cardiol 2021;78:960-93).
3. Factors to consider for patient management groups:
   • Adherence to lifestyle modifications and adherence to evidence-based guideline-recommended statin therapy.
   • Risk-enhancing factors: family history of premature ASCVD; primary hypercholesterolemia with LDL-C >160 mg/dL or non–HDL-C >190 mg/dL; metabolic syndrome; chronic kidney disease (estimated glomerular filtration rate 15-59 ml/min/1.73 m²); chronic inflammatory conditions such as psoriasis, rheumatoid arthritis, or HIV/AIDS; premature menopause at age <40 years; pregnancy conditions that increase risk such as eclampsia and gestational diabetes; high-risk races/ethnicities (e.g., southeast Asia); persistently elevated primary hypertriglyceridemia ≥175 mg/dL.
   • If measured, biomarker with increased risk: high-sensitivity C-reactive protein ≥2 mg/dL, lipoprotein a ≥50 mg/dL or ≥125 nmol/L, apolipoprotein B >130 mg/dL, ankle-brachial index <0.9.
   • Control of other risk factors.
   • Clinician–patient decision about the potential benefits, potential harms, and patient preferences with regard to the addition of nonstatin therapies.
   • Percentage LDL-C reduction and absolute LDL-C or non–HDL-C level achieved.
   • Monitoring of response to lifestyle modification, adherence, and therapy.
   • Cost of therapy.
   • Statin-associated side effects.
   • Persistent hypertriglyceridemia.
   • Referral to lipid specialist and registered dietitian/nutritionist.
   • Bile acid sequestrants.
   • Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody (mAb) (alirocumab, evolocumab).
   • LDL apheresis by lipid specialist for heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH).
   • Lomitapide limited to HoFH.
   • Evinacumab limited to HoFH.
4. In view of the twice-yearly dosing regimen, inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs. Patients with adverse effects from both PSCK9 mAbs or those who may be unable to self-inject may also be considered for therapy with inclisiran. There is currently no evidence or mechanistic plausibility for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with/without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be used in place of a PCSK9 mAb inhibitor.
5. Two of the authors, Donald M. Lloyd-Jones, MD (Chair) and Pamela B. Morris, MD (Vice Chair), created a list of the most important points providers or payers need to know about the ECDP. In the clinical setting:
   • Clinical ASCVD at very high risk and patients with clinical ASCVD and clinical diagnosis or genetic confirmation of familial hypercholesterolemia on high-intensity statin therapy, a lower LDL-C threshold of LDL-C ≥55 mg/dL (or non–HDL-C ≥85 mg/dL) is recommended for addition of nonstatin therapy.
   • Clinical ASCVD at very high risk or clinical ASCVD with baseline LDL-C >190 mg/dL or familial hypercholesterolemia with inadequate lowering of LDL-C on maximally tolerated statin therapy, either a PCSK9 mAb or ezetimibe are initial nonstatin therapy. Some patients may require greater LDL-C reduction than any additional agent alone can expect to achieve, and it may be reasonable to consider the addition of two agents simultaneously to reduce risk of recurrent events more rapidly. Options may include either combination therapy with high-intensity or maximally tolerated statin and ezetimibe or maximally tolerated statin with/without ezetimibe and PCSK9 mAb. If the patient achieves <50% reduction in LDL-C or LDL-C remains above threshold of >55 mg/dL, consideration may be given to the addition of bempedoic acid. In view of the twice-yearly dosing regimen, inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs. Patients with adverse effects from both PSCK9 mAb(s) or those who may be unable to self-inject may also be considered for therapy with inclisiran.
   • Patients with or without clinical ASCVD and clinical diagnosis or genetic confirmation of HoFH may be considered for therapy with evinacumab, lomitapide, or LDL apheresis under the care of a lipid specialist if there is inadequate lowering of LDL-C on maximally tolerated statin with/without ezetimibe, PCSK9 inhibitor therapy, and/or bempedoic acid.
   • Clinical ASCVD not at very high risk or clinical ASCVD with baseline LDL-C >190 mg/dL without clinical diagnosis or genetic confirmation of familial hypercholesterolemia, the LDL-C threshold of >70 mg/dL (or non–HDL-C >100 mg/dL) is recommended for consideration of addition of nonstatin therapies to maximally tolerated statin therapy.
   • Clinical ASCVD not at very high-risk, ezetimibe 10 mg daily should be the initial nonstatin agent, given the benefits on ASCVD outcomes and demonstrated safety of ezetimibe in patients with acute coronary syndrome treated with ezetimibe plus simvastatin versus simvastatin monotherapy. If patients who are on maximally tolerated statin–ezetimibe achieve a less-than-anticipated response, a PCSK9 mAb (in addition to or in place of ezetimibe) may be considered as a second step to achieve further LDL-C reduction. If the patient achieves <50% reduction in LDL-C or LDL-C remains above threshold of >70 mg/dL (or non–HDL-C >100 mg/dL), consideration may be given to the addition of bempedoic acid. In view of the twice-yearly dosing regimen, inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs. Patients with adverse effects from both PSCK9 mAbs or those who may be unable to self-inject may also be considered for therapy with inclisiran.
   • Primary prevention patients aged 40-75 years with diabetes are candidates for at least moderate-intensity statin therapy. High-intensity statin should be considered in those patients with 10-year risk >7.5% or with diabetes-specific risk enhancers. If patients with diabetes have 10-year ASCVD risk >20% and there is <50% reduction in LDL-C and/or LDL-C >70 mg/dL (or non–HDL-C >100 mg/dL) on maximally tolerated statin therapy, they may be considered for the addition of ezetimibe.
   • For primary prevention patients without diabetes, moderate- to high-intensity statin is the foundation of therapy. If the 10-year ASCVD risk is >20% and there is inadequate lowering of LDL-C on maximally tolerated statin therapy, the addition of ezetimibe may be considered.
   • Considerations for LDL-C lowering in subclinical atherosclerosis on imaging: For patients with coronary artery calcium (CAC) score of 1-99 Agatston units (AU) or <75th percentile, moderate- to high-intensity statin therapy is recommended. If the CAC score is 100-999 AU or >75th percentile, moderate- to high-intensity statin therapy is recommended. If the patient fails to achieve >50% lowering of LDL-C or LDL-C >70 mg/dL, the addition of ezetimibe may be considered. If the CAC score is >1000 AU and the patient fails to achieve >50% lowering of LDL-C or LDL-C >70 mg/dL on maximally tolerated statin plus ezetimibe, the addition of a PCSK9 mAb may be considered.
   • In clinical ASCVD, baseline LDL-C >190 mg/dL, familial hypercholesterolemia, high-risk diabetes, high-risk primary prevention, or evidence of significant subclinical atherosclerosis who are unable to tolerate evidence-based statin therapy may be candidates for nonstatin therapies for further lowering of LDL-C. Eligibility for each therapy depends on the patient's baseline level of ASCVD risk and the available evidence base for the therapeutic agent.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Atherosclerosis, Cardiovascular Diseases, Cholesterol, LDL, Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Hypertriglyceridemia, Lipids, Metabolic Syndrome, PCSK9 protein, human, Primary Prevention, Renal Insufficiency, Chronic, Risk Factors

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