The following are key points to remember from a review article on a stepwise approach to prescribing novel lipid-lowering therapies:

1. The authors aim to familiarize clinicians with novel lipid-lowering therapies and provide a concise and practical guide for how to prescribe these agents in clinical practice.
2. The article reviews the efficacy and safety of novel lipid-lowering agents, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bempedoic acid, icosapent ethyl, evinacumab, and lomitapide. The latter two are indicated for management of homozygous familial hypercholesterolemia.
3. The authors endorse use of pharmacologic therapies¹ with proven cardiovascular benefit, i.e., statins, ezetimibe, PCSK9 monoclonal antibodies (evolocumab and alirocumab), and icosapent ethyl.
4. Statins are the drugs of choice for initial reduction of low-density lipoprotein cholesterol (LDL-C) because a large body of evidence supports efficacy and safety of statins.
5. Patients with statin intolerance should receive the maximally tolerated statin dose even if ultra-low (e.g., rosuvastatin 2.5 mg three times per week), rather than discontinue statins altogether.
6. In patients at very high risk of atherosclerotic cardiovascular disease (ASCVD), i.e., those with a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions:
   • Ezetimibe should be added if LDL-C is ≥70 mg/dL on maximally tolerated statin therapy.
   • PCSK9 monoclonal antibody therapy should be added if LDL-C remains ≥70 mg/dL or non–high-density lipoprotein cholesterol (non–HDL-C) ≥100 mg/dL despite ezetimibe and maximally tolerated statin.
     • Bempedoic acid may be considered if concerned about the expense of PCSK9 inhibitor.
     • Inclisiran may be considered in patients who prefer less frequent injections.
   • Lomitapide or evinacumab should be considered in patients with homozygous familial hypercholesterolemia.
7. In patients not at very high risk of ASCVD who are ≤75 years of age:
   • Ezetimibe should be added if LDL-C ≥70 mg/dL on maximally tolerated statin. therapy
   • Bempedoic acid should be considered if LDL-C remains ≥70 mg/dL despite ezetimibe and maximally tolerated statin.
8. In patients not at very high risk of ASCVD who are >75 years of age, either moderate-intensity or high-intensity statin may be utilized, with subsequent intensification if indicated.
9. Icosapent ethyl should be considered in patients with triglycerides ≥135 mg/dL who meet REDUCE-IT criteria.²
10. In the future, new lipid-modifying agents based on gene silencing technology may become available. The new therapies may target lipids other than LDL-C, e.g., HDL-C, triglycerides, and lipoprotein(a).

¹ A cardiovascular outcomes trial of bempedoic acid (CLEAR Outcomes) was completed November 7, 2022. On December 7, 2022, the trial sponsor reported that the CLEAR Outcomes trial met its primary endpoint of statistically significant reduction in MACE-4 (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) with bempedoic acid compared with placebo. The trial sponsor subsequently announced that full results of the trial will be presented March 4, 2023, at the ACC.23 Annual Scientific Session.

² Established ASCVD or diabetes mellitus plus two of the following ASCVD risk factors: cigarette smoking, hypertension, age ≥50 years, HDL ≤40 mg/dL for males or ≤50 mg/dL for females, high-sensitivity C-reactive protein >3 mg/L, creatinine clearance <60 mL/min, retinopathy, micro- or macroalbuminuria, and ankle-brachial index <0.9.

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

Keywords: Acute Coronary Syndrome, Atherosclerosis, Cholesterol, LDL, Drug Therapy, Dyslipidemias, Ezetimibe, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hypertriglyceridemia, Lipids, Lipoprotein(a), Metabolic Syndrome, Myocardial Ischemia, PCSK9 protein, human, Patient Care Team, Primary Prevention, Triglycerides

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