Advances in Beyond Statin Lipid Therapies for ASCVD Risk Reduction

See article vol. 33: 55-77

LDL Cholesterol and ASCVD Events

Elevated plasma low-density lipoprotein cholesterol (LDL-C) levels are a major causative factor for atherosclerotic cardiovascular disease (ASCVD) in both developed and developing countries. For secondary prevention, a meta-analysis by the Cholesterol Treatment Trials Consortium (CTTC) demonstrated that a 1-mmol/L (or 39-mg/dL) reduction in LDL-C resulted in a 12% decrease in all-cause mortality, a 23% decrease in myocardial infarction or coronary death, a 24% decrease in coronary revascularization procedures, and a 17% decrease in nonfatal stroke ¹⁾ . This demonstrates the benefit of achieving LDL-C levels lower than the previously recommended 70 mg/dL in high-risk patients or those with a history of ASCVD ²⁾ .

Based on this evidence, the 2018 American College of Cardiology (ACC) and American Heart Association (AHA) guidelines set LDL-C ＜70 mg/dL as the threshold for adding non-statin medications ³⁾ . Further, the 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines recommend an LDL-C target of ＜55 mg/dL for ultra-high-risk groups for primary and secondary prevention (Class I recommendation) ^{4 , 5)} . The American Association of Clinical Endocrinology Consensus Statement recommends an LDL-C level ＜55 mg/dL for patients with cardiometabolic disorders, cardiovascular disease, or multiple risk factors ⁶⁾ . Statins are globally recommended as a first-line therapy for both primary and secondary cardiovascular prevention because of their favorable risk-benefit profile ^{4 , 5)} .

Lovastatin was the first statin approved for clinical use by the U.S. Food and Drug Administration (FDA), receiving approval on September 1, 1987. Since then, various statins with different chemical structures, biological properties, pharmacologic characteristics (pharmacokinetics, potency of LDL-C lowering), and clinical features (safety and potential for drug interactions) have been introduced into clinical practice.

Residual ASCVD Risk and Beyond Statin Lipid Therapies

Even when optimal LDL-C reduction is achieved with statin therapy, unmet needs for residual cardiovascular risk persist ⁷⁾ , and treatment options for lipid-lowering drugs continue to expand ^{8 - 10)} . Currently, in addition to statin lipid therapies in clinical practice, there are proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators (monoclonal antibodies and small interfering RNA molecules), ATP citrate lyase inhibitors, angiopoietin-like protein 3 inhibitors (ebinacumab), and microsomal triglyceride transfer protein inhibitors (romitapid), among others ( Fig.1 ) ^{8 , 9 , 11)} .

Fig.1. Beyond statin lipid therapies.

Established or emerging targets of lipid therapies are shown. Blue characters indicate drug or chemical names. ⊖: inhibition; ⊕: stimulation. ABCA1: ATP-binding cassette protein A1; ABCG1: ATP-binding cassette protein G1; ANGPL3: angiopoietin-like protein 3; CE: cholesterol ester; CETP: cholesteryl ester transfer protein; FC: free cholesterol; HDL: high-density lipoprotein; IDL: intermediate-density lipoprotein; LCAT: lecithin:cholesterol acyltransferase; LDL: low-density lipoprotein; LDLR: low-density lipoprotein receptor; LPL: lipoprotein lipase; MTTP: microsomal triglyceride transfer protein; NPCL1: Niemann-Pick C1 like 1 protein; PCSK9: proprotein convertase subtilisin kexin 9; TG: triglycerides; VLDL: very-low-density lipoprotein;

MN-001 (cipercast) is an orally administered small-molecule compound with multiple mechanisms of action, including leukotriene receptor antagonism, phosphodiesterase 3/4 inhibition, 5-lipoxygenase inhibition, phospholipase C inhibition, and thromboxane A₂ inhibition ¹²⁾ . Qi et al. demonstrated that MN-002, a metabolite of MN-001, exerts anti-atherosclerotic effects by promoting cholesterol efflux through an increased expression of ABCA1 and ABCG1 via PPAR-α and LXRα pathways ¹³⁾ . Therefore, these compounds warrant further investigation as potential beyond-statin lipid therapies.

Conflicts of Interest

None.