Advances in Beyond Statin Lipid Therapies for ASCVD Risk Reduction

Q: Why is LDL cholesterol central to reducing ASCVD risk?

Elevated LDL-C is described as a major causative factor for ASCVD. Lowering LDL-C is associated with reductions in mortality and multiple cardiovascular events.

Q: What do major guidelines recommend for LDL-C thresholds in high-risk patients?

ACC/AHA guidelines set LDL-C <70 mg/dL as the threshold for adding non-statin therapy, while ESC/EAS guidelines recommend LDL-C targets <55 mg/dL for ultra-high-risk groups.

Q: What “beyond statin” lipid therapies are discussed to address residual risk?

The text highlights options such as PCSK9 modulators, ATP citrate lyase inhibitors, ANGPTL3 inhibitors (ebinacumab), microsomal triglyceride transfer protein inhibitors (romitapid), and investigational compounds targeting additional pathways.

Sep 30, 2026

Uploaded by Valentina

LDL cholesterol is a key causative factor in atherosclerotic cardiovascular disease, and intensive LDL-C lowering reduces downstream ASCVD outcomes. Guidelines from ACC/AHA and ESC/EAS, along with expert consensus, progressively lower LDL-C targets for high- and ultra-high-risk populations. Despite statin use, residual cardiovascular risk persists, driving development of “beyond statin” lipid therapies. Emerging approaches include PCSK9 modulators, ATP citrate lyase inhibition, ANGPTL3 inhibition, microsomal triglyceride transfer protein inhibition, and additional investigational mechanisms targeting cholesterol metabolism and efflux.

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CategoryHealthcare

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LDL Cholesterol and ASCVD Events

Residual ASCVD Risk and Beyond Statin Lipid Therapies

Investigational Agents and Mechanisms

Correspondence, Received/Accepted, and Publication Notes

The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Editorial J Atheroscler Thromb, 2026; 33: 26-28. [http://doi.org/10.5551/jat.ED296](http://doi.org/10.5551/jat.ED296) Advances in Beyond Statin Lipid Therapies for ASCVD Risk Reduction Michio Shimabukuro Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical University School of Medicine, Fukushima, Japan 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 allcause 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/dLas 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 firstline 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, angiopoietinlike protein 3 inhibitors (ebinacumab), and microsomal triglyceride transfer protein inhibitors (romitapid), among others (Fig.1) 8, 9, 11) . 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 antiatherosclerotic 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. Address for correspondence: Michio Shimabukuro, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan [E-mail: mshimabukuro-ur@umin.ac.jp](E-mail: mshimabukuro-ur@umin.ac.jp

FAQs

Why is LDL cholesterol central to reducing ASCVD risk?

Elevated LDL-C is described as a major causative factor for ASCVD. Lowering LDL-C is associated with reductions in mortality and multiple cardiovascular events.

What do major guidelines recommend for LDL-C thresholds in high-risk patients?

ACC/AHA guidelines set LDL-C <70 mg/dL as the threshold for adding non-statin therapy, while ESC/EAS guidelines recommend LDL-C targets <55 mg/dL for ultra-high-risk groups.

What “beyond statin” lipid therapies are discussed to address residual risk?

The text highlights options such as PCSK9 modulators, ATP citrate lyase inhibitors, ANGPTL3 inhibitors (ebinacumab), microsomal triglyceride transfer protein inhibitors (romitapid), and investigational compounds targeting additional pathways.

Sep 30, 2026

Uploaded by Valentina