Advances in targeting LDL cholesterol: PCSK9 inhibitors and beyond

Abstract

There is a direct relationship between the duration and level of exposure to low density lipoprotein cholesterol (LDL-C) levels over one's lifespan and cardiovascular events. Early treatment to lower elevated LDL-C is crucial for better outcomes with multiple therapies currently available to reduce atherogenic lipoproteins. Statins remain the foundation of LDL-C lowering therapy as one of the most cost-effective drugs to reduce atherosclerotic events (ASCVD) and mortality. Nonetheless, LDL-driven goal attainment remains suboptimal globally, highlighting a considerable need for non-statin therapies to address residual risk related to statin intolerance, non-adherence, and inherited lipoprotein disorders. LDL-C lowering interventions beyond statins include ezetimibe, PCSK9 monoclonal antibodies, inclisiran and bempedoic acid with specific guideline recommendations as to when to consider each. For patients with homozygous familial hypercholesterolemia requiring more advanced therapy, lomitapide and evinacumab are available, providing mechanisms that are not LDL receptor dependent. Lipoprotein apheresis remains an effective option for clinical familial hypercholesterolemia as well as elevated lipoprotein (a). There are investigational therapies being explored to add to our current armamentarium including CETP inhibitors, a third-generation PCSK9 inhibitor (small recombinant fusion protein oral PCSK9 inhibitor) and gene editing which aims to directly restore or disrupt genes of interest at the DNA level. This article is a brief review of the pharmacotherapy options beyond statins for lowering LDL-C and their impact on ASCVD risk reduction. Our primary aim is to guide physicians on the role these therapies play in achieving appropriate LDL-C goals, with an algorithm of when to consider each based on efficacy, safety and outcomes.

Keywords: Advanced therapies; Lipid-lowering; Non-statins; Precision lipidology.

Fig. 1

Current therapeutic armamentarium of approved lipid-modifying agents. Schematic diagram of the site and mechanism of action, affecting various steps in the LDL synthesis and clearance pathway. With permission and modifications from Safarova et al. [12]. Abbreviations: LDL-C: low density lipoprotein cholesterol; NPC1L1: Niemann-Pick C1-Like 1; LDL-R: low density lipoprotein receptor; ACL: ATP citrate lyase inhibitor; PCSK9: Proprotein convertase subtilisin/kexin type 9; siRNA: Small interfering ribonucleic acid; ANGPTL3: Angiopoietin-like 3; ApoB: Apolipoprotein B; FFA: free fatty acids, CETP cholesteryl ester transfer protein; MTP Microsomal Triglyceride Transfer Protein; HDL high-density lipoprotein.

Fig. 2

Therapeutic thresholds in primary and secondary prevention of ASCVD. Individualized approach to the reduction of the lipoprotein-driven risk of ASCVD should be based on the: 1) preferred route of administration, 2) preferred frequency of administration, 3) medication-specific side effects, 4) clinical profile of the patient, 5) LDL-lowering potential, 6) Lp(a)-lowering potential. **As of 2024, bempedoic acid is FDA-approved for primary prevention of ASCVD and FH with or without maximally tolerated statin therapy. No data on safety and efficacy exists on combining monoclonal antibodies to PCSK9 and siRNA to PCSK9. Therefore, this group does not recommend this combination at this time. Intensification of the lipid-lowering therapy and aggressive LDL-C lowering should be considered in individuals without a prior index event but severe coronary artery calcification, such CAC score ≥1000 [124] or left main coronary artery involvement [125] The presence of any degree of coronary calcification should warrant at least a moderate potency statin.

Fig. 3

Milestones in non-statin therapies for LDL-C lowering based on the data supporting the routine use of U.S. Food and Drug Administration (FDA)-approved non-statin drugs combined with statin therapy for LDL-C reduction with the goal of further reducing ASCVD events. Abbreviations: LDL-C: low density lipoprotein cholesterol; NCEP-ATP III: National Cholesterol Education Program Adult Treatment Panel-III; PCSK9: Proprotein convertase subtilisin/kexin type 9; mAB: monoclonal antibody; ASCVD: Atherosclerotic cardiovascular disease; CETPi: cholesterol ester transfer protein inhibitor.