A Comprehensive Review of the Latest Approaches to Managing Hypercholesterolemia: A Comparative Analysis of Conventional and Novel Treatments: Part II

Abstract

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with hypercholesterolemia identified as a major, but modifiable risk factor. This review serves as the second part of a comprehensive analysis of dyslipidemia management. The first installment laid the groundwork by detailing the key pathophysiological mechanisms of lipid metabolism, the development of atherosclerosis, major complications of hyperlipidemia, and the importance of cardiovascular risk assessment in therapeutic decision-making. It also examined non-pharmacological interventions and conventional therapies, with a detailed focus on statins and ezetimibe. Building upon that foundation, the present article focuses exclusively on emerging pharmacological therapies designed to overcome limitations of standard treatment. It explores the mechanisms, clinical applications, safety profiles, and pharmacogenetic aspects of novel agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (alirocumab, evolocumab), small interfering RNA (siRNA) therapy (inclisiran), adenosine triphosphate-citrate lyase (ACL) inhibitor (bempedoic acid), microsomal triglyceride transfer protein (MTP) inhibitor (lomitapide), and angiopoietin-like protein 3 (ANGPTL3) inhibitor (evinacumab). These agents offer targeted strategies for patients with high residual cardiovascular risk, familial hypercholesterolemia (FH), or statin intolerance. By integrating the latest advances in precision medicine, this review underscores the expanding therapeutic landscape in dyslipidemia management and the evolving potential for individualized care.

Keywords: PCSK9 inhibitors; bempedoic acid; cardiovascular risk reduction; emerging therapies for dyslipidemia; hypercholesterolemia; inclisiran; lipid-lowering therapies; lomitapide.

Figure 1

PCSK9 inhibitors—mechanism of action (Created with BioRender.com). Abbreviations: PCSK9—proprotein convertase subtilisin/kexin type 9; LDL-C—low-density lipoprotein cholesterol; LDL-R—low-density lipoprotein receptors; PCSK9i—proprotein convertase subtilisin/kexin type 9 inhibitors; ↑—increase; ↓—decrease; →—which leads to. Legend: A. LDL-C binds to the LDLR and enters the hepatocyte via receptor-mediated endocytosis. From there, the complex (LDLR—LDL-C) enters the lysosome, LDL-C will be degraded, while the LDLR gets recycled, is externalized at the surface of the membrane and the cycle restarts. B. PCSK9 protein binds to LDLR and enters the hepatocyte via receptor-mediated endocytosis. Due to the presence of PCSK9, the endosome can no longer dissociate this complex, so the LDLR is degraded together with PCSK9 protein. This leads to a decrease in the expression of LDLRs on the surface of the hepatocyte. C. PCSK9 inhibitor specifically binds to the PCSK9 protein, thus blocking its binding to the LDLR. Therefore, the LDLR will be recycled by the same mechanism previously described in point A.

Figure 2

Inclisiran—mechanism of action (Created with BioRender.com). Note: Inclisiran is a chemically synthesized small interfering RNA (siRNA) therapy that targets PCSK9 mRNA in hepatocytes, leading to its degradation via the RNA-induced silencing complex (RISC) and thereby reducing PCSK9 protein synthesis. Post-transcriptional modifications refer to chemical or structural alterations made to RNA molecules after they are transcribed from DNA but before they are translated into proteins. Inclisiran incorporates several such modifications to enhance its stability, efficacy, and liver-specific delivery. These include 2′-O-methyl or 2′-fluoro substitutions on the ribose sugars to protect against nuclease degradation, phosphorothioate backbone linkages for increased enzymatic resistance, and conjugation to triantennary N-acetylgalactosamine (GalNAc), which facilitates selective uptake by hepatocytes via asialoglycoprotein receptors. In contrast, post-translational modifications are chemical changes that occur to proteins after their synthesis (translation), such as glycosylation, phosphorylation, or proteolytic cleavage, which often affect protein function, localization, or stability. While inclisiran itself does not undergo post-translational modifications, its mechanism of action prevents the production of PCSK9 protein, thereby indirectly abolishing any post-translational modifications that PCSK9 would normally experience. This highlights inclisiran’s novel role as a post-transcriptional gene-silencing therapy with implications in lipid lowering and cardiovascular risk reduction [38,39]. Abbreviations: mRNA—messenger ribonucleic acid; siRNA—small interfering ribonucleic acid; PCSK9—proprotein convertase subtilisin/kexin type 9; LDL-C—low-density lipoprotein cholesterol; LDLR—low-density lipoprotein cholesterol receptor; GalNAc—N-acetylgalactosamine; ASGPR—asialoglycoprotein receptor; RISC—ribonucleic acid-induced silencing complex; →—which leads to; ↓—decrease; ↑—increase.