Lipid Lowering Drugs: Present Status and Future Developments

Abstract

Purpose of review Based on the recent data of the DA VINCI study, it is clear that, besides utilization of statins, there is a need to increase non-statin lipid lowering approaches to reduce the cardiovascular burden in patients at highest risk. Recent findings For hypercholesterolemia, the small synthetic molecule bempedoic acid has the added benefit of selective liver activation, whereas inclisiran, a hepatic inhibitor of the PCSK9 synthesis, has comparable effects with PCSK9 monoclonal antibodies. For hypertriglyceridemia, cardiovascular benefit has been achieved by the use of icosapent ethyl, whereas results with pemafibrate, a selective agonist of PPAR-α, are eagerly awaited. In the era of RNA-based therapies, new options are offered to dramatically reduce levels of lipoprotein(a) (APO(a)LRX) and of triglycerides (ANGPTL3LRX and APOCIII-LRx). Summary Despite the demonstrated benefits of statins, a large number of patients still remain at significant risk because of inadequate LDL-C reduction or elevated blood triglyceride-rich lipoproteins or lipoprotein(a). The area of lipid modulating agents is still ripe with ideas and major novelties are to be awaited in the next few years.

Assessment and management of the heightened risk for atherosclerotic cardiovascular events in patients with lupus erythematosus or dermatomyositis

“… Bile acid sequestrants, which lower plasma LDL cholesterol concentrations and ASCVD event risk but can have significant gastrointestinal side effects in some patients and can raise plasma concentrations of triglycerides ( Hegele et al, 2015 ). Bempedoic acid, a new agent that inhibits ATP citrate lyase, an enzyme that leads to both fatty acid and cholesterol biosynthesis in a step that is upstream of HMG-CoA reductase, the target of statins ( Ruscica et al, 2021 ). Bempedoic acid appears to have no effects in muscle ( Ruscica et al, 2021 ).…”

“… Bempedoic acid, a new agent that inhibits ATP citrate lyase, an enzyme that leads to both fatty acid and cholesterol biosynthesis in a step that is upstream of HMG-CoA reductase, the target of statins ( Ruscica et al, 2021 ). Bempedoic acid appears to have no effects in muscle ( Ruscica et al, 2021 ). Bempedoic acid was recently FDA-approved for LDL lowering in heterozygous familial hypercholesterolemia or established ASCVD.…”

“… Candidate therapies under investigation in dyslipoproteinemias and ASCVD events Pemafibrate is a new fibrate that lowers plasma triglyceride concentrations and is under evaluation in the PROMINENT trial for effects on ASCVD events in the context of baseline statin therapy. Previous ASCVD event trials of fibrates added to statins failed to achieve their primary prespecified outcomes on ASCVD event reduction ( Hegele et al, 2015 ), but the PROMINENT trial has a different design that specifically focuses on patients with high plasma triglycerides and low HDLc ( Ruscica et al, 2021 ). Liver-directed, modified siRNA against PCSK9 mRNA, recently approved in Europe for lowering LDLc; after two loading doses it is administered only twice per year, which may improve convenience and compliance ( Khvorova, 2017 ; Ray et al, 2020 ).…”

Breaking Therapeutic Inertia With Alirocumab in an 80-Year-Old Patient With Severe Hypercholesterolemia: A Case Report

“…In our case, simple and validated tools have contributed to refine estimates of the risk and guide personalized treatment thus maximizing the likelihood of a positive outcome. The area of lipid-modulating agents is constantly evolving, and new pharmacological molecules (e.g., inclisiran and bempedoic acid) with novel mechanisms of action have recently been approved ( 24 ). Having new opportunities in the treatment of hypercholesterolemia could mark a major advance in the care of patients with high and very high-risk cardiovascular disease, and not only in statin-intolerant individuals.…”

Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis

“…Lipid-lowering drugs, which are pivotal in the treatment of atherosclerotic cardiovascular diseases (ASCVD), can reduce major adverse cardiovascular events (MACE) to a certain extent ( Bonovas et al, 2011 ). Currently, the clinically recommended lipid-lowering drugs are statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) ( Ruscica et al, 2021 ). As the commonly used lipid-lowering drugs since the mid-1980s, statins can decrease low-density lipoprotein cholesterol (LDL-C) levels ( Reiner, 2013 ).…”