The class
Review surveys the evolving landscape of lipid-lowering drug targets, from statins to CETP and Lp(a) inhibition (Eur Heart J 2025)
Original title: The evolving landscape of targets for lipid lowering: from molecular mechanisms to translational implications
This review summarises current and emerging targets for lipid lowering beyond LDL cholesterol, including triglycerides, apolipoprotein B and lipoprotein(a), which contribute to residual cardiovascular risk. It covers statins acting via HMG-CoA reductase, bempedoic acid acting upstream via ATP citrate lyase, PCSK9 inhibitors preventing LDL receptor degradation, and ezetimibe limiting intestinal cholesterol absorption, alongside emerging targets ANGPTL3 and apolipoprotein C-III that act independently of the LDL receptor. The review notes that CETP inhibition increases catabolism of apoB-containing lipoproteins, positioning it alongside Lp(a)-lowering antisense strategies as part of an evolving, expanding set of tools for patients resistant to current therapies or with specific lipid abnormalities.
Original abstract
Cardiovascular disease remains a major global health challenge, with dyslipidaemia being a key modifiable risk factor. While low density lipoprotein cholesterol (LDL-C) is the primary target for lipid-lowering therapies, recent evidence highlights the importance of triglycerides, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] for residual cardiovascular risk. Current lipid-lowering therapies target key enzymes and proteins involved in cholesterol and lipid metabolism. Statins inhibit HMG-CoA reductase, reducing cholesterol biosynthesis and increasing LDL receptor (LDLR) expression in the liver. Bempedoic acid inhibits ATP citrate lyase, the enzyme upstream of HMG-CoA reductase in the mevalonate pathway, offering an alternative to statins by selectively acting in the liver, minimizing muscle-related side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide decanoate (MK0616)] prevent LDLR degradation, while ezetimibe limits intestinal cholesterol absorption. Emerging lipid-lowering targets include angiopoietin-like 3 protein (ANGPTL3) and apolipoprotein C-III (apoC-III). Inhibiting ANGPTL3 reduces both triglycerides and LDL-C independently of LDL receptor. Inhibition of apoC-III unleashes lipoprotein lipase (LPL) activity, promoting triglyceride-rich particle catabolism, even in complete LPL deficiency. Cholesteryl ester transfer protein (CETP) inhibition also increases the catabolism of apoB-containing lipoproteins. Ongoing research into strategies to reduce Lp(a), primarily but not exclusively through antisense therapies, aims to demonstrate the cardiovascular benefits of targeting this lipoprotein. In summary, the field of targets for lipid and lipoprotein lowering is constantly evolving and offers new strategies for patients resistant to current therapies or with specific lipid profile abnormalities.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.