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  • Review Article
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Novel and future lipid-modulating therapies for the prevention of cardiovascular disease

Nature Reviews Cardiology volume 20, pages 600–616 (2023)Cite this article

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Abstract

Lowering the levels of LDL cholesterol in the plasma has been shown to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Several other lipoproteins, such as triglyceride-rich lipoproteins, HDL and lipoprotein(a) are associated with atherosclerosis and ASCVD, with strong evidence supporting causality for some. In this Review, we discuss novel and upcoming therapeutic strategies targeting different pathways in lipid metabolism to potentially attenuate the risk of cardiovascular events. Key proteins involved in lipoprotein metabolism, such as PCSK9, angiopoietin-related protein 3, cholesteryl ester transfer protein and apolipoprotein(a), have been identified as viable targets for therapeutic intervention through observational and genetic studies. These proteins can be targeted using a variety of approaches, such as protein inhibition or interference, inhibition of translation at the mRNA level (with the use of antisense oligonucleotides or small interfering RNA), and the introduction of loss-of-function mutations through base editing. These novel and upcoming strategies are complementary to and could work synergistically with existing therapies, or in some cases could potentially replace therapies, offering unprecedented opportunities to prevent ASCVD. Moreover, a major challenge in the prevention and treatment of non-communicable diseases is how to achieve safe, long-lasting reductions in causal exposures. This challenge might be overcome with approaches such as small interfering RNAs or genome editing, which shows how far the field has advanced from when the burden of achieving this goal was placed upon patients through rigorous adherence to daily small-molecule drug regimens.

Key points

  • LDL cholesterol is a causal and cumulative factor in the development of atherosclerosis; therefore, reducing plasma LDL cholesterol levels, irrespective of the approach used, decreases the risk of cardiovascular disease.

  • Data from observational and genetic studies have revealed novel treatment targets beyond LDL cholesterol lowering.

  • Novel treatment targets can be classified into those that increase the number of LDL receptors (LDLRs) in hepatocytes and those that interfere with the modification and composition of atherogenic lipoproteins.

  • Besides statins and ezetimibe, treatments that enhance LDLR function (LDLR-dependent treatments) include bempedoic acid, which targets ATP citrate lyase, and PCSK9-targeting therapies, such as monoclonal antibodies or the small interfering RNA inclisiran.

  • Emerging treatments that modify lipoprotein composition target apolipoprotein C-III, ANGPTL3, cholesteryl ester transfer protein and lecithin–cholesterol acyltransferase; therapies that modify lipoprotein number target apolipoprotein(a); and those that enhance lipoprotein function target apolipoprotein A-I.

  • Novel approaches with sustained effects and infrequent dosing regimens might overcome the issues with treatment adherence that are common to therapies requiring more frequent dosing.

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Fig. 1: Novel and emerging LDL-lowering therapies targeting PCSK9.
Fig. 2: Novel and emerging lipid-lowering therapies targeting apoC-III.
Fig. 3: Novel and emerging lipid-lowering therapies targeting ANGPTL3.
Fig. 4: Emerging lipid-lowering therapies targeting Lp(a).

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Acknowledgements

K.K.R. acknowledges support from the NIHR Imperial Biomedical Research Centre and the NIHR ARC for Northwest London.

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  1. Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK

    Julia Brandts & Kausik K. Ray

  2. Department of Internal Medicine I, University Hospital RWTH Aachen, Aachen, Germany

    Julia Brandts

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J.B. received research grant support from AstraZeneca and speaker honoraria from Amgen. K.K.R. received grants from Amgen, grants and personal fees from Amgen, Daiichi Sankyo, MSD, Pfizer and Sanofi/Regeneron, and personal fees from Aegerion Cerenis, Abbvie, Akcea, Algorithm, Astra Zeneca, Bayer, Boehringer Ingelheim, Cipla, Dr Reddy’s Laboratories, Esperion, Kowa, Lilly, the Medicines Company, Novartis, Silence Therapeutics, Takeda and Zuelling Pharma.

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Brandts, J., Ray, K.K. Novel and future lipid-modulating therapies for the prevention of cardiovascular disease. Nat Rev Cardiol 20, 600–616 (2023). https://doi.org/10.1038/s41569-023-00860-8

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