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Review
. 2025 Feb 26;27(1):35.
doi: 10.1007/s11883-025-01281-3.

Quo Vadis after AEGIS: New Opportunities for Therapies Targeted at Reverse Cholesterol Transport?

Nick S R Lan  1   2 , Gerald F Watts  3   4
Affiliations
Review

Quo Vadis after AEGIS: New Opportunities for Therapies Targeted at Reverse Cholesterol Transport?

Nick S R Lan et al. Curr Atheroscler Rep. .

Abstract

Purpose of review: High-density lipoprotein (HDL) is integral to reverse cholesterol transport (RCT), a process considered to protect against atherosclerotic cardiovascular disease (ASCVD). We summarise findings from the recent AEGIS-II trial and discuss new opportunities for HDL therapeutics targeted at RCT.

Recent findings: Mendelian randomisation studies have suggested a causal association between the functional properties of HDL and ASCVD. However, the AEGIS-II trial of CSL112, an apolipoprotein A-I therapy that enhances cholesterol efflux, did not meet its primary endpoint. Exploratory analyses demonstrated that CSL112 significantly reduced ASCVD events among participants with a baseline low-density lipoprotein (LDL)-cholesterol ≥ 100 mg/dL, suggesting that RCT may depend on LDL-cholesterol levels. The role of HDL therapeutics in patients with familial hypercholesterolaemia, inherited low HDL-cholesterol and impaired HDL function, especially with inadequately controlled LDL-cholesterol, merits further investigation. The treatment of patients with monogenic defects in HDL metabolism remains a significant gap in care that needs further research.

Keywords: Cardiovascular diseases; Cholesterol; Coronary artery disease; Dyslipidaemia; Lipid-lowering therapy; Risk factors.

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Conflict of interest statement

Declarations. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors. Conflicts of Interest: N.S.R.L. has received research funding from Sanofi as part of a Clinical Fellowship in Endocrinology and Diabetes, education support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Seqirus, Eli Lilly, Novartis and Pfizer, speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Menarini, Novartis and Sanofi, and has participated in advisory boards for Eli Lilly. G.F.W. has received honoraria for advisory boards and research grants from Amgen, Arrowhead, Esperion, Gemphire, Kowa, Novartis, Pfizer, Sanofi, Novo Nordisk and Regeneron.

Figures

Fig. 1
Fig. 1
A simplified overview of reverse cholesterol transport [20]. Reproduced with permission from Oxford University Press (Allard-Ratick MP, et al. Eur J Prev Cardiol 2021).[20]. A) Free cholesterol is effluxed from lipid-laden macrophages (or foam cells) to nascent HDL particles in a process mediated by ABCA1. B) Free cholesterol is also effluxed from macrophages to mature HDL in a process mediated by ABCG1. C) LCAT esterifies free cholesterol to cholesteryl esters in nascent HDL, leading to the formation of mature HDL. D) Mature HDL is taken up by the liver via SR-B1 receptors. E) Cholesteryl esters are transferred from mature HDL to apoB-containing lipoproteins such as LDL and VLDL in a process mediated by CETP. F) LDL and VLDL are taken up by the liver via LDL receptors. Apolipoprotein A-I (not depicted) is the major structural protein of nascent and mature HDL particles. Abbreviations: ABCA1 ATP-binding cassette A1; ABCG1 ATP-binding cassette G1; apoB apolipoprotein B; CETP cholesteryl ester transfer protein; HDL high-density lipoprotein; LCAT lecithin:cholesterol acyltransferase; LDL low-density lipoprotein; SR-B1 scavenger receptor class B type 1; VLDL very low-density lipoprotein
Fig. 2
Fig. 2
Cumulative incidence of time to first occurrence of the composite primary endpoint in the AEGIS-II trial at 90, 180 and 365 days [55]. Reproduced with permission from Oxford University Press (Gibson CM, et al. Eur Heart J 2024).[55]. A) Among patients with a baseline low-density lipoprotein cholesterol level ≥ 100 mg/dL who were prescribed statin therapy. B) Among patients with a baseline low-density lipoprotein cholesterol level < 100 mg/dL who were prescribed statin therapy
See this image and copyright information in PMC

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