R3i Editorials

January 2024
Targeting residual cardiovascular risk: what’s in the pipeline?
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Individuals with atherosclerotic cardiovascular disease remain at high risk of recurrent events. Some of this risk may be ascribed to practical factors such as clinical inertia or cross-country disparities in access to effective lipid lowering therapies, as highlighted by the EU-wide DA VINCI study. Across 18 countries in the European Union, less than half of secondary prevention patients received high intensity statin therapy for managing low-density lipoprotein cholesterol (LDL-C), as recommended by clinical guidelines (1,2). Inadequacies in guideline implementation are also common to other global regions (3). Additionally, strict reimbursement criteria or lack of funding limit access to newer treatments in some regions. Even with best guideline-based treatment, however, lipid-related residual risk is a major contributor to the substantial risk of recurrent events, underlining the need to identify atherogenic targets beyond LDL-C.

An ongoing focus of interest is triglyceride-rich lipoproteins (TRL) and their remnants, supported by extensive evidence from epidemiologic, mechanistic and genetic studies (4). Even with intensive statin therapy, the residual risk associated with TRL still predicts cardiovascular risk (5,6). An ongoing conundrum is how best to target this TRL-associated risk, given mixed results from clinical outcomes studies evaluating different therapeutic approaches (7-9). In part, the lack of clarity relates to the complexity of TRL metabolism, suggesting that it may be necessary to target production, remodelling and clearance of TRL for significant clinical benefit (5). New data presented at this year’s European Society of Cardiology Congress highlight new therapeutic strategies for reducing TRL. First in-man data for ARO-ANG3, a novel RNA interference (RNAi) therapy targeting angiopoietin-like protein 3 (ANGPTL3) showed almost complete inhibition of ANGPTL3 and up to 70% reduction in plasma triglycerides, as well as modest lowering of LDL-C and apolipoprotein (apo) B, with a short-term multiple dose regimen (10). Additionally, there were promising preclinical data with anti-APOC3 GalNAc-siRNA agent, RBD5044, targeting apoC3, which showed more than 50% reduction in plasma triglycerides in different animal models (11).
Another important contributor to lipid-related residual risk is lipoprotein(a) [Lp(a)]. While extensive observational and genetic evidence supports elevated Lp(a) as causal for atherosclerotic cardiovascular disease (12), clinicians lack targeted treatments to manage this risk factor. PCSK9 monoclonal antibody therapy has been shown to lower Lp(a) levels by 20-30%, but most of the risk reduction associated with these treatments is attributed to the substantial lowering of LDL-C levels with PCSK9 inhibition (13).

There is hope on the horizon for specific Lp(a)-lowering treatments. The first of these novel agents, pelacarsen, an antisense oligonucleotide targeting apo(a) synthesis, has been shown to reduce Lp(a) levels by up to 80% and was well tolerated (14). In addition, there are at least two short interference RNA (siRNA) therapies under investigation (olpasiran and SLN360), both shown to being highly effective in lowering Lp(a) concentration (15,16). However, these agents are injectables, which may adversely impact patient access and acceptability. The ‘holy grail’ is an oral treatment; first in-man data with muvalaplin, an oral small molecule inhibitor of Lp(a) formation, which is discussed in this month’s Landmark report, indicates potential for addressing this unmet need (17). The key uncertainty is whether lowering Lp(a) reduces cardiovascular outcomes in patients at very high risk of recurrent events, which is being evaluated in two ongoing outcomes studies, HORIZON and OCEAN(a).
The future offers the prospect of new strategies for managing lipid-related residual cardiovascular risk. Now the focus should be on improving the identification of these risk factors by incorporating them into routine lipid testing in high-risk patients in clinical practice.

References

  1. Ray KK, Molemans B, Schoonen WM, et al. EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study. Eur J Prev Cardiol 2021;28:1279–89.
    2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–88.
    3. Yang YS, Lee SY, Kim JS, et al. Achievement of LDL-C targets defined by ESC/EAS (2011) guidelines in risk-stratified Korean patients with dyslipidemia receiving lipid-modifying treatments. Endocrinol Metab (Seoul) 2020;35:367–76.
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    11. Luo H, Guo Z, Zheng S et al. RBD5044 – a novel anti-APOC3 GalNAc-siRNA drug resulted in sustained and profound reduction of triglycerides in mice and Rhesus monkeys. Presented at ESC Congress 2023, Amsterdam, The Netherlands (25-28 August). Session: Hypertriglyceridaemia treatment: icosapent ethyl and fibrates
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    16. Nissen SE, Wolski K, Balog C, et al. Single ascending dose study of a short interfering RNA targeting Lipoprotein(a) production in individuals with elevated plasma Lipoprotein(a) levels. JAMA 2022;327:1679-87.
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