R3i Editorials

R3i editorials, created by members of the R3i board, focus on addressing the persistent challenges of residual cardiovascular risk. These editorials serve to educate healthcare professionals about emerging insights and therapeutic strategies related to lipid-related risk factors, such as triglyceride-rich lipoproteins and lipoprotein(a).

November 2025
What’s new in lipid research? Insights from AHA 2025
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco, Prof. Lale Tokgözoglu 

The 2025 American Heart Association (AHA) Scientific Sessions did not disappoint, premiering exciting new data in the lipid field. One of the stars was VESALIUS-CV with the PCSK9 inhibitor evolocumab (1), a landmark trial in high-risk patients who had not yet experienced a first cardiovascular event. With atherosclerotic cardiovascular disease (ASCVD) considered as a continuum of risk, guidelines recommend that the extent of low-density lipoprotein cholesterol (LDL-C) lowering required should be guided by baseline risk (2,3). Undoubtedly, patients with a major adverse cardiovascular event (MACE) are at highest risk and usually require the addition of a PCSK9 inhibitor to conventional lipid lowering therapy (statin and ezetimibe) to attain guideline-recommended targets (2,3). For other patient cohorts deemed to be high risk, such as those with high-risk cardiovascular–kidney–metabolic syndrome (4), clinical trial evidence to support intensification of LDL-C lowering therapy is less robust.

VESALIUS-CV included over 12,000 patients with atherosclerosis or high-risk diabetes, but without a prior cardiovascular event. The trial convincingly demonstrated that lowering LDL-C levels to a median of 45 mg/dL, (approaching the LDL-C target of <40 mg/dL recommended by European guidelines for very high-risk patients) (3), resulted in 25% reduction in the 3-point MACE of coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke, 19% reduction in the 4-point MACE which also included ischemia-driven arterial revascularization, as well as 36% reduction in first MI (1). CHD death was reduced by 11%; the lack of statistical significance, likely due to the small numbers of events, precluded testing for other endpoints. However, reduction in cardiovascular death by 21%, all-cause death by 20%, and ischemic stroke by 21% are clinically meaningful findings (1). Taken together, the results of VESALIUS-CV reinforce the concept that lower LDL-C is better for clinical outcome (5). Guideline implementation, however, remains problematic, as shown by the global real-world study VESALIUS-REAL, which showed that 82% patients with similar characteristics as in VESALIUS-CV failed to achieve guideline-recommended LDL-C targets (6). Clearly, improvement is needed to achieve best practice. As an aside, the advent of an oral PCSK9 inhibitor, enlicitide, which achieved durable LDL-C reduction of up to 60% in the CORALreef Lipids trial (7), may offer practical advantages for attaining LDL-C goal.

Beyond LDL-C, there were data for novel triglyceride-lowering therapies. In the setting of severe hypertriglyceridemia, the CORE studies (CORE-TIMI 72a and CORE2-TIMI 72b) which included over 1000 patients, showed that treatment with the apolipoprotein CIII (APOC3)

antisense oligonucleotide olezarsen (50 mg or 80 mg monthly) led to substantial and durable reduction in plasma triglyceride levels (8). At 12 months, 86% of patients in either olezarsen dose group attained triglyceride levels below 500 mg/dL, and between one-third and one-half of patients attained plasma triglycerides below 150 mg/dL (1.69 mmol/L). Additionally, pooled olezarsen data showed an 85% reduction in the incidence of pancreatitis versus placebo, yielding a number needed to treat of 20 over 1-year to prevent one episode of acute pancreatitis (8). Another agent investigated in severe hypertriglyceridemia was DR10624, a first-in-class triple-therapy which simultaneously targets FGF21 (Fibroblast Growth Factor 21), glucagon and glucagon-like peptide-1 (GLP-1) receptors. Although limited by a small study cohort comprising almost all Han Chinese patients and short treatment duration, reduction in plasma triglycerides of about 70% or higher at 12 weeks suggests therapeutic promise for this novel approach (9). Together, these findings bring new hope to the management of patients with severe hypertriglyceridemia for whom conventional triglyceride-lowering therapies, the mainstay of treatment, have only modest efficacy in lowering triglyceride levels and no effect on pancreatitis risk (10).

Perhaps the most exciting star of the meeting, however, was a new ‘once and done’ gene editing approach targeting ANGPTL3 (11). This follows a gene editing therapy targeting PCSK9 gene in the liver, which was shown to reduce LDL-C levels by approximately 50% following a single infusion in patients with familial hypercholesterolemia (12).

CTX310 was developed using clustered regularly interspaced short palindromic repeats–Cas9 endonuclease (CRISPR-Cas9) technology. In this phase I study in 15 adults with uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia, the primary focus was safety. Single infusion with CTX310 (0.1, 0.3, 0.6, 0.7, or 0.8 mg/kg) was associated with few adverse events and resulted in over 70% reduction in ANGPTL3 levels at the two highest doses. Moreover, this treatment also produced simultaneous reduction in both LDL-C and triglyceride levels by up to 60% at the highest doses (11). Understandably, long-term safety is a major concern, with safety monitoring continuing for up to 15 years as per FDA requirements. In the meantime, these preliminary data offer a tantalising possibility that a ‘once and done’ single treatment could transform the management of refractory dyslipidemia, hypercholesterolemia and hypertriglyceridemia.

Once again, AHA Scientific Sessions 2025 lived up to past expectations. We look forward to future chapters in the ongoing lipid story.

References

  1. 1. Bohula EA, Marston NA, Bhatia AK, et al. Evolocumab in patients without a previous myocardial Infarction or stroke. N Engl J Med 2025; DOI: 10.1056/NEJMoa2514428.
    1. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis 2019;290:140–205.
    2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 139(25): e1046-e1081.
    3. Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation 2023; 148: 1606-35.
    4. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.
    5. Chan Q, Sakhula S, Ochs A, et al. Lipid lowering therapy use in high risk RISK ASCVD patients without prior MI or stroke – preliminary data from the VESALIUS-REAL, US. JACC 2025;185(12): Supplement A.
    6. Navar AM, et al. Efficacy and safety of enlicitide, an oral PCSK9 inhibitor, for lowering LDL cholesterol in adults with or at-risk for ASCVD: the Phase 3 CORALreef Lipids Trial. American Heart Association Scientific Sessions 2025, Late-Breaking Science Abstract 4391578.
    7. Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med 2025; DOI: 10.1056/NEJMoa2512761
    8. Li J et al. American Heart Association Scientific Sessions 2025, Abstract 4392939.
    9. Filtz A, Parihar S, Greenberg GS, et al. New approaches to triglyceride reduction: is there any hope left? Am J Prev Cardiol 2024; 18: 100648.
    10. Laffin LJ, Nicholls SJ, Scott RS, et al. Phase 1 trial of CRISPR-Cas9 gene editing targeting ANGPTL3. N Engl J Med 2025; DOI: 10.1056/NEJMoa2511778.
    11. First in vivo base editing lowers cholesterol. Nat Biotechnol 2023;41:1665.

     

    Key words: AHA Scientific Sessions 2025; triglycerides; low-density lipoprotein cholesterol; VESALIUS-CV; olarsarzen; CTX310; gene-editing