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).

December 2025
Looking back at 2025: What made the news
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco, Prof. Lale Tokgözoglu 

As we say farewell to 2025, what did we learn this year about residual cardiovascular risk?

Crucially, our knowledge of lipid-related residual risk continues to expand. Results from the VESALIUS-CV trial demonstrated clinical benefit from intensive lipid-lowering therapy in high-risk patients without prior history of cardiovascular events. Reduction in low-density lipoprotein cholesterol (LDL-C) levels to a median of 45 mg/dL with the PCSK9 inhibitor evolocumab on top of conventional lipid lowering therapy resulted in reduction of first major cardiovascular events by 25% (1). By extending the evidence for PCSK9 inhibition from secondary to primary prevention settings (2,3), these landmark findings reaffirm the mantra – lower is better – for LDL-C across the spectrum of risk.
Lipoprotein(a) [Lp(a)] continues to be a focus of attention, not just for its association with cardiovascular events but also adverse lower limb events. Real-world data from over 21,000 patients in the Mass General Brigham Lp(a) registry showed that patients with peripheral artery disease (PAD) with the highest Lp(a) concentration (quartile 4, 132–855 nmol/L) had 36% higher risk for cardiovascular events, as well as 19% higher risk of major adverse lower limb events, including a 20% risk for peripheral revascularization compared with the reference group (4). These findings strengthen the case for one-off measurement of Lp(a) to aid the identification of patients at highest risk who would benefit from intensive intervention to improve clinical outcomes.

Targeting triglyceride-rich lipoproteins and remnant cholesterol is an ongoing quest. 2025 heralded important developments in novel treatments targeting angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein CIII (APOC3), both of which play key roles in triglyceride metabolism. Solbinsiran, a small interfering RNA (siRNA) targeting hepatic ANGPTL3 showed promise in mixed dyslipidemia, reducing triglycerides and very low-density lipoprotein cholesterol by over 50% at higher doses, together with modest benefit in lowering LDL-C (5). The APOC3 antisense oligonucleotide olezarsen showed benefit in both moderate and severe hypertriglyceridemia (6,7). In ESSENCE-TIMI 73b in patients with moderate hypertriglyceridemia (150−499 mg/dL) and elevated cardiovascular risk, at least 85% of patients attained triglyceride levels <150 mg/dL with olezarsen treatment (6). Additionally, in the CORE studies (CORE-TIMI 72a and CORE2-TIMI 72b) in severe hypertriglyceridemia, 86% of patients achieved triglyceride levels <500 mg/dL with olezarsen; better triglyceride control was accompanied by 85% reduction in the incidence of pancreatitis versus placebo (7).

Perhaps one of the most exciting news reports from 2025 related to a novel gene editing approach targeting ANGPTL3 using CRISPR-Cas9 technology. First-in-man data from patients with refractory dyslipidemia showed that CTX310 reduced both LDL-C and triglyceride levels by up to 60% at the highest doses (8). While longer-term safety remains an understandable concern warranting further study, these results suggest the possibility of a ‘once and done’ single treatment able to transform the clinical management of dyslipidemia.

Rounding off 2025, reports highlighted two key challenges facing clinicians: obesity-associated cardiovascular risk and residual inflammatory risk.

We are facing a continuing – and escalating – pandemic of obesity among adults and even more worryingly, among adolescents and children. According to latest data from the Global Burden of Disease study, the global prevalence of obesity among adolescents and children tripled from 1990 to 2021, with the highest prevalence in North Africa and the Middle East. If these trends continue, globally about one-third of children and adolescents will be overweight or obese by 2050 (9). Urgent action is needed, as these trends threaten the cardiovascular health of future generations.

Globally, cardiovascular disease is the leading cause of death in individuals who are either overweight or obese, and the incidence has more than doubled since 1990 (10). New approaches are therefore needed to address the unmet clinical needs of obesity-associated cardiovascular risk. Insights from the FOURIER study showed that treatment with evolocumab attenuated cardiovascular risk among patients with the highest body mass index (and therefore at highest risk) (11). However, given the interplay between mechanisms affected by cardiometabolic dysregulation, management of obesity-related cardiovascular risk will likely involve the combination of different therapeutic approaches. Critical to management will be how to identify those patients at highest risk.

Finally, 2025 closed with a landmark trial that clearly made the case for routine measurement of high-sensitivity C-reactive protein (hsCRP) to improve ASCVD prevention beyond traditional risk factors (12). Action is now needed to implement this in guidelines. Not only will measurement of hsCRP provide added prognostic value in risk scores, but it will also aid identification of patients at high residual risk who would benefit from anti-inflammatory therapy.

We look forward to expanding horizons about residual cardiovascular risk in 2026.

References

    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.
    2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-22.
    3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
    4. McClintick DJ, Biery DW, Berman AN, et al. Association between lipoprotein(a) and cardiovascular events in patients with peripheral artery disease: the Mass General Brigham Lp(a) registry. Eur J Prevent Cardiol 2025; https://doi.org/10.1093/eurjpc/zwaf475
    5. Ray KK, Oru E, Rosenson RS, et al. Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet 2025; https://doi.org/10.1016/S0140-6736(25)00507-0.
    6. Bergmark BA, Marston NA, Prohaska TA, et al; Essence–TIMI 73b Investigators. Targeting APOC3 with olezarsen in moderate hypertriglyceridemia. N Engl J Med 2025 Aug 30. doi: 10.1056/NEJMoa2507227.
    7. 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. 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.
    9. GBD 2021 Adolescent BMI Collaborators. Global, regional, and national prevalence of child and adolescent overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet 2025; 405: 785–812
    10. Lopez-Jimenez F, Di Cesare M, Powis J, et al. The weight of cardiovascular diseases: Addressing the global cardiovascular crisis associated with obesity. Global Heart 2025; doi.org/10.5334/gh.1451.
    11. Kang YM, Giugliano RP, Keech AC, et al. Obesity-associated cardiovascular risk and benefit from PCSK9 inhibition. A prespecified analysis from FOURIER. J Am Coll Cardiol 2025; doi.org/10.1016/j.jacc.2025.10.036.
    12. Kurt B, Reugels M, Schneider KM, et al. C-reactive protein and cardiovascular risk in the general population. Eur Heart J 2025; doi.org/10.1093/eurheartj/ehaf937.

     

    Key words: Residual risk; triglycerides; remnant cholesterol; inflammation; obesity; treatments