Evolocumab reduces coronary event risk regardless of baseline Lp(a)

In a pre-specified analysis of VESALIUS-CV, higher baseline Lp(a) levels were associated with an increased risk of coronary events in patients with established atherosclerosis or high-risk diabetes but without prior MI or stroke. In addition, evolocumab reduced the risk of major coronary events in this patient population regardless of baseline Lp(a).

This summary is based on the publication of Monguillon V, Marston NA, Bohula EA, et al. - Lipoprotein(a) Levels, Risk of Cardiovascular Events and Benefit of Evolocumab: Findings From the VESALIUS-CV Trial. Circulation. 2026 Jun 23;153(25):1960-1968. Epub 2026 May 25. doi: 10.1161/CIRCULATIONAHA.126.080999.

Introduction and methods

Background

Lipoprotein(a) [Lp(a)] is a risk factor for coronary heart disease and is believed to contribute to residual cardiovascular risk even among individuals who achieve low LDL-c levels [1-3]. It is unknown whether elevated baseline Lp(a) identifies higher risk patients without prior MI or stroke who obtain greater benefit from treatment with the PCSK9 inhibitor evolocumab.

Aim of the study

The aim of the study was to evaluate the association between baseline Lp(a) concentrations and cardiovascular outcomes, and to assess the efficacy of evolocumab according to baseline Lp(a) levels in patients at risk for a first cardiovascular event.

Methods

This was a pre-specified analysis of the VESALIUS-CV trial, which enrolled 12,257 patients with established atherosclerosis or high-risk diabetes, but without prior MI or ischemic stroke. Participants were randomized to evolocumab 140 mg every 2 weeks or placebo and followed for a median of 4.6 years. Baseline Lp(a) measurements were available in 7,557 participants.

The median baseline Lp(a) concentration was 28 nmol/L, and 28.7% of patients had Lp(a) levels >105 nmol/L.

Outcomes

The primary outcome for this analysis was major coronary events, defined as a composite of coronary heart disease death, MI, or urgent coronary revascularization.

Main results

Baseline Lp(a) concentration and cardiovascular outcomes in placebo-treated patients

• Among placebo-treated patients, higher baseline Lp(a) was independently associated with an increased risk of major coronary events:
  • Each 100 nmol/L increase in Lp(a) was associated with a 15% higher risk of major coronary events (adjusted HR: 1.15; 95%CI: 1.05–1.26; P=0.004).
  •  The association was strongest for MI, with a 23% higher risk per 100 nmol/L increase in Lp(a) (adjusted HR: 1.23; 95%CI: 1.10–1.38; P<0.001).
  • No association was observed between Lp(a) and ischemic stroke (adjusted HR: 1.00; 95%CI: 0.84–1.19; P=0.99).

Efficacy of evolocumab

• After 48 weeks, evolocumab reduced LDL-c and Lp(a) concentrations across all baseline Lp(a) categories:
  • In patients with baseline Lp(a) >105 nmol/L, LDL-c was reduced by 66.8 mg/dL and Lp(a) by 38.0 nmol/L.
  • In patients with baseline Lp(a) ≤105 nmol/L, LDL-c was reduced by 61.1 mg/dL and Lp(a) by 6.0 nmol/L.
• Evolocumab reduced the risk of major coronary events regardless of baseline Lp(a):
  • Patients with Lp(a) >105 nmol/L experienced a 41% relative risk reduction (HR: 0.59; 95%CI: 0.41–0.83).
  • Patients with Lp(a) ≤105 nmol/L experienced a 35% relative risk reduction (HR: 0.65; 95%CI: 0.51–0.82).
  • There was no significant interaction between baseline Lp(a) and the relative treatment effect of evolocumab (P for interaction=0.45).
• Because patients with elevated Lp(a) had a higher baseline coronary risk, absolute benefits tended to be greater (P for interaction=0.09):
  • Absolute risk reduction for major coronary events was 3.7% in patients with Lp(a) >105 nmol/L versus 2.5% in those with lower Lp(a).
  • The number needed to treat (NNT) over 5 years was 28 in the Lp(a) >105 nmol/L group compared with 40 in the lower-Lp(a) group.

Conclusion

In patients with established atherosclerosis or high-risk diabetes but without prior MI or stroke, elevated Lp(a) was independently associated with a higher risk of major coronary events, particularly MI, but not ischemic stroke. Evolocumab reduced the relative risk of major coronary events across the entire spectrum of baseline Lp(a) levels. Because patients with elevated Lp(a) were at higher baseline risk, they experienced a numerically greater absolute benefit from treatment, although this difference was not statistically significant.

Find this article online at Circulation

References

1. Patel AP, Wang M, Pirruccello JP, Ellinor PT, Ng K, Kathiresan S, et al. Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank. Arterioscler Thromb Vasc Biol 2021;41:465–474.
2. Bhatia HS, Wandel S, Willeit P, Lesogor A, Bailey K, Ridker PM, et al. Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol–Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis. Circulation 2025;151:312–321. 10. 11. 12. 13. 14. 15.
3. Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925–3946.