Cardiovascular disease (CVD) remains the leading cause of mortality and morbidity worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) representing a well-established modifiable risk factor.^1,2 While the FOURIER trial demonstrated that adding evolocumab to statin therapy in very high-risk patients with a prior myocardial infarction (MI) or stroke reduced subsequent major adverse cardiovascular events (MACE), the role of evolocumab in high-risk patients without a previous major ischemic event was less clear.^2,3 New phase 3 VESALIUS-CV findings show that evolocumab added to optimized LDL-C lowering therapies significantly reduced first MACE in high-risk adults without a prior MI or stroke.²

A first major adverse cardiovascular (CV) event substantially increases the risk of recurrent events, especially when modifiable risk factors, including LDL-C, are inadequately managed.⁴ Evidence demonstrated that each 1mmol/L reduction in LDL-C reduces MACE by 20%.⁵ However, a substantial proportion of high-risk patients fail to achieve guideline-recommended LDL-C targets despite statin therapy, highlighting a significant residual risk and unmet clinical need in the population.¹ Evolocumab, a human monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), prevents LDL receptor degradation and thereby increases LDL uptake to lower circulating LDL-C levels.⁶

Evolocumab has been shown in the FOURIER study to reduce MACE in very high-risk patients with a prior MI or stroke.^2,3 Building on this evidence, the VESALIUS-CV trial evaluated the impact of LDL-C lowering with evolocumab on MACE in a broader population of adults at elevated CV risk without prior history of MI or stroke.² VESALIUS-CV is a global, double-blind, randomized, placebo-controlled phase 3 trial enrolling more ≥12,000 adults with established atherosclerotic cardiovascular disease (ASCVD) or high-risk diabetes, with one or more additional high-risk features for CVD, without a prior history of MI or stroke.² Participants had LDL-C ≥90mg/dL, non-high-density lipoprotein cholesterol (non-HDL-C) ≥120mg/dL, or apolipoprotein B ≥80mg/dL, despite maximally tolerated statin therapy ± ezetimibe.² Patients were randomized 1:1 to receive evolocumab or placebo in addition to optimized lipid-lowering therapy and were followed for a median of approximately 4.6 years.²

Evolocumab achieved a 25% relative risk reduction in the primary composite endpoint of coronary heart disease (CHD) death, MI, or ischemic stroke (3-point MACE) compared with placebo (HR=0.75; 95% CI: 0.65-0.86; p<0.001).² For the broader composite endpoint that included ischemia-driven revascularization as the 4-point MACE, the relative risk reduction was 19% (HR=0.81; 95% CI: 0.73-0.89; p<0.001).² In a lipid substudy, patients treated with evolocumab achieved a median LDL-C of 45mg/dL vs. 109mg/dL in the placebo arm, further reinforcing the evidence that intensive LDL-C lowering translates into clinically meaningful CV risk reduction.² These findings extend FOURIER evidence to support aggressive LDL-C lowering in both secondary prevention and high-risk primary prevention populations, underscoring the proven benefits of evolocumab across the CVD continuum.²

Significant reductions were observed across the majority of secondary composite endpoints.² Evolocumab reduced the risk of the composite of MI, ischemic stroke, or ischemia-driven arterial revascularization by 21% (HR=0.79; 95% CI: 0.72-0.88; p<0.001), and the composite of CHD death, MI, or ischemia-driven arterial revascularization by 21% (HR=0.79; 95% CI: 0.72-0.88; p<0.001).² The risk of the composite of CV death, MI, or ischemic stroke was reduced by 27% (HR=0.73; 95% CI: 0.64-0.84; p<0.001), and the risk of coronary heart disease death or MI by 27% (HR=0.73; 95% CI: 0.62-0.87; p<0.001).² Notably, evolocumab also reduced the risk of MI by 36% (HR=0.64; 95% CI: 0.52-0.79; p<0.001) and ischemia-driven arterial revascularization by 21% (HR=0.79; 95% CI: 0.70-0.88; p<0.001).² With nearly 60% of the trial participants having diabetes, the observed reductions in CV events underscore the critical need for optimized LDL-C management in this high-risk population.² The safety profile of evolocumab in VESALIUS-CV was consistent with prior experience, with no new safety signals identified and no between-group differences in the incidence of safety events.²

In conclusion, VESALIUS-CV demonstrates that intensive LDL-C lowering with evolocumab significantly reduces the risk of first MACE among high-risk patients, establishing evolocumab as the first PCSK9 inhibitor to show a significant benefit in both primary and secondary prevention across a broad CVD spectrum.²