The international VESALIUS-CV clinical trial has revealed that the PCSK9 inhibitor evolocumab significantly reduces the risk of first major cardiovascular events in adults with atherosclerotic cardiovascular disease or diabetes who have no history of heart attack or stroke. These findings, presented at the American Heart Association's Scientific Sessions 2025 and simultaneously published in The New England Journal of Medicine, represent a potential paradigm shift in cardiovascular prevention strategies.
During a median follow-up of 4.6 years, participants receiving evolocumab experienced a 25% reduction in the risk of coronary heart disease death, heart attack, or ischemic stroke compared to those receiving placebo. The study also demonstrated a 19% reduction in the risk of coronary heart disease death, heart attack, ischemic stroke, or arterial revascularization. Additional benefits included a 27% reduction in cardiovascular death, heart attack, or ischemic stroke and a 36% reduction in heart attack specifically.
Lead study author Erin A. Bohula, M.D., D.Phil., emphasized the significance of these results, stating that they represent the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor in patients without previous heart attacks or strokes who were already receiving high-intensity lipid-lowering regimens. The study included 12,257 adults with an average age of 66 years from 33 countries, conducted at 745 healthcare sites between June 2019 and November 2021.
The importance of these findings lies in addressing atherosclerotic cardiovascular disease, which remains the leading cause of morbidity and mortality globally. ASCVD encompasses conditions including coronary heart disease, cerebrovascular disease, peripheral artery disease, and aortic atherosclerotic disease. For patients at elevated cardiovascular risk but without prior major events, these results suggest that more aggressive cholesterol management could prevent first cardiovascular events.
Lipid measurements from the study showed dramatic improvements, with evolocumab lowering LDL cholesterol by nearly 55% from a median baseline of 115 mg/dL to 45 mg/dL at 48 weeks, while placebo group levels remained elevated at 109 mg/dL. Bohula noted that the magnitude of cardiovascular benefit per unit of LDL-C reduction aligns with observations from statin trials, as described by the Cholesterol Treatment Trialists' Collaboration available at https://www.ctsu.ox.ac.uk/research/meta-trials/cholesterol-treatment-trialists-ctt-collaboration.
The study population consisted of patients with LDL-C levels of at least 90 mg/dL who had atherosclerosis or high-risk diabetes with additional cardiovascular risk factors. Approximately two-thirds met criteria for atherosclerosis without prior heart attack or stroke, while 50% had diabetes. Most participants (72%) were already on high-intensity lipid-lowering regimens at study enrollment.
These findings have substantial implications for clinical practice, suggesting that intensive LDL-C lowering to targets around 40 mg/dL may help prevent first major cardiovascular events. However, accessibility remains a concern, as PCSK9 inhibitors may not be covered by some health insurance plans, potentially creating barriers for patients who could benefit from this treatment approach. The American Heart Association provides additional cardiovascular prevention resources at https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol.
While the study demonstrated consistent results across key subgroups, including patients with high-risk diabetes without qualifying ASCVD, researchers acknowledge limitations including the need for future studies with more diverse racial and ethnic populations. The findings support long-term LDL-C lowering with PCSK9 inhibitors to improve cardiovascular morbidity and potentially mortality over time, marking an important advancement in primary cardiovascular prevention strategies for high-risk populations worldwide.
