Results from the international VESALIUS-CV (TIMI 66) clinical trial presented at the American Heart Association’s Scientific Sessions 2025 demonstrate that the PCSK9 inhibitor evolocumab significantly reduces the risk of first major cardiovascular events in adults with atherosclerotic cardiovascular disease (ASCVD) or diabetes who have not experienced a prior heart attack or stroke. The study, simultaneously published in The New England Journal of Medicine, found that adding evolocumab to a high-intensity lipid-lowering regimen lowered the risk of coronary heart disease death, heart attack, or ischemic stroke by 25% over a median follow-up of 4.6 years.
“The results from the VESALIUS-CV trial represent the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor, or any non-statin for that matter, in patients without a previous heart attack or stroke who are already being treated with a high-intensity lipid-lowering regimen,” said lead study author Erin A. Bohula, M.D., D.Phil., an assistant professor of medicine at Harvard Medical School and an investigator with the TIMI Study Group. ASCVD, caused by plaque buildup in arterial walls, remains the leading cause of morbidity and mortality globally, encompassing conditions such as coronary heart disease, cerebrovascular disease, and peripheral artery disease.
The trial enrolled 12,257 adults (average age 66; 43% women) across 745 sites in 33 countries. Participants had LDL-C levels of at least 90 mg/dL or met other lipid criteria, along with qualifying atherosclerosis or high-risk diabetes and at least one additional cardiovascular risk factor. Patients with prior heart attack or stroke were excluded. At baseline, 72% were on high-intensity lipid-lowering therapy, and median LDL-C was 115 mg/dL. Participants were randomized to subcutaneous evolocumab 140 mg or placebo every two weeks.
Results showed a 25% reduction in the dual primary endpoint of coronary heart disease death, heart attack, or ischemic stroke with evolocumab versus placebo. A secondary endpoint combining these events with ischemia-driven arterial revascularization was reduced by 19%. Additionally, evolocumab led to a 27% reduction in cardiovascular death, heart attack, or ischemic stroke and a 36% reduction in heart attack alone. Nominally lower rates of cardiovascular death (2.8% vs. 3.6%) and all-cause death (7.9% vs. 9.7%) were observed. At 48 weeks, LDL-C decreased by nearly 55% in the evolocumab group to a median of 45 mg/dL, while levels remained elevated in the placebo group at 109 mg/dL.
“Interestingly, the magnitude of cardiovascular benefit per unit of LDL-C reduction is similar to what has been observed in statin trials,” Bohula noted, attributing the clear benefit to the longer follow-up compared to prior PCSK9 inhibitor trials. The findings were consistent across subgroups, including one-third of participants with high-risk diabetes without qualifying ASCVD. Study limitations include a small proportion (8%) not on any lipid-lowering therapy at baseline and the predominantly white study population, suggesting future research should include more diverse groups.
“Together with data from genetic studies of PCSK9 variants and other PCSK9 inhibitor outcomes studies, our findings suggest that long-term lowering with PCSK9 inhibitors can help to improve cardiovascular morbidity and potentially mortality over time,” Bohula said. The results support intensive LDL-C lowering to achieve targets around 40 mg/dL to prevent first major cardiovascular events. Evolocumab is FDA-approved for high LDL-C, though insurance coverage may be a barrier for some patients.
This research was presented as a late-breaking science at the American Heart Association’s Scientific Sessions 2025, held Nov. 7-10 in New Orleans. The Association receives more than 85% of its revenue from non-corporate sources, with strict policies to prevent influence on its science content. More information is available at newsroom.heart.org.
