PCSK9 Inhibitor Shows Significant Reduction in First Major Cardiovascular Events in High-Risk Patients

Adding the PCSK9 inhibitor evolocumab to high-intensity cholesterol-lowering regimens significantly reduces the risk of first major cardiovascular events in adults with atherosclerotic cardiovascular disease or diabetes, according to findings from the international VESALIUS-CV clinical trial presented at the American Heart Association's Scientific Sessions 2025. The results, simultaneously published in The New England Journal of Medicine, represent a breakthrough in preventive cardiovascular care for patients at elevated risk but without prior cardiac events.

The trial found that participants taking evolocumab experienced a 25% reduction in the risk of coronary heart disease death, heart attack, or ischemic stroke over a median follow-up period of more than four and a half years. Additionally, there was a 19% reduction in the risk of coronary heart disease death, heart attack, ischemic stroke, or arterial revascularization. The study also showed a 27% reduction in cardiovascular death, heart attack, or ischemic stroke and a 36% reduction in heart attack specifically among evolocumab recipients compared to placebo.

Lead study author Erin A. Bohula, M.D., D.Phil., emphasized the significance of these findings, stating that this represents the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor in patients without previous heart attack or stroke who are already receiving high-intensity lipid-lowering treatment. 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 lipid sub-study revealed dramatic cholesterol reductions, with median LDL-C levels dropping from 115 mg/dL at enrollment to 45 mg/dL at 48 weeks in the evolocumab group, representing a nearly 55% reduction. In contrast, placebo group participants maintained elevated LDL-C levels at a median of 109 mg/dL. Bohula noted that the magnitude of cardiovascular benefit per unit of LDL-C reduction aligns with findings from statin trials 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 atherosclerotic cardiovascular disease or diabetes and at least one additional cardiovascular risk factor, but excluded those with prior heart attacks or strokes. About two-thirds met criteria for atherosclerosis without prior major cardiac events, while 50% had diabetes. At study initiation, 72% of participants were already on high-intensity lipid-lowering regimens, with average LDL-C levels of 122 mg/dL.

Bohula explained that the longer follow-up period in VESALIUS-CV compared to prior PCSK9 inhibitor trials may have captured the full clinical benefit, as there's typically a delay in measurable cardiovascular benefits from LDL-C reduction. The findings support intensive LDL-C lowering to achieve targets around 40 mg/dL for preventing first major cardiovascular events. Additional American Heart Association resources on cholesterol management can be found at https://www.heart.org/en/health-topics/cholesterol.

While evolocumab is FDA-approved for treating high LDL-C levels, the researchers noted that insurance coverage barriers may limit access for some patients. The study authors also highlighted the need for future research including more diverse racial and ethnic populations, as 93% of participants self-identified as white. The consistent results across key subgroups, including patients with high-risk diabetes without qualifying ASCVD, strengthen the evidence for broader application of this preventive approach.