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Adding the PCSK9 inhibitor evolocumab to a high-intensity, cholesterol-lowering regimen reduced the risk of a first major cardiovascular event among adults with atherosclerotic cardiovascular disease (ASCVD) or diabetes , according to a preliminary late-breaking science presentation today at the American Heart Association’s Scientific Sessions 2025. The meeting, Nov. 7-10, in New Orleans, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science.

“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, Brigham & Women’s Hospital and an investigator with the TIMI Study Group.

According to the American Heart Association, atherosclerotic cardiovascular disease, otherwise known as ASCVD, is caused by plaque buildup in arterial walls and refers to conditions that include:

• Coronary Heart Disease (CHD), such as myocardial infarction, angina and coronary artery stenosis.
• Cerebrovascular disease, such as a transient ischemic attack, ischemic stroke and carotid artery stenosis.
• Peripheral artery disease such as claudication.
• Aortic atherosclerotic disease, such as abdominal aortic aneurysm and descending thoracic aneurysm.

Currently, ASCVD-related conditions remain the leading cause of morbidity and mortality globally.

The VESALIUS-CV trial examined if adding evolocumab, a non-statin PCSK9 inhibitor medication to lower low-density lipoprotein cholesterol (LDL-C), to existing cholesterol treatment reduced the risk of a first major cardiovascular event in people with ASCVD or diabetes who had no history of a major CV event, such as heart attack or stroke.

After an average of 4.6 years of follow-up, the study found:

• Patients in the evolocumab group had a significantly reduced risk of the dual primary endpoints: by 25% for coronary heart disease deaths, heart attack or ischemic stroke and by 19% for coronary heart disease death, heart attack, ischemic stroke or ischemia-driven arterial revascularization, compared to patients in the placebo group.
• There was also a 27% reduction in cardiovascular death, heart attack or ischemic stroke and a 36% reduction in heart attack among participants in the evolocumab group, compared to placebo.
• Nominally lower rates of death from cardiovascular causes (2.8% versus 3.6%, respectively) and death from all causes (7.9% versus 9.7%, respectively) were noted in the evolocumab group compared to the placebo group.
• Findings for the dual primary endpoints were consistent across key subgroups, including in participants with high-risk diabetes without qualifying ASCVD, which represented one-third of the total study population.
• In a sub-study that evaluated participants’ lipids measures over time, the median LDL-C at enrollment was 115 mg/dL. At 48 weeks, LDL-C was lowered by nearly 55% in the evolocumab group, resulting in a median LDL-C level of 45 mg/dL.
• In contrast, LDL-C levels remained elevated among those in the placebo group, at a median of 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, as described by the Cholesterol Treatment Trialists’ Collaboration,” said Bohula.

We suspect this is related to the longer follow up in our study, as compared to prior, shorter PCSK9 inhibitor trials, that may have underestimated the long-term clinical benefit. It has been well-described that there is a delay in the onset for cardiovascular benefits from lowering LDL-C levels, and it takes time for these benefits to be measurable.”

Erin A. Bohula, Assistant Professor, Medicine, Brigham & Women’s Hospital 

Study details, background and design:

• The study included 12,257 adults who were an average age of 66 years old.
• Of the participants, 43% were women, and the majority (93%) of participants self-identified as white, and about 17% self-reported their race as Hispanic or Latino.
• The study was conducted at 745 health care sites in 33 countries including the U.S. between June 2019 and November 2021.
• Participants were eligible for the study if they had an LDL-C of at least 90 mg/dL (or met non-high-density lipoprotein cholesterol or apolipoprotein B criteria), met study inclusion criteria for atherosclerosis (coronary artery, peripheral artery or cerebrovascular disease) or high-risk diabetes, and had at least one other cardiovascular risk factor. Patients with a prior heart attack or stroke were excluded.
• At the start of the study, about two-thirds of the participants met the study inclusion criteria for atherosclerosis (without a prior heart attack or stroke), and 50% met inclusion criteria for diabetes; the average level LDL-C level was 122 mg/dL; the average level of apolipoprotein-B (Apo-B) was 101 mg/dL; and 72% of participants were on a high-intensity lipid-lowering regimen.
• Participants were randomized to one of the two treatment groups: 140 mg of evolocumab injected under the skin every two weeks, or a placebo also injected every 2 weeks, for the duration of the trial, an average of 4.6 years.

The study had several limitations to note. There was a small group of patients (8%) who were not being treated with any cholesterol-lowering treatment at the beginning of the study. The authors noted that the majority of patients (72%) were on a high-intensity regimen when they enrolled in the trial. In addition, the researchers suggest future studies including adults from various racial and ethnic backgrounds are needed to confirm if these findings apply across diverse populations.

“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. The findings also support the use of intensive LDL-C lowering to achieve targets of around 40 mg/dL to help prevent a first major cardiovascular event ,” said Bohula.

Evolocumab is a newer type of cholesterol-lowering medication called a PCSK9 inhibitor that binds to and inactivates a protein in the liver to lower LDL cholesterol. Evolocumab is FDA-approved to treat high LDL-C levels; however, PCSK9 inhibitors may not be covered by some health insurance plans, which may be a barrier for some people. Other research studies have confirmed that evolocumab reduces the risk of major adverse cardiovascular events in people who have ASCVD, peripheral artery disease (PAD) with symptoms or have had a prior heart attack or stroke.