VESALIUS-CV: Making the Case for PCSK9 Inhibition Before Atherosclerosis

The VESALIUS-CV trial, published in JAMA and presented at ACC 2026 as a late-breaking abstract, marks a significant expansion in how PCSK9 inhibitors are understood to benefit patients. While prior evidence established their role in secondary prevention, this analysis from the VESALIUS trial zeroes in on a subset of patients who had diabetes and cardiovascular risk factors but no documented atherosclerosis—representing a high-risk primary prevention population increasingly common in clinical practice.

In this subgroup of approximately one-third of the total VESALIUS trial population, evolocumab produced a 31% relative risk reduction in the primary outcome of myocardial infarction, stroke, and cardiovascular death over approximate 5 years of follow-up. The results also showed a 32% lower risk of cardiovascular death and a 24% reduction in all-cause mortality—outcomes rarely seen in primary prevention trials. LDL levels in the treated group fell to a median of 52 mg/dL at 48 weeks and 44 mg/dL at 96 weeks, levels typically associated with high-risk secondary prevention targets.

An important contextual note: imaging to rule out atherosclerosis was not performed in all participants. Given that these patients had diabetes and multiple risk factors, it is plausible that many carried subclinical plaque burden. This reflects real-world primary prevention practice, where imaging is not routinely used to establish treatment eligibility. The magnitude of benefit aligns with the Cholesterol Treatment Trialists' meta-analysis, which predicts a 22% reduction in major cardiovascular events per 39 mg/dL reduction in LDL—reinforcing that the benefit is fundamentally about LDL lowering, regardless of which agent achieves it. These findings make a strong case for targeting LDL below 55 mg/dL even in high-risk patients who have not yet experienced a cardiac event.