In the prespecified subgroup analysis of the VESALIUS-CV trial, evolocumab significantly reduced the risk of first major adverse cardiovascular (CV) events (MACE) in individuals without known significant atherosclerosis and with diabetes.
In this high-risk primary prevention subgroup, adding evolocumab to baseline lipid-lowering therapy (LLT) led to a 31-percent relative reduction in the risk of three-point (3-P) and four-point (4-P) MACE, noted Dr Nicholas Marston from the Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, US, at ACC.26.
3-P MACE was a composite of coronary heart disease (CHD) death, MI, or ischaemic stroke (IS), while 4-P MACE comprised 3-P MACE plus ischaemia-driven arterial revascularization (IDR). [Marston, et al, ACC 2026]
At 5 years, the cumulative incidence of 3-P MACE with evolocumab was 5 percent, as opposed to 7.1 percent with placebo. A comparison between arms yielded an absolute risk reduction (ARR) of 2.1 percent with the experimental agent and a hazard ratio (HR) of 0.69 (p=0.009). A similar pattern for 4-P MACE was observed (7.6 percent vs 10.5 percent; ARR, 2.9 percent; HR, 0.69; p=0.001).
These treatment effects were lower than those observed in individuals with significant atherosclerosis (HRs, 0.77 and 0.84 for 3-P and 4-P MACE, respectively). Moreover, the incidence of 4-P MACE after 1 year was lower among those without known atherosclerosis as opposed to those who had (HR, 0.61 vs 0.86).
Treatment with evolocumab also led to reductions in the cumulative incidences of CV death (2.6 percent vs 4 percent; HR, 0.68; nominal p=0.046) and all-cause mortality (7.8 percent vs 10.1 percent; HR, 0.76; nominal p=0.017) compared with placebo.
The benefit of evolocumab treatment was consistently observed across the four* secondary composite endpoints, with HRs ranging from 0.68 to 0.73.
Study characteristics
“VESALIUS-CV was the first CV outcomes trial to evaluate the effect of a PCSK9 inhibitor on CV events in patients without a history of [MACE], including patients without known significant atherosclerosis,” noted Marston and colleagues in the published manuscript. [JAMA 2026:e263277]
The investigators defined no known significant atherosclerosis as no prior arterial revascularization, arterial stenosis ≥50 percent, or coronary artery calcium score ≥100 Agatston units.
Thirty percent (n=3,655; median age 65 years, 57 percent women, median LDL-C 132 mg/dL) of the VESALIUS-CV cohort met the above-noted criteria. The participants were randomized 1:1 to either evolocumab 140 mg administered subcutaneously Q2W or a matching placebo on top of optimally tolerated statin therapy. The median follow-up was 4.8 years. Among those who were on any LLT (89 percent), 68 percent were on a high-intensity regimen.
Almost all (99.5 percent) participants had high-risk diabetes (≥10 years’ duration, daily insulin use, or evidence of microvascular disease). “[Hence,] validation in other types of high-risk patients without known atherosclerosis will be important,” Marston noted.
Lipid substudy
In the lipid substudy (n=548; median LDL-C 121 mg/dL), there were substantially greater LDL-C reductions with evolocumab than with placebo at week 48 (52 vs 111 mg/dL; p<0.001) and week 96 (44 vs 105 mg/dL).
The LDL-C level achieved with evolocumab at week 96 is consistent with the target typically reserved for very high-risk secondary prevention (40–55 mg/dL). [Eur Heart J 2020;41:111-188; Eur Heart J 2025;46:4359-4378]
“Lowering LDL-C to these levels resulted in large reductions in the risk of CV events, supporting lower LDL-C goals in high-risk primary prevention and making a case for a single LDL-C target for all high-risk individuals, regardless of where they are in the continuum of their atherosclerotic CV disease (CVD) course,” noted Marston and colleagues.
Implications
“[Taken together, the current findings show] that the clinical efficacy of intensive LDL-C lowering extends beyond patients with established significant atherosclerotic CVD and has a benefit in a high-risk primary prevention population without a prior ischaemic event or any known atherosclerosis and with diabetes,” the investigators noted.
At the ACC.26 press briefing, Marston noted that the current results support intensification of LLT beyond statins earlier in the atherosclerotic CVD process. “The consistency of the magnitude of clinical benefit is similar to what was expected from the CTTC** meta-regression and underscores the value of lowering LDL-C down to approximately 40 mg/dL in these patients.”
“Thus, these data strongly support that in these lower-risk patients, we should be targeting LDL-C goals typically reserved for very high-risk secondary prevention patients,” Marston concluded.