VESALIUS-CV: Evolocumab Cuts First MACE Risk in Diabetes Without Atherosclerosis

Published on: March 28, 2026

Conference | American College of Cardiology

A subgroup analysis of VESALIUS-CV suggests evolocumab could have a role in prevention of primary events in some high-risk patients.

An analysis of the VESALIUS-CV trial is extending the evidence base for intensive LDL-C lowering beyond established secondary prevention populations.

A prespecified subgroup analysis of the VESALIUS-CV trial, results suggest the PCSK9 inhibitor evolocumab significantly reduced the risk of a first major cardiovascular event in high-risk primary prevention patients with diabetes and no known significant atherosclerosis.1

“I think this study changes the paradigm,” said Nicholas Marston, MD, MPH, a cardiologist and assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, who presented the data at the American College of Cardiology's Annual Scientific Session (ACC.26).2

VESALIUS-CV Subgroup Design and Population

VESALIUS-CV was a randomized, double-blind, placebo-controlled trial of evolocumab conducted across 774 sites in 33 countries, enrolling 12,257 patients without prior myocardial infarction or stroke who had qualifying atherosclerosis or high-risk diabetes and an LDL-C level of 90 mg/dL or greater.1

This prespecified subgroup analysis examined the 3655 patients without known significant atherosclerosis, defined as the absence of prior arterial revascularization, arterial stenosis of 50% or greater, or a coronary artery calcium score of 100 Agatston units or greater. All patients in this subgroup had diabetes and the median follow-up was 4.8 years.1

Patients were randomized 1:1 to subcutaneous evolocumab 140 mg every 2 weeks or matching placebo added to optimally tolerated statin therapy. The median age was 65 years, 57% were female, 89% were receiving lipid-lowering therapy at baseline, and 64% were on high-intensity statin therapy. Median baseline LDL-C was 132 mg/dL.

The dual primary endpoints were 3-point MACE, which was defined as coronary heart disease death, myocardial infarction, or ischemic stroke, and 4-point MACE, which also included ischemia-driven arterial revascularization.1

31% Reduction in MACE Across Both Primary Endpoints

At the 5-year Kaplan-Meier estimate, evolocumab reduced the 3-point MACE rate from 7.1% to 5.0% (hazard ratio [HR], 0.69; 95% CI, 0.52-0.91; P = .009), representing a between-group difference of 2.1%. The 4-point MACE rate was reduced from 10.5% to 7.6% (HR, 0.69; 95% CI, 0.55-0.86; P = .001), a between-group difference of 2.9%.1

Evolocumab also reduced the risk of cardiovascular death (HR, 0.68; 95% CI, 0.46-0.99) and all-cause mortality (HR, 0.76; 95% CI, 0.61-0.95), though the investigators noted that due to the prespecified hierarchical testing order, mortality reductions should be considered exploratory. Among the lipid substudy participants, median LDL-C at 48 weeks was 52 mg/dL in the evolocumab group versus 111 mg/dL in the placebo group.1

An additional analysis demonstrated the treatment benefit became more apparent after year 1, with 41% and 39% reductions in 3-point and 4-point MACE risk in subsequent years, consistent with an expected lag in clinical benefit in patients without pre-existing plaque.1

The investigators noted current US guidelines assign only a class 2b recommendation for adding a nonstatin agent in high-risk primary prevention patients with diabetes whose LDL-C remains above 70 mg/dL, resulting in infrequent intensification of therapy in this population.1,3

“In current practice, PCSK9 inhibitors are largely reserved for patients who have had a prior heart attack or stroke,” Marston added. “But here we see a benefit of using evolocumab not only to treat patients without a history of heart attack or stroke, but without known significant atherosclerosis. It’s a message to physicians and patients that we don’t have to wait until someone has atherosclerosis to treat them intensively. We can—and should—be much more proactive.”

Investigators called attention to several limitations warranting consideration. These included the analysis being a prespecified subgroup, imaging to detect atherosclerosis was not performed in all patients, and the population was predominantly White and entirely composed of high-risk diabetic patients.

References

Marston NA, Bohula EA, Bhatia AK, et al. Evolocumab to Reduce First Major Cardiovascular Events in Patients Without Known Significant Atherosclerosis and With Diabetes: Results From the VESALIUS-CV Trial. JAMA. Published online March 28, 2026. doi:10.1001/jama.2026.3277
American College of Cardiology. Evolocumab Cuts Cardiac Risk in Patients Without Known Atherosclerosis and With Diabetes - American College of Cardiology. American College of Cardiology. Published March 28, 2026. Accessed March 28, 2026. https://www.acc.org/About-ACC/Press-Releases/2026/03/28/15/33/Evolocumab-Cuts-Cardiac-Risk-in-Patients-Without-Known-Atherosclerosis-and-With-Diabetes
Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol. 2022;80(14):1366-1418. doi:10.1016/j.jacc.2022.07.006

VESALIUS-CV: Evolocumab Cuts First MACE Risk in Diabetes Without Atherosclerosis

Key Facts

VESALIUS-CV Subgroup Design and Population

31% Reduction in MACE Across Both Primary Endpoints