NEW ORLEANS — Patients with diabetes who have not been diagnosed with atherosclerotic cardiovascular disease would benefit by taking the PCSK9 inhibitor evolocumab to lower their LDL cholesterol to levels significantly below what existing clinical guidelines call for, a subgroup analysis of the VESALIUS-CV clinical trial has found.

Patients in the original study taking evolocumab, sold as Repatha by Amgen, achieved an average LDL-C of 44 mg/dL at 96 weeks vs 105 mg/dL for the placebo group and maintained that level out to at least 5 years. That reduction in cholesterol was associated with a 31% reduction in major adverse cardiovascular events (MACE), the researchers reported. 

“This subgroup analysis in particular is practice-changing because we currently are using evolocumab in patients with high-risk atherosclerosis, so this group with unknown atherosclerosis is really a novel group,” Nicholas Marston, MD, MPH, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School in Boston told Medscape Medical News. 

Marston presented results from the VESALIUS-CV subgroup analysis here at the 2026 annual meeting of the American College of Cardiology. The results have been published simultaneously in JAMA. 

The subgroup analysis included 3655 patients representing 30% of the total population of VESALIUS-CV, the results of which were presented last fall at the 2025 annual meeting of the American Heart Association. The patients had high-risk diabetes, defined as disease duration for at least 10 years, taking daily insulin, or having microvascular disease. Participants also had no known significant atherosclerosis, including no known coronary artery calcium score of 100 Agatston units or greater. Women represented 57% of the group and 93% were White. The average LDL-C on enrollment was 132 mg/dL.

Lipid-Lowering, MACE Outcomes

Patients taking evolocumab achieved an average LDL-C of 44 mg/dL at 96 weeks vs 105 mg/dL for the placebo group, Marston said. The treatment group maintained that level out to 5 years.

Patients taking evolocumab experienced a 31% relative risk reduction at 5 years in three-point MACE — defined as coronary heart death, myocardial infarction, or ischemic stroke — with rates of 5% for the drug and 7.1% for placebo (P = .009). 

For a four-point MACE outcome, which included ischemia-driven revascularization, the 5-year rates were 7.6% and 10.5% for the respective groups, Marston said, matching the 31% relative risk reduction for three-point MACE with evolocumab.

Mortality rates also varied significantly, Marston said. Rates of cardiovascular death were 2.6% and 4% in the evolocumab and placebo groups, while those for all-cause mortality were 7.8% and 10.1%, respectively. 

“The benefits seen in this subgroup support intensification of lipid-lowering therapy beyond statins earlier in the atherosclerotic cardiovascular disease process,” Marston told attendees. 

The analysis included a Cholesterol Treatment Trialists’ Collaboration meta-regression that determined lowering cholesterol in the study population led to reduced cardiovascular events, Marston said. 

“This underscores the value of lower LDL cholesterol down to around 40 mg/dL in these patients,” he said. "Thus, these data strongly support that in these lower-risk patients, we should be targeting LDL cholesterol goals typically reserved for very high-risk secondary prevention patients.”

“I do think it’s practice-changing,” John Bucheit, PharmD, of the Virginia Commonwealth University School of Pharmacy in Richmond, told Medscape Medical News of the new analysis. 

The evidence would have been strong enough for inclusion in the latest updated clinical practice guidelines on dyslipidemia management from the American Heart Association and the American College of Cardiology, Bucheit said, but the study’s timing 2 weeks after the guidelines appeared did not work out. 

"Now we have additional analysis that’s really impactful,” he said. 

“We all see these high-risk patients with diabetes in the clinic, but it has been an evidence-based gap,” Bucheit added. “The trial and the subgroup analysis really helps us get there.

"This trial to me reinforces that lower is better. As we go forward, we have to look at our high-risk primary prevention patients and really think about reexamining targets.”

The next key step would involve obtaining insurance coverage for PCSK9 inhibitors for these patients, Bucheit added.

The study was funded by Amgen. Marston reported financial relationships with Amgen, Arboretum, Radence, Ionis, and Marea. Bucheit reported no relevant financial relationships. 

Richard Mark Kirkner is a medical journalist based in Philadelphia.