PCSK9 Inhibitor Very Effective in High-risk Patients Without ASCVD: VESALIUS-CV

NEW ORLEANS—Adding the PCSK9 inhibitor evolocumab (Repatha; Amgen) to statin therapy significantly cuts the risk of major cardiovascular events when compared with statins alone in high-risk patients without evidence of atherosclerosis, a prespecified subgroup analysis of the VESALIUS-CV trial shows.

These new data, which were presented today at the American College of Cardiology 2026 Scientific Session and published simultaneously in JAMA, suggest that some high-risk patients without cardiovascular disease should be treated to LDL-cholesterol targets typically reserved for secondary prevention, say investigators.

“We are currently using evolocumab for patients with high-risk atherosclerosis, so this subgroup with no known atherosclerosis is really a novel group,” Nicholas Marston, MD (Brigham and Women’s Hospital, Boston, MA), who led the analysis, said during a media briefing. “I think targeting LDL down below 55 [mg/dL]—down to 40 [mg/dL] in high-risk diabetes without known atherosclerosis—is certainly something we should be seeing in the next round of the guidelines.”

The latest dyslipidemia guidelines were released just last week, however. In the 2026 iteration, it’s recommended that patients who have diabetes but not clinical atherosclerotic cardiovascular disease (ASCVD) should be treated with a moderate-intensity statin to achieve an LDL cholesterol target of less than 100 mg/dL. For the patient with diabetes and multiple ASCVD risk factors, the target is less than 70 mg/dL. In the guidelines, a target of less than 55 mg/dL is reserved for the very-high-risk patient with ASCVD.

Ann Marie Navar, MD, PhD (UT Southwestern Medical Center, Dallas, TX), one of the discussants following the presentation, said that prevention is shifting in the US such that there’s a growing awareness that lower is better, even in primary prevention.

“I think our challenge now is to figure out how to translate that into clinical practice,” she said.

Marston, a preventive cardiologist, said he is likely more aggressive than others with respect to LDL lowering, but these high-risk patients with diabetes are typically not seen in cardiology clinics. They are treated by endocrinologists or in diabetes clinics.

“PCSK9 inhibitors have been approved now for 11 years, and we just haven’t seen the uptake throughout medical practice,” he told TCTMD. “I hope that with this analysis we can really message the importance of PCSK9 inhibitor use out to community primary care and other specialties.”  

There is a bit of an “evidence gap” around high-risk patients with diabetes in the current clinical guidelines, said John D. Bucheit, PharmD (Virginia Commonwealth University, Richmond), a member of the ACC’s Prevention Council.

“We all see these patients in clinic,” he said. “We have high-risk patients with diabetes, and this subgroup analysis really helps us. This trial, to me, reinforces that lower is better and that we are going to continue as we go forward to look at our high-risk primary prevention patients and really think about reexamining LDL targets.”

VESALIUS-CV

VESALIUS-CV included 12,257 patients at high cardiovascular risk—defined as having diabetes plus a cardiovascular risk enhancer or atherosclerosis with or without diabetes and elevated LDL cholesterol (≥ 90 mg/dL)—who were randomized to placebo or evolocumab 140 mg every 2 weeks on top of statin therapy. As TCTMD reported last fall, the main results showed that evolocumab significantly reduced the absolute and relative risks of death from coronary heart disease, MI, or stroke.

The findings from VESALIUS-CV were not incorporated into the dyslipidemia guidelines as they’d already been submitted for review and publication before the trial was published. However, in an editorial accompanying that document, the writing committee acknowledged that the trial provided evidence for more-intensive lipid-lowering targets in patients with diabetes and high-risk features.

This VESALIUS-CV subgroup analysis focused on 3,355 patients (mean age 65 years; 57% female) with diabetes but without atherosclerosis who were randomized to statin therapy plus evolocumab or to statin therapy alone. At baseline, the median LDL cholesterol in this subgroup was 121 mg/dL. After 48 weeks, treatment with evolocumab reduced LDL levels by 51%, down to a median achieved level of 52 mg/dL. This resulted in a 59-mg/dL difference in LDL cholesterol between the placebo- and evolocumab-treated patients. At 96 weeks, the median achieved LDL level in the evolocumab group was 44 mg/dL.

The co-primary endpoint of three-point MACE (coronary heart disease death, MI, or ischemic stroke) was reduced by an absolute of 2.1% at 5 years with evolocumab (5.0% vs 7.1%; HR 0.69; 95% CI 0.52-0.91). The other coprimary endpoint of four-point MACE, which included ischemia-driven revascularization, was reduced by an absolute of 2.9% at 5 years with evolocumab (7.6% vs 10.5%; HR 0.69; 95% CI 0.55-0.86). Both all-cause and cardiovascular mortality were significantly lower in the evolocumab-treated patients: by 1.4% and 2.3%, respectively.  

“The benefit seen in this subgroup really supports intensification of lipid-lowering therapy beyond statins earlier in the atherosclerotic cardiovascular disease process,” said Marston. “The consistency of the magnitude of clinical benefit here is similar to what was expected from the [Cholesterol Treatment Trialists Collaboration] meta-regression [analysis], and it really supports the value of lowering LDL cholesterol down to 40 mg/dL in these patients.”

Trying to Get to Goal

Discussing the trial, Navar pointed out that while the subgroup focused on patients without significant atherosclerosis, most patients with long-standing diabetes, some diagnosed more than 10 years ago, are going to have some degree of coronary calcification. Additionally, most patients had hypertension and high LDL cholesterol levels at baseline.

In the guidelines, there are no direct recommendations for PCSK9 inhibitors as a second-line approach for patients without ASCVD. To get to the less than 70-mg/dL target in high-risk primary prevention patients, high-intensity statin therapy, and ezetimibe as necessary, is the advised approach (class 2a recommendation). PCSK9 inhibitors are reserved in the guidelines for high-risk patients with ASCVD on maximally tolerated statin therapy and/or ezetimibe.

Karen Aspry, MD (Brown University Health, East Greenwich, RI), who discussed the findings during a media briefing, as well as the Ez-PAVE study results, noted that ezetimibe is a more cost-effective strategy than PCSK9 inhibition. In the Ez-PAVE trial, investigators added ezetimibe to high-intensity statin therapy to bring patients to targets of less than 55 and 70 mg/dL.

“As much as we do like [PCSK9 inhibitors] and use them, we have to always think about cost,” she said.

To TCTMD, Marston noted that it would have been challenging to lower LDL-cholesterol levels to even less than 100 mg/dL in VESALIUS-CV by adding ezetimibe to statin therapy. In this trial, patients had relatively high LDL at baseline compared with the 76-mg/dL level in Ez-PAVE.

“It’s not going to get you to the goal, to the guideline-directed target of less than 70 mg/dL, on average, in that group,” said Marston. “I think, and this is true clinically, a lot times you need a larger benefit or larger reduction with your drug. Sometimes we just need a little bit, and you can use ezetimibe. Sometimes we need [to use] both. Sometimes just skipping to the PCSK9 inhibitor is appropriate.”

Given the significant benefit in this high-risk primary prevention cohort, Bucheit said he is hopeful to see improved coverage of PCSK9 inhibitors by payers.