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Evolocumab to Reduce First Major Cardiovascular Events in Patients Without Known Significant Atherosclerosis and With
Nicholas A Marston1, Erin A Bohula1, Ajay K Bhatia2
1TIMI Study Group, Heart and Vascular Institute, Brigham and Women's Hospital, Boston, Massachusetts.
Insights
Evolocumab significantly reduced major cardiovascular events in high-risk diabetic patients without diagnosed atherosclerosis. This PCSK9 inhibitor offers a new preventive strategy for this patient group.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Intensive low-density lipoprotein cholesterol (LDL-C) lowering with PCSK9 inhibitors is typically for patients with established atherosclerosis.
- The role of PCSK9 inhibitors in primary prevention for high-risk individuals without significant atherosclerosis is less understood.
Purpose of the Study:
- To evaluate the efficacy of evolocumab in preventing a first major cardiovascular event (MACE) in patients with diabetes but without known significant atherosclerosis.
Main Methods:
- VESALIUS-CV was a randomized, double-blind, placebo-controlled trial involving 3655 patients with diabetes, LDL-C ≥90 mg/dL, and no prior myocardial infarction/stroke or significant atherosclerosis.
- Patients received subcutaneous evolocumab (140 mg every 2 weeks) or placebo, in addition to statin therapy, with a median follow-up of 4.8 years.
Main Results:
- Evolocumab significantly reduced the composite of coronary heart disease death, myocardial infarction, or ischemic stroke (3-P MACE) by 31% (HR, 0.69; P=.009).
- The composite of 3-P MACE plus arterial revascularization (4-P MACE) was reduced by 31% (HR, 0.69; P=.001).
- All-cause mortality was also reduced in the evolocumab group (HR, 0.76; P=.045).
Conclusions:
- In high-risk patients with diabetes and without known significant atherosclerosis, evolocumab effectively reduces the risk of first major cardiovascular events.
- This study supports the use of PCSK9 inhibitors like evolocumab for primary cardiovascular event prevention in select high-risk diabetic populations.
Importance:
Intensive lowering of low-density lipoprotein cholesterol (LDL-C) levels with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors for cardiovascular event reduction has largely been reserved for patients with significant atherosclerosis.
Objective:
To investigate whether evolocumab could prevent a first major cardiovascular event (MACE) in patients without known significant atherosclerosis.
Design, Setting, And Participants:
VESALIUS-CV was a randomized, double-blind, placebo-controlled trial of evolocumab conducted across 774 sites in 33 countries and enrolling 12 257 patients with no prior myocardial infarction or stroke, LDL-C level 90 mg/dL or greater, and qualifying atherosclerosis or high-risk diabetes. This prespecified subgroup analysis examined outcomes in patients without known significant atherosclerosis (none of the following: prior arterial revascularization, arterial stenosis ≥50%, or coronary artery calcium score ≥100 Agatston units), all of whom had diabetes. Enrollment started in June 2019 and the last patient visit was July 2025, with a median follow-up of 4.8 years.
Intervention:
Patients were randomized in a 1:1 ratio to subcutaneous administration of either evolocumab (140 mg every 2 weeks) or matching placebo added to optimally tolerated statin therapy.
Main Outcomes And Measures:
The dual primary end points were composites of coronary heart disease death, myocardial infarction, or ischemic stroke (3-P MACE) and 3-P MACE plus ischemia-driven arterial revascularization (4-P MACE). Secondary end points included all-cause mortality.
Results:
This predefined subgroup included 3655 patients (1849 in the evolocumab group and 1806 in the placebo group) with a median age of 65 years (57% female). Among those in the lipid substudy, the median LDL-C level at 48 weeks was 52 mg/dL in the evolocumab group vs 111 mg/dL in the placebo group (P < .001). A 3-P MACE event occurred in 83 patients (5-year Kaplan-Meier estimate, 5.0%) in the evolocumab group compared with 117 patients (5-year Kaplan-Meier estimate, 7.1%) in the placebo group (hazard ratio [HR], 0.69 [95% CI, 0.52-0.91]; P = .009; between-group difference, 2.1% [95% CI, 0.4%-3.8%]). A 4-P MACE event occurred in 127 patients (5-year Kaplan-Meier estimate, 7.6%) in the evolocumab group compared with 178 patients (5-year Kaplan-Meier estimate, 10.5%) in the placebo group (HR, 0.69 [95% CI, 0.55-0.86]; P = .001; between-group difference, 2.9% [95% CI, 0.9%-4.9%]). There were 136 deaths (5-year Kaplan-Meier estimate, 7.8%) in the evolocumab group compared with 172 deaths (5-year Kaplan-Meier estimate, 10.1%) in the placebo group (HR, 0.76 [95% CI, 0.61-0.95]).
Conclusions And Relevance:
In high-risk patients without known significant atherosclerosis and with diabetes, evolocumab reduced the risk of a first major cardiovascular event.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03872401.
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