A new subgroup analysis from the Phase 3 VESALIUS-CV clinical trial (NCT03872401) indicates that Amgen’s Repatha (evolocumab), when added to optimized statin therapy, significantly reduces the risk of a first major adverse cardiovascular event (MACE) in high-risk patients.
The findings, presented at the American College of Cardiology’s 75th Annual Scientific Session and published in the Journal of the American Medical Association (JAMA), focus specifically on patients with diabetes who have no known significant atherosclerosis.
Repatha is a top-selling drug for Amgen. The monoclonal antibody raked in $3 billion in sales last year, up 36% from 2024. In August 2025, the US Food and Drug Administration broadened the approved use of Repatha to include adults at increased risk for major adverse CV events due to uncontrolled LDL-C.
Repatha reduced the risk of the composite primary endpoint—comprising coronary heart disease death, myocardial infarction, or ischemic stroke (3-P MACE)—by 31% compared to placebo. The median follow-up period for the analysis was 4.8 years.
JAMA Publication Details Key Absolute Risk Differences
The JAMA publication provides specific details on the magnitude of the benefit in this primary prevention subgroup of 3,655 patients. The 5-year Kaplan-Meier estimate for the 3-P MACE outcome was 5.0% in the evolocumab group compared to 7.1% in the placebo group (Hazard Ratio [HR], 0.69; 95% CI, 0.52-0.91). This represents an absolute risk reduction of 2.1% over the study period.
The analysis also examined a broader composite endpoint that included ischemia-driven arterial revascularization (4-P MACE). For this outcome, the 5-year Kaplan-Meier estimate was 7.6% in the treatment arm versus 10.5% in the placebo arm (HR, 0.69; 95% CI, 0.55-0.86), an absolute reduction of 2.9%.
LDL-C Reduction Achieved Below Typical Statin Targets
A key component of the analysis centered on the low-density lipoprotein cholesterol (LDL-C) levels achieved with the PCSK9 inhibitor. In a lipid substudy of this patient cohort, the median achieved LDL-C level at 48 weeks was 52 mg/dL in the Repatha group compared to 111 mg/dL in the placebo group. The overall trial data showed a median achieved LDL-C of 44 mg/dL at 96 weeks in the Repatha arm versus 105 mg/dL in the control group.
Amgen noted that this level of reduction, below 45 mg/dL, is not typically achieved with statins or ezetimibe alone and demonstrates the potential value of earlier, more intensive lipid-lowering intervention.
Mortality Trends and Secondary Endpoints
While the study was not specifically powered for mortality endpoints in this subgroup, the analysis demonstrated numerical trends toward reduced death rates. The JAMA publication notes there were 136 deaths (5-year Kaplan-Meier estimate, 7.8%) in the evolocumab group compared to 172 deaths (5-year estimate, 10.1%) in the placebo group (HR, 0.76; 95% CI, 0.61-0.95). Relative risk reductions were observed in cardiovascular death (32%) and all-cause death (24%).
Among individual components of the primary endpoint, the analysis showed numerical reductions in the risk of heart attack by 31%, ischemia-driven revascularization by 34%, and ischemic stroke by 33%.
The data reinforce the rationale for treating high-risk primary prevention patients before atherosclerotic cardiovascular disease (ASCVD) becomes clinically evident or advanced. The JAMA publication specified that patients in this subgroup had none of the following qualifying criteria for significant atherosclerosis: prior arterial revascularization, arterial stenosis of 50% or greater, or a coronary artery calcium score of 100 Agatston units or higher.
“This analysis clearly demonstrates that the CV benefit of Repatha in the VESALIUS-CV study includes those who had no known ASCVD,” said Dr Nicholas Marston of the TIMI Study Group and Brigham and Women’s Hospital in the press release. “Lowering LDL-C earlier with more intensive therapy in high-risk primary prevention patients, before plaque becomes advanced, can prevent the clinical onset of heart disease.”
