Objective

To investigate whether evolocumab could prevent a first major cardiovascular event (MACE) in patients without known significant atherosclerosis with diabetes.

Study design

VESALIUS-CV (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke) was a randomized, double-blind, placebo-controlled trial of evolocumab in 12,257 with no prior myocardial infarction or stroke, low-density lipoprotein cholesterol (LDL-C) ≥90 mg/dL, and qualifying atherosclerosis or high-risk diabetes. Central block randomization was used to randomly assign patients in a 1:1 ratio to treatment with subcutaneous injections of evolocumab 140 mg every 2 weeks or matching placebo. Randomization was stratified by LDL-C levels (<160 or ≥160 mg/dL) and geographic region.

Study population

This prespecified subgroup analysis included 3,655 patients (1,849 in the evolocumab group and 1,806 in the placebo group) with diabetes and without known significant atherosclerosis. No known significant atherosclerosis was defined as none of the following: prior arterial revascularization, arterial stenosis ≥50%, and coronary artery calcium score ≥100 Agatston units. Lipid inclusion criteria were LDL-C ≥90 mg/dL (≥2.3 mmol/L), non–high-density lipoprotein cholesterol ≥120 mg/dL (≥3.1 mmol/L), or apolipoprotein B ≥80 mg/dL (≥1.56μmol/L), with at least 2 weeks of stable, optimized, lipid-lowering therapy.

Main study variables

There were 2 primary endpoints: 1) 3-point MACE (composite of coronary heart disease [CHD] death, myocardial infarction [MI], or ischemic stroke; and 2) 4-point MACE: 3-point MACE plus ischemia-driven arterial revascularization. Secondary efficacy end points included 4 composites: 1) MI, ischemic stroke, or ischemia-driven arterial revascularization; 2) CHD death, MI, or ischemia-driven arterial revascularization; 3) cardiovascular death, MI, or ischemic stroke; and 4) CHD death or MI, as well as the individual end points of MI, ischemia-driven arterial revascularization, CHD death, cardiovascular death, all-cause mortality, and ischemic stroke.

Methods

Primary and secondary analyses were intention-to-treat. For the lipid substudy, all randomized patients who received at least 1 dose of study drug and had at least one post-baseline lipid measurement were evaluated.

Time-to-event analyses were performed using the log-rank test, stratifying for baseline LDL-C and geographic region. Hazard ratios (HRs) with 95% confidence intervals (CI) were estimated from a Cox model.

Key results

Baseline characteristics of the two treatment groups were well balanced; median age was 65 years (interquartile range [IQR] 60-70), 57% were female, and 88% had hypertension. Median baseline LDL-C was 132 mg/dL (IQR, 108-156), with 89% of patients treated with lipid-lowering therapy, predominantly a statin (84%, including 64% on high-intensity statin therapy).

In total, 548 patients were included in the lipid substudy, with a median baseline LDL-C level of 121 mg/dL (IQR, 100-147). After 48 weeks, treatment with evolocumab resulted in a least-squares mean 51% reduction in LDL-C (95% CI, 57%-45%) and a median achieved LDL-C of 52 mg/dL (IQR,31-75) compared with 111 mg/dL(IQR, 90-149) in the placebo group. After 96 weeks, the median achieved LDL-C was 44 mg/dL (IQR,29-68) in the evolocumab group versus 105 mg/dL (IQR,79-137) in the placebo group.

Treatment with evolocumab was associated with 31% reduction in the risk of 3-point and 4-point MACE endpoints (Table 1). The effect of evolocumab was more evident after the first year of treatment, with 41% (HR 0.59 [95% CI 0.43-0.81]) and 39% (HR 0.61 [95%CI 0.48-0.79]) reductions in the risk of 3-point and 4-point MACE, respectively, in the following years. The effects of evolocumab among patients with versus without known significant atherosclerosis were similar for both primary endpoints.

Table 1. Effect of evolocumab treatment on key endpoints

Author conclusions

Treatment with evolocumab was also associated with reduction in cardiovascular and all-cause death (Table 1), although given the prespecified hierarchical testing order, these findings should be considered exploratory.

In high-risk patients without known significant atherosclerosis and with diabetes, evolocumab reduced the risk of a first major cardiovascular event.