Researchers evaluated proprotein convertase subtilisin/kexin type 9 inhibition in patients with diabetes without known significant atherosclerosis and found that evolocumab lowered the risk of a first major cardiovascular event.

In a prespecified subgroup analysis of the VESALIUS-CV randomized clinical trial, evolocumab reduced the incidence of initial major cardiovascular events among high-risk patients with diabetes and no known significant atherosclerosis.

The global trial was conducted across 774 sites in 33 countries and enrolled 12,257 patients without prior myocardial infarction or stroke who had qualifying atherosclerosis or high-risk diabetes and elevated lipid levels despite optimized lipid-lowering therapy. This analysis focused on 3,655 patients with diabetes and no known significant atherosclerosis, defined as no prior arterial revascularization, no known arterial stenosis of at least 50%, and no known coronary artery calcium score of at least 100 Agatston units.

Patients were randomly assigned in a 1:1 ratio to receive subcutaneous evolocumab, 140 mg every 2 weeks, or placebo, in addition to optimally tolerated statin therapy. Median follow-up was 4.8 years.

Lipid Lowering and Achieved Levels

In a lipid substudy, low-density lipoprotein cholesterol levels decreased to a median of 52 mg/dL with evolocumab compared with 111 mg/dL with placebo. At 96 weeks, median levels were 44 mg/dL vs 105 mg/dL, respectively.

Primary Outcomes

A three-component major adverse cardiovascular event—defined as coronary heart disease death, myocardial infarction, or ischemic stroke—occurred in 5% of patients receiving evolocumab compared with 7% receiving placebo, an absolute difference of about 2%.

A four-component outcome that included ischemia-driven arterial revascularization occurred in 8% of patients receiving evolocumab vs 11% receiving placebo.

In a landmark analysis following the first year, evolocumab was associated with 41% and 39% reductions in the three- and four-component outcomes, respectively, with treatment effects becoming more apparent over time.

Secondary and Mortality Outcomes

Evolocumab was associated with consistent reductions across secondary composite outcomes, including:

• 34% reduction in myocardial infarction, ischemic stroke, or revascularization

• 31% reduction in coronary heart disease death, myocardial infarction, or revascularization

• 32% reduction in cardiovascular death, myocardial infarction, or ischemic stroke

Cardiovascular death occurred in about 2% of patients receiving evolocumab compared with about 3% receiving placebo. All-cause mortality occurred in about 7% vs 10% of patients. These mortality findings were considered exploratory based on the study’s hierarchical testing design.

Subgroup and Consistency Analyses

Results were consistent among patients younger than and older than 65 years, men and women, and those with low-density lipoprotein cholesterol levels above and below the median of 132 mg/dL.

Treatment effects did not differ statistically between patients with and without known significant atherosclerosis, although benefit appeared to emerge earlier in those with known disease.

Safety

Serious adverse events occurred in 25% of patients receiving evolocumab and 26% receiving placebo, with similar rates between groups.

Limitations

Assessment of atherosclerosis with imaging was not performed in all patients, raising the possibility that some had unrecognized disease. All patients in this subgroup had high-risk diabetes, which may limit generalizability to other populations. In addition, the study population was predominantly White patients.

Although prespecified, this analysis remains a subgroup analysis and requires confirmation in prospective studies.

“Lowering LDL-C to these levels resulted in large reductions in the risk of cardiovascular events, supporting lower LDL-C goals in high-risk primary prevention and making a case for a single LDL-C target for all high-risk individuals, regardless of where they are in the continuum of their atherosclerotic cardiovascular disease course,” wrote lead researcher Nicholas A. Marston, MD, of the TIMI Study Group and Heart and Vascular Institute at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues.

Full disclosures, including study funding by Amgen, are available in the study.

Source: JAMA