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. To investigate whether evolocumab could prevent a first major cardiovascular event (MACE) in patients without known significant atherosclerosis. 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. 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. 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. 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]). In high-risk patients without known significant atherosclerosis and with diabetes, evolocumab reduced the risk of a first major cardiovascular event. ClinicalTrials.gov Identifier: NCT03872401.