Impact of Diabetes on Coronary Plaque Stabilization With Evolocumab: Insights From the YELLOW III Trial.

PURPOSE: Diabetes is associated with high-risk coronary plaque features and residual cardiovascular risk. Whether diabetes modifies plaque response to PCSK9 inhibition remains uncertain. We assessed the impact of diabetes on coronary plaque stabilization with evolocumab. METHODS: This post hoc analysis of the YELLOW III trial included 110 patients with chronic coronary disease and lipid-rich, non-obstructive coronary lesions identified by optical coherence tomography (OCT). Patients were on maximally tolerated statin therapy and received evolocumab 140 mg every 2 weeks for 26 weeks. Serial OCT, near-infrared spectroscopy, and intravascular ultrasound were performed at baseline and follow-up. Peripheral blood mononuclear cell RNA sequencing compared transcriptomic profiles by diabetes status. RESULTS: Among 110 patients, 56 had diabetes and 54 did not. At baseline, patients with diabetes had thinner minimum fibrous cap thickness (FCT), higher maximum lipid core burden index within 4 mm (maxLCBI4mm), and greater percent atheroma volume (PAV). LDL cholesterol reduction was similar between groups (-61.8 ± 26.8 vs -53.5 ± 30.9 mg/dL; p=0.137). Plaque response did not differ significantly by diabetes status for minimum FCT (29.3 ± 21.7 vs 24.3 ± 22.7 µm; p=0.231), maxLCBI4mm (-92.9 ± 142.3 vs -94.6 ± 139.9; p=0.948), and PAV (-1.4 ± 1.4 vs -1.3 ± 1.5%; p=0.698). Baseline diabetes-associated neutrophil- and platelet-related pathway enrichment was attenuated at follow-up. CONCLUSION: Despite maximally tolerated statin therapy, patients with diabetes exhibited more adverse plaque features. Evolocumab was associated with similar short-term plaque stabilization regardless of diabetes status, suggesting potential mechanistic insight into PCSK9 inhibition in diabetes.