Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects. Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects

Abstract: BACKGROUND: Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 monoclonal antibody inhibitors (PCSK9mAb) not only reduce low density lipoprotein cholesterol (LDL-C) but can also modulate inflammation. OBJECTIVES: This trial was designed to define the impact of evolocumab on circulating immune cell properties in high-risk ASCVD subjects. METHODS: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level of >70 mg/dL on maximum tolerated statin therapy to receive either subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were the change in lipoproteins, blood viscosity, and circulating immune cell transcriptional response at 2 weeks and 12 weeks with evolocumab compared with matching placebo. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS: All 41 randomized subjects completed the 2-week visit. Six subjects (4 evolocumab, 2 placebo) did not receive study medication consistently after the 2-week visit due to suspension of research activities during the COVID-19 pandemic. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p70 mg/dL on maximum tolerated statin therapy to receive either subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were the change in lipoproteins, blood viscosity, and circulating immune cell transcriptional response at 2 weeks and 12 weeks with evolocumab compared with matching placebo. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population.