Beyond lipid lowering: Effects of PCSK9 inhibition on inflammation and HDL function

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition effectively lowers low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, but its pleiotropic effects remain insufficiently defined. This study examined whether PCSK9 inhibition influences vascular and systemic inflammation and high-density lipoprotein (HDL) antioxidant function.

To investigate the effects of PCSK9 inhibition on vascular inflammation, systemic inflammatory markers, and HDL antioxidant function in a real-world patient cohort.

In this monocentric, prospective study, blood samples from 89 patients were collected before and 3 to 6 months after initiation of PCSK9 inhibitor therapy. Lipoprotein-associated phospholipase A2 (LpPLA₂) was measured as a marker of vascular inflammation. HDL antioxidant function was assessed by HDL lipid peroxide content (HDL_ox). Systemic inflammation was evaluated via high-sensitivity C-reactive protein (hsCRP) and a predefined cytokine panel.

Seventy-three patients (82.0%) received alirocumab or evolocumab, and 16 (18.0%) received inclisiran. LDL-C decreased by 46.7% (120-64.5 mg/dL, P < .0001). LpPLA₂ declined significantly (443.5-265.5 IU/L, P < .0001) and correlated with LDL-C reduction (R² = 0.58, P < .0001). HDL_ox did not change (1.190-1.210, P = .3438). Interferon gamma-induced protein (IP) 10 (P = .0141) and interleukin (IL)-2 (P = .0371) decreased, whereas hsCRP and other cytokines-including IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17A, tumor necrosis factor-α, monocyte chemotactic protein-1, interferon-γ, and free radicals-remained unchanged (all P > .05).

PCSK9 inhibition reduces LpPLA₂ and IP-10 without changing global inflammatory response or antioxidant function of HDL, which might indicate a decrease in chronic vascular inflammation without an undesired broad systemic immune alteration.