PCSK9 Inhibitors Reduce Oxidative Stress Biomarkers in Heterozygous Familial Hypercholesterolemia

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab and evolocumab, effectively reduce LDL-C levels, improve cardiovascular outcomes, and are well tolerated in the treatment of heterozygous familial hypercholesterolemia (HeFH). Oxidative stress, increased in HeFH, leads to DNA damage, LDL oxidation (ox-LDL), and reduced total plasma antioxidant capacity, which promotes the development of atherosclerosis. The aim of the study was to assess whether treatment with PCSK9 inhibitors reduces ox-LDL, anti-ox-LDL antibodies, oxidative stress, and DNA damage, including 8-OH-Gua levels. The study included 40 patients with HeFH diagnosed clinically or genetically, and 33 healthy volunteers at low cardiovascular risk as controls. Blood samples were collected from all participants for lipid profile, Lp(a), oxidative stress markers (ox-LDL, 8-OHdG, anti-oxLDL antibodies), total antioxidant capacity of plasma (TAC), and DNA damage status (using the comet assay with repair enzymes). The study showed that treatment with PCSK9 inhibitors (alirocumab or evolocumab) in HeFH patients significantly improved lipid profiles and reduced levels of oxidative stress markers such as 8-OHdG and ox-LDL, while increasing levels of anti-ox-LDL and TAC. This therapy also significantly reduced purine and pyrimidine DNA damage, although not to the level observed in the control group. The efficacy of reducing DNA damage was greater with alirocumab, which could be related to higher baseline levels of Lp(a) and oxidative damage in these patients. Treatment with PCSK9 inhibitors in HeFH patients reduces oxidative stress and DNA damage, indicating additional non-lipid benefits that support their use in preventing atherosclerotic complications.