Abstract Background PCSK9 inhibitors are recommended as lipid-lowering therapy for patients who do not achieve target LDL cholesterol (LDL-C) levels despite combination therapy with a statin and ezetimibe, as well as for those with statin intolerance. However, in some cases, the addition of a PCSK9 inhibitor (PCSK9i) does not produce the expected therapeutic effect. Objective The aim of this study was to compare the lipid-lowering effects of different PCSK9i and assess the frequency of treatment resistance, defined as an LDL-C reduction of 30% from baseline levels. Materials and Methods A total of 107 patients were analyzed, with 24 receiving alirocumab, 29 evolocumab, and 52 inclisiran. LDL cholesterol levels were compared before initiating PCSK9i therapy (after optimal statin/ezetimibe treatment) and after 3-6 months of PCSK9i administration. Results The mean LDL-C level decreased from 3.97 mmol/L to 1.92 mmol/L (p0.001). The most effective LDL-C reduction was observed with alirocumab (63 ± 27%), followed by evolocumab (57.1 ± 25.5%), The weakest effect was seen with inclisiran (43.2 ± 28.2%; p=0.007). Treatment resistance to PCSK9i occurred in 21 patients (20%), including: 14 patients (26.9%) treated with inclisiran, and 7 patients (13.2%) treated with monoclonal antibodies (alirocumab/evolocumab)(p=0.079). Switching therapy from inclisiran to a monoclonal antibody resulted in a ≥30% LDL reduction in 3 out of 4 cases, whereas switching from a monoclonal antibody to inclisiran was effective in only 1 out of 3 cases (p=0.27). Non-responders did not significantly differ from other patients regarding: - Baseline lipid parameters (Table), - Prevalence of familial hypercholesterolemia (FH) (71.4% vs 69%; p=0.832), - Diabetes occurrence (9.5% vs 22.6%; p=0.18), - Intensive statin therapy (76.2% vs 69%; p=0.521, - Statin intolerance (28.6% vs 25%; p=0.88). Conclusions 1. PCSK9 inhibitors effectively lower LDL-C levels, but their efficacy varies between different agents. 2. Alirocumab and evolocumab demonstrate greater efficacy in LDL-C reduction compared to inclisiran. 3. Treatment resistance to PCSK9i affects approximately 20% of patients, most commonly those receiving inclisiran. 4. In patients resistant to inclisiran, switching to a monoclonal antibody (alirocumab/evolocumab) may result in better LDL-C reduction, whereas switching from a monoclonal antibody to inclisiran appears less effective. 5. Metabolic factors, genetic predisposition, and baseline lipid parameters do not significantly influence the likelihood of resistance to PCSK9i therapy.LDL-C reduction depending on PCSK9i Baseline characteristics
Streb et al. (Sat,) studied this question.