Carmine De Luca (1), Luigi Junior Valletta (1), Martina Ferrandino (2), Maria Donata Di Taranto (2), Giuliana Fortunato (2), Gabriella Iannuzzo (1), Matteo Di Minno (1), Ilenia Lorenza Calcaterra (1)

(1) Dipartimento di Medicina Clinica e Chirurgia.
(2) Dipartimento di Medicina Molecolare e Biotecnologie Mediche.

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Background: Bempedoic acid, an ATP citrate lyase inhibitor, is indicated for patients with hypercholesterolemia who are statin-intolerant or inadequately controlled by standard therapy. Although randomized trials demonstrated efficacy, evidence from real-world, genetically characterized cohorts remains limited.

Methods: We retrospectively analyzed a cohort of patients followed at our lipid clinic that underwent to genetic test and lipid profile assessment at baseline and follow-up. Paired Student’s t tests evaluated intra-group changes; ANOVA compared genetic subgroups.

Results: The cohort included 70 patients (mean age 59.5 ± 12.7 years, 57% women), of whom 42 received bempedoic acid. 64% had hypertension, 13% type 2 diabetes (with an additional 6% with suggestive findings), 29% were current smokers, and 59% had hepatic steatosis. Family history of cardiovascular disease was reported in 84% of patients. Overall, the population can be classified as high to very-high risk according to ESC/EAS criteria. Genetic testing identified polygenic hypercholesterolemia in 44%, LDLR variants in 14%, APOB variants in 1%, negative testing in 14%; 21% had no available genetic data. Chronic kidney disease was present in 5.7% of patients, while 11.4% were in secondary prevention. Evidence of vascular organ damage was documented in nearly half of the cohort, with 34% showing overt atherosclerosis, 19% subclinical carotid IMT, and 7% polyvascular involvement. At baseline, mean LDL-C was 131.8 mg/dl and total cholesterol 209.1 mg/dl. At follow-up, LDL-C decreased to 74.8 mg/dl (Δ=−54.3 mg/dl, p <0.001) and total cholesterol to 150.5 mg/dl (Δ −55.0 mg/dl, p <0.001). Reductions were significant in both monogenic (LDLR) and polygenic subgroups, with mean LDL-C percentage changes of −45.8% and −42.9%, respectively. ANOVA showed no significant differences in LDL-C reduction across subgroups (p = 0.797), suggesting consistent treatment effect irrespective of genetic status.

Conclusions: In this real-world Italian cohort, bempedoic acid achieved robust LDL-C and total cholesterol reductions across genetic subgroups. Beyond lipid lowering, these improvements may contribute to mitigating organ damage associated with dyslipidemia, including atherosclerosis, diabetes-related vascular injury, and chronic kidney disease. Our findings align with the 2025 ESC/EAS consensus, which emphasizes aggressive lipid lowering and early treatment intensification, and support bempedoic acid as a valuable tool in both primary and secondary cardiovascular prevention.