Clinical management of homozygous familial hypercholesterolemia: Perspectives from an expert panel

Abstract

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare but severe genetic disorder characterized by extremely elevated LDL-C levels from birth, leading to accelerated atherosclerosis and premature cardiovascular disease. Despite advances in lipid-lowering therapies, the evidence guiding clinical practice remains heterogeneous, highlighting the need for an expert consensus to synthesize available data and provide practical recommendations. Objective: This narrative review aims to unify current medical evidence to guide the management of homozygous familial hypercholesterolemia (HoFH). Through a multidisciplinary expert consensus, the panel seeks to synthesize the available scientific information on HoFH. The main objective is to provide the medical community with practical, clear recommendations to optimize patient care, emphasizing three fundamental areas: improving the accuracy of early diagnosis, structuring comprehensive clinical management, and evaluating the effectiveness of emerging therapies. Ultimately, the panel's goal is to support actions to reduce the risk of premature cardiovascular disease, as well as to standardize the care of HoFH. Methodology: This narrative review was developed through a multidisciplinary consensus process. Experts in internal medicine, cardiology, endocrinology, paediatrics, and medical genetics defined key topics, drafted sections according to their expertise, and iteratively refined the content through collaborative discussions. Evidence was selected pragmatically, based on clinical relevance and applicability, to inform diagnosis, management, and emerging therapies for HoFH. Results: The review addresses major domains in the care of HoFH, including clinical and genetic diagnosis, differential diagnosis, cascade screening, cardiovascular risk assessment, and therapeutic approaches. Both non-pharmacological and pharmacological interventions are discussed, from statins and ezetimibe to lomitapide, evinacumab, and novel emerging therapies. Special populations such as paediatric patients and pregnant women are also considered. Additionally, the review highlights the social and public health impact of HoFH, emphasizing the importance of early detection and equitable access to advanced therapies. Conclusions: HoFH is more prevalent than previously recognised and requires early diagnosis and comprehensive management. This consensus synthesizes expert experience and current evidence to provide practical guidance for clinicians. By integrating pharmacological, non-pharmacological, and genetic strategies, it aims to improve outcomes and reduce the cardiovascular burden of HoFH.