We Can Do Better: Analysis of the Worldwide Experience of the Homozygous Familial Hypercholesterolemia

Quick Takes

  • The Homozygous Familial Hypercholesterolemia (HoFH) International Clinical Collaborators registry represents the largest database worldwide evaluating the characteristics, diagnosis, and treatment patterns for patients with HoFH.
  • Many HoFH patients are often diagnosed too late when clinically significant atherosclerotic disease is already present and are undertreated, despite substantial advances in lipid lowering therapies.
  • There are considerable disparities in care between patients from high-income versus non-high-income countries. Thus, there is an urgent need to update global policies that provide early pediatric cholesterol screening and improve access to treatment for patients with HoFH.

Brief Overview
Homozygous Familial Hypercholesterolemia (HoFH) is an inherited genetic disorder that results in extremely high low-density lipoprotein cholesterol (LDL-C) levels and elevated risk for premature atherosclerotic disease. Since the severity and duration of exposure to elevated LDL-C levels determine prognosis, early diagnosis and initiation of lipid lowering therapies (LLT) are critical for reducing long-term cardiovascular risk.

To date, current practice guidelines and outcomes are derived from small studies of primarily European ancestry populations from high-income countries. Global differences in detection, management, and outcomes of HoFH remain unclear, prompting the establishment of the HoFH International Clinical Collaborators registry to assess demographic and genetic profiles, treatment strategies, and health outcomes of a diverse population.1

The objective of this study is to evaluate the characteristics, diagnosis, treatment, and impact of current practice guidelines on health outcomes of patients with HoFH on a global scale and by country income status.

Study Design/Methods
This retrospective cohort study used data from 88 institutions around the world and included patients who had a clinical or genetic diagnosis of HoFH. Patients with HoFH were eligible for inclusion if they were alive and received follow-up in, or after, 2010. The study enrolled 751 individuals (52% female) from 38 different countries, of which 20 were classified as high-income countries and 18 as non-high-income countries. There were 17 countries from Asia, 14 from Europe, 4 from North/South America, 2 from Africa, and 1 from Australia. Of the 527 patients with race reported, 64% were White, 23% were Asian, and 13% were Black or mixed race.

The primary outcome was major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG).

The median age at diagnosis was 12 years (Interquartile range [IQR] 5.5-27.0). Patients were diagnosed at a later age in high-income countries compared to non-high-income countries, 16 years (IQR 6.0-33.0) versus 10 years (IQR 5.5-20.0), respectively. Untreated LDL-C levels were higher in non-high-income countries (15.8 mmol/L, IQR 12.9-19.2) compared to high-income countries (13.5 mmol/L, IQR 10.4-17.2).

In terms of LLT, most patients were treated with a statin (93%) including 83% on high intensity therapy. Ezetimibe was prescribed in 72% of patients from high-income countries versus 54% of patients from non-high-income regions. The overall use of other LLT including PCSK9 inhibitors (22.1%), lomitapide (8.4%), and evinacumab (4.4%) was low and concentrated in high-income countries. Patients who underwent lipoprotein apheresis had a higher untreated LDL-C level at diagnosis (17.2 mmol/L, IQR 13.9-21.4) and began treatment at 15 years of age (IQR 10.0-28.0).

Despite the high utilization of LLT, only 12% of patients achieved guideline directed LDL-C targets for primary and secondary prevention per the 2016 European Society of Cardiology/European Atherosclerosis Society dyslipidemia management guidelines. The LDL-C goal was more readily achieved with higher number of LLT (30% on monotherapy compared to >65% on three or more therapies). Patients from high-income countries were much more likely to achieve LDL-C targets compared to non-high-income countries (21% vs. 3%).

The median age at which MACE occurred was 31 years (IQR 22.0-42.0) and 9% of patients experienced a non-fatal myocardial infarction, aortic stenosis, or underwent PCI/CABG at time of HoFH diagnosis. Overall, there were 37 deaths, including 76% from cardiovascular causes. MACE-free survival was lower in patients from non-high-income countries (24.5 years, IQR 17-34.5) compared to high-income countries (35.0 years, IQR 25.0-49.0). Patients with higher untreated LDL-C levels had a greater risk of MACE compared to the lowest LDL-C tercile reference group (HR 3.60, 95% CI: 2.22-5.84, p<0.05).

Clinical Implications
The results from this worldwide registry highlight that patients with HoFH are diagnosed too late and remain substantially undertreated. Almost one in ten patients have clinically significant cardiovascular disease at the time of diagnosis and only 12% achieve guideline recommended LDL-C levels. Additionally, there are significant disparities between high- and non-high-income countries regarding time to diagnosis, treatment regimens, optimal LDL-C control, and MACE-free survival.

There are several limitations to this study that can help to direct future research opportunities. Many of the patients from this cohort were from urban academic centers concentrated in a small number of select countries with a substantial proportion (37%) of patients from Italy, Turkey, and South Africa, which may introduce selection bias. By contrast, only 12 patients were enrolled from the United States. Additionally, African and Latin American countries were underrepresented, possibly reflecting the social and economic disparities that may impact access to diagnosis and treatment. It is also important to understand how other risk factors, such as lipoprotein (a) levels, enhance cardiovascular risk in this population, as they may impact selection of LLT.2

Better methods to assess for subclinical atherosclerosis in this high-risk population to optimize therapy are needed. For pediatric patients, computed tomography coronary artery assessment is technically difficult due to higher resting heart rates and small coronary artery anatomy, while invasive coronary angiography is not practical in this age group.3 While this study demonstrates that additional LLT can lower LDL-C levels and reduce risk of MACE, there are substantial challenges with respect to cost and access for these therapies.

Treatments such as apheresis or biologically targeted therapies such as evinacumab are mostly inaccessible in non-high-income countries. Even if these therapies become readily available, there are practical challenges of medication stacking and compliance, especially in the pediatric population. Patient age, cultural and socioeconomic status, schedule and route of medication administration, potential side effects with polypharmacy, and the family's understanding of the disease process can contribute to medication nonadherence.4 Additionally, clinicians may have therapeutic inertia to add on multiple therapies because of the limited long term cardiovascular outcome data of LLT in the pediatric population.

Based on the findings of this study, it is clear that we all need to take collective responsibility to advocate for policy changes that promote early pediatric screening of cholesterol level (LDL-C), improve access to treatment and detection of subclinical atherosclerosis, and engage key stakeholders to improve cardiovascular outcomes in HoFH patients.5


  1. Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet 2022;399:719-28.
  2. Loh WJ, Chan DC, Mata P,Watts GF. Familial hypercholesterolemia and elevated lipoprotein (a): cascade testing and other implications for contextual models of care. Front Genet 2022;13:905941.
  3. Abbara S, Blanke P, Maroules CD, et al. SCCT guidelines for the performance and acquisition of coronary computed tomographic angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee Endorsed by North American Society for Cardiovascular Imaging (NASCI). J Cardiovasc Comput Tomogr 2016;10:435-49.
  4. Ivanovska V, Rademaker CM, van Dijk L, Mantel-Teeuwisse AK. Pediatric drug formulations: a review of challenges and progress. Pediatrics 2014;134:361-72.
  5. Wilemon KA, Patel J, Aguilar-Salinas C, et al. Reducing the clinical and public health burden of familial hypercholesterolemia: a call to global action. JAMA Cardiol 2020;5:217-29.

Clinical Topics: Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and VHD, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Nuclear Imaging, Diabetes and Cardiometabolic Disease

Keywords: Cholesterol, LDL, Cardiovascular Diseases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, PCSK9 protein, human, PCSK9, Hypercholesterolemia, Proprotein Convertase 9, Secondary Prevention, Follow-Up Studies, Retrospective Studies, Coronary Vessels, Coronary Angiography, Genetic Profile, Heart Rate, Percutaneous Coronary Intervention, Polypharmacy, Risk Factors, Blood Component Removal, Registries, Coronary Artery Bypass, Medication Adherence, Myocardial Infarction, Health Services Accessibility, Heart Disease Risk Factors, Atherosclerosis, Aortic Valve Stenosis, Early Diagnosis, Outcome Assessment, Health Care, Lipoprotein(a), Ezetimibe

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