HoFH International Clinical Collaboration – HICC

The HoFH International Clinical Collaboration (HICC) registry, launched in 2016, aims to create a formal international network of healthcare providers who manage HoFH patients that transcends the regional nature of current efforts. The registry has allowed collection of de-identified data relating to the clinical, genetic features and treatment of HoFH. This will provide insight into the prevalence, clinical consequences and treatment of HoFH and promote actions to improve current approaches to diagnosis and therapy.

Homozygous Familial Hypercholesterolaemia International Clinical Collaboration (HICC) registry: levelling up access to treatment urgently needed

Commentary, January 2022

Familial hypercholesterolaemia (FH) is an inherited condition characterised by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, which if undiagnosed and untreated, confer an increased risk of premature atherosclerotic cardiovascular disease. The most severe presentation is homozygous FH, estimated to affect about one in 300,000 people(1,2). These individuals exhibit extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and often experience their first cardiovascular event during childhood or adolescence(3). LDL-C goal is rarely if ever achieved.

Given their very high risk, treatment with combination lipid lowering therapy and lipoprotein apheresis is foundational(3,4). Newer therapies including PCSK9 inhibitors, lomitapide and the ANGPTL3 (angiopoietin like 3) inhibitor evinacumab provide potential for improved LDL-C management (5-9), but at a cost. As highlighted by the first report from the Homozygous Familial Hypercholesterolaemia International Clinical Collaboration (HICC) registry(10) this cost usually prevents access to these newer, highly effective treatments in less affluent countries.

The HICC registry is a unique global study of patients with homozygous FH, which is partially funded under the umbrella of the European Atherosclerosis Society FH Studies Collaboration (EAS FHSC), a global FH registry(11). Both initiatives aim to generate large-scale, robust data on the burden of FH worldwide. This first report from the HICC covers data for 751 individuals from 38 countries, both high-income (n=20) and non-high-income countries (n=18). Overall, delayed diagnosis is the norm, usually in the second decade (overall median 12 years). Because of this, almost one in 10 people already had experienced a coronary event or had aortic valve stenosis by the time they were diagnosed. Baseline characteristics highlight differences between the two groups of countries. Despite being younger at diagnosis (10 versus 16 years), patients in less affluent countries had significantly higher untreated LDL-C levels than those in high-income countries (15.8 versus 13.5 mmol/L), and usually a more severe phenotype.

In the video below, Professor Frederick J. Raal, Steering Committee member HICC Registry and Executive Committee member of the FHSC (University of the Witwatersrand, Johannesburg, South Africa) discusses the findings from the HICC registry

Access to guideline-recommended lipid lowering therapy was a major factor limiting LDL-C control, especially among less affluent regions, from detailed information for 534 patients. While overall almost all patients (92%) received a statin, patients in non-high-income countries were less likely to receive additional treatment such as ezetimibe (54% versus 72% in high-income countries), rarely a PCSK9 inhibitor (17% versus 26%), and almost never lomitapide (2% versus 14%). While access to lipoprotein apheresis was comparable across high- and non-high-income countries (38-40%), initiation was delayed in less affluent regions (median age 17.5 versus 13 years). Even with multiple lipid lowering therapies, including lipoprotein apheresis, only 12% of patients in the overall study population, almost none (3%) in non-high-income countries, attained LDL-C goal.

This clear treatment disparity between high-income and non-high-income countries had a major impact on the cardiovascular health of patients. Cardiovascular events occurred about a decade earlier among patients in less affluent countries (median age at onset 24.5 versus 37 years in high-income countries). Moreover, the risk of incident cardiovascular events was about 2-fold higher among patients in non-high-income countries.

There are some caveats to the HICC data. Mainly, these relate to the composition of patients in the registry. Most were white, with underrepresentation from Asia, Africa and Latin America. South Africa was the main recruiter in Africa, with diverse characteristics compared with many African countries, and also accounted for a significant proportion of the total number of patients.

There are important take home messages from this unique global registry (Table 1). Early diagnosis and initiation of combination lipid lowering therapy are essential to improve LDL-C management and patient outcome(3). It is evident that diagnosis in the second decade of life, the norm for patients in this registry, is too late; already one in ten had experienced their first coronary event at this time. The ideal should be to screen and identify patients at or before birth. Second, it is clear that we lack information about homozygous FH in many regions, notably Africa, underlining the need for renewed action for education and awareness of FH.

Third, current real-world management of homozygous FH lags guideline recommendations, especially regarding the use of combination lipid lowering therapy(3,4,12). Treatment inequity across the world is a major factor. Even though access to newer lipid lowering therapies was limited in high-income countries, with only about one in four receiving a PCSK9 inhibitor, access was even more restrictive in less affluent regions. This inequity in FH care highlights the need for urgent action to improve healthcare policy and funding, especially among less affluent countries which have the largest burden of disease.

Until now, information about the care of homozygous FH patients has been fragmented, mainly confined to single countries. These findings from the HICC registry, the only global study of homozygous FH, provide unique perspectives into the care of this rare, serious condition in different world regions. In particular, these data highlight how access to treatment and patient outcome aligns with the economy of individual countries. For a very select group of patients treated with five lipid-lowering therapies in high income countries, we can ‘control’ LDL-C levels for the first time. Going forward, the challenge will be to address this treatment inequity and improve cardiovascular health among all individuals with this life-limiting condition.

Table 1. Take home messages from the HICC data
• The HICC registry is a unique global cohort study of homozygous FH.

• This report includes data from 751 patients from 38 countries, including 18 non-high-income countries.

• Overall, patients were diagnosed too late, at a median age of 12 years, when about one in 10 already had experienced coronary events.

• Although patients in non-high-income countries were diagnosed earlier, their LDL-C levels were higher and clinical phenotype more severe than in high-income countries.

• Treatment inequity is a major issue that influences cardiovascular health. Patients in non-high-income countries are less likely to receive combination lipid lowering therapy. There is almost no access to newer LDL-lowering therapies.

• First cardiovascular events occur about a decade earlier among patients in non-high-income countries.

• Leveraging these data from the HICC registry will be crucial to levelling up global health policy and treatment access among patients with homozygous FH.


  1. Hu P, Dharmayat KI, Stevens CAT, et al. Prevalence of Familial Hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Circulation 2020;141:1742–59.
  2. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects. J Am Coll Cardiol 2020;75:2553–66.
  3. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146–57.
  4. Hegele RA, Borén J, Ginsberg HN, et al. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol 2020;8:50–67.
  5. Raal FJ, Honarpour N, Blom DJ, et al; TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341-50.
  6. Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol 2017;5:280–90.
  7. Blom DJ, Harada-Shiba M, Rubba P, et al. Efficacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol 2020;76:131-42.
  8. Blom DJ, Averna MR, Meagher EA, et al. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation 2017;136:332–5.
  9. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020;383:711–20.
  10. Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. The Lancet; https://doi.org/10.1016/S0140-6736(21)02001-8. Published Online January 28, 2022. Link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02001-8/fulltext
  11. EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet 2021;398:1713-25.
  12. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–88.

HICC reports at EAS 2021 Congress

May 2021

The unveiling of posters at EAS Helsinki 2021 provided important news from the EAS-led Homozygous familial hypercholesterolaemia International Clinical Collaboration (HICC) registry, the largest global database of homozygous familial hypercholesterolaemia (HoFH) patients (1). HoFH is the most severe form of FH, thought to affect about one in 300,000 to one in a million people, and is characterised by extremely high levels of low-density lipoprotein cholesterol (LDL-C) from birth and severe atherosclerotic cardiovascular disease (2). Many patients may have their first heart attack in childhood (2).

The HICC was launched in 2016 aiming to provide data about the prevalence, clinical consequences and treatment of HoFH, as well as promote actions to improve care. Patients are included in the registry based on clinical or genetic criteria for HoFH.

This latest report provides data on 765 patients from 38 countries world-wide, the majority (75%) diagnosed by genetic criteria. Categorising the data by high-income countries (n=410) versus non-high-income countries (n=355) revealed disparities in FH care.

According to Professor Derick Raal, co-coordinator of the HICC Registry (University of the Witwatersrand, Johannesburg, South Africa): ‘These new findings from the HICC Registry underline the need for action to ensure equity in care for this rare, severe condition, crucial to improve prognosis and freedom from early heart attack, often during childhood.’

While patients from non-high-income countries were diagnosed earlier than those in high-income countries (median 10 versus 16 years), access to novel treatments which are now part of the armamentarium of managing HoFH was much more limited. Among non-high-income countries, significantly fewer patients received PCSK9 inhibitors (17% versus 25% in high-income countries, p<0.001) and lomitapide (2% versus 13%, p<0.001), and no patients (versus 4.3%) received evinacumab. Consequently on-treatment LDL-C levels were much higher for patients in lower-income countries, about double those in high-income regions (mean 9.6 versus 4.7 mmol/L, p<0.001). Overall, while only a minority of patients attained guideline-recommended LDL-C goal, almost none were in non-high-income countries (2.6% versus 21.4% in high-income countries, p<0.001). 

Importantly, limited access to novel therapies and higher on-treatment LDL-C levels significantly impacted outcome. The cardiovascular burden of HoFH was greater among non-high-income countries, with earlier onset of major coronary events (median 24 versus 35 years) and younger age of cardiovascular death (median 24 versus 40 years). Thus, inequity in treatment almost halved the age of death due to cardiovascular causes among patients in non-high-income regions.

In conclusion, patients in high-income countries had access to novel lipid-lowering therapies more frequently, attained lower LDL-C levels and had longer event-free survival. These new findings from the HICC reinforce the value of this global registry for highlighting inequities in resource allocation for FH care, in particular the limited availability of contemporary and novel therapies. Going forward, this information will be critical in discussions with all stakeholders in FH care.


  1. Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide perspective on homozygous familial hypercholesterolemia diagnosis, treatment and outcome – Results from the HICC Registry. Poster session. Presented at EAS Helsinki 2021 Virtual – 30th May -2 June 2021.
  2. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57. 

Late breaking news on Homozygous Familial Hypercholesterolaemia from the EAS 2018 Congress in Lisbon, Portugal

EAS- led Homozygous Familial Hypercholesterolaemia International Clinical Collaborators (HICC) registry: Dr Merel Hartgers (Academic Medical Center, Amsterdam, The Netherlands) discusses why this is important.

Consider joining the EAS-led HoFH International Clinical Collaboration (HICC) registry

Professor Derick Raal (University of the Witwatersrand, Johannesburg, South Africa) and Dr. Kees Hovingh (Academic Medical Center, Amsterdam, the Netherlands) discuss this critically important international HoFH registry, part of the EAS FH Studies Collaboration during the EAS 2017 Congress.

The key aims of this registry are to understand the prevalence, clinical consequences and treatment of HoFH with the ultimate aim of improving the diagnosis and care of this severe group.

For more information, contact coordinator@eas-hicc.org