HICC registry: levelling up access to treatment urgently needed

Commentary to publication: Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. The Lancet; https://doi.org/10.1016/S0140-6736(21)02001-8. 

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.

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.


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For further information on the HoFH International Clinical Collaboration – HICC. https://www.eas-society.org/page/hicc (6 December 2021).