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

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]Hu P. Dharmayat K.I. Stevens C.A.T. 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: 1742-1759Google Scholar,[2]Beheshti S.O. Madsen C.M. Varbo A. Nordestgaard B.G. Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects.J. Am. Coll. Cardiol. 2020; 75: 2553-2566Google Scholar]. These individuals exhibit extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and often experience their first cardiovascular event during childhood or adolescence [[3]Cuchel M. Bruckert E. Ginsberg H.N. 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: 2146-2157Google Scholar]. 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]Cuchel M. Bruckert E. Ginsberg H.N. 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: 2146-2157Google Scholar,[4]Hegele R.A. Borén J. Ginsberg H.N. et al.Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement.Lancet Diabetes Endocrinol. 2020; 8: 50-67Google Scholar]. Newer therapies including PCSK9 inhibitors, lomitapide and the ANGPTL3 (angiopoietin like 3) inhibitor evinacumab provide potential for improved LDL-C management [5Raal F.J. Honarpour N. Blom D.J. 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: 341-350Google Scholar, 6Raal F.J. Hovingh G.K. 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: 280-290Google Scholar, 7Blom D.J. 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: 131-142Google Scholar, 8Blom D.J. Averna M.R. Meagher E.A. et al.Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia.Circulation. 2017; 136: 332-335Google Scholar, 9Raal F.J. Rosenson R.S. Reeskamp L.F. et al.Evinacumab for homozygous familial hypercholesterolemia.N. Engl. J. Med. 2020; 383: 711-720Google Scholar], but at a cost. As highlighted by the first report from the Homozygous Familial Hypercholesterolaemia International Clinical Collaboration (HICC) registry [[10]Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet; https://doi.org/10.1016/S0140-6736(21)02001-8. Published Online January 28, 2022.Google Scholar] 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]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: 1713-1725Google Scholar]. 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. 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]Cuchel M. Bruckert E. Ginsberg H.N. 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: 2146-2157Google Scholar]. 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.Table 1Take 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. Open table in a new tab Third, current real-world management of homozygous FH lags guideline recommendations, especially regarding the use of combination lipid lowering therapy [[3]Cuchel M. Bruckert E. Ginsberg H.N. 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: 2146-2157Google Scholar,[4]Hegele R.A. Borén J. Ginsberg H.N. et al.Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement.Lancet Diabetes Endocrinol. 2020; 8: 50-67Google Scholar,[12]Mach F. Baigent C. Catapano A.L. et al.ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2019; 41 (2020) (For further information on the HoFH International Clinical Collaboration – HICC) (6 December 2021): 111-188https://www.eas-society.org/page/hiccGoogle Scholar]. 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. The author declared she does not have anything to disclose regarding conflict of interest with respect to this manuscript.