Featured commentary on Homozygous familial hypercholesterolaemia

Management of homozygous familial hypercholesterolaemia is challenging. What are the prospects for attaining LDL cholesterol goal with novel therapies? This latest commentary discusses the new findings for evinacumab, an ANGPTL3 monoclonal antibody.

Homozygous familial hypercholesterolaemia: new hope for getting patients to goal?

The European Atherosclerosis Society (EAS) continues to be a key player in familial hypercholesterolaemia (FH), raising awareness and supporting research to promote early diagnosis and treatment.1 While the primary focus of the global call to action on FH has been heterozygous FH, understandable given its prevalence, affecting about one in 200-250 people in Europe,2 the rarer and more severe form, homozygous FH, also has been highlighted. Untreated, the very high levels of low-density lipoprotein cholesterol (LDL-C) that characterise homozygous FH promote accelerated atherosclerosis and premature death, on average before 20 years.3 Even among treated patients the risk of cardiovascular complications is very high; among the first 220 treated patients in the EAS-led homozygous FH International Clinical Collaboration (HICC) registry, the average age of first myocardial infarction was 35 years, but some experienced this as young as 17.4 Delays in diagnosis and treatment are typical of this disorder.

Yet even when patients are identified early, management of the extreme hypercholesterolaemia evident in homozygous FH is challenging. Almost no patients attain LDL-C goal on a combination of maximally tolerated statin and non-statin LDL- lowering therapy, in addition to diet and lipoprotein apheresis.5 New treatments, notably PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibodies and the oral MTP (microsomal triglyceride transfer protein) inhibitor lomitapide provide further LDL-C-lowering but are not without limitations. Treatment with a PCSK9 inhibitor typically lowers LDL-C by about 30% (on top of statin, ezetimibe and lipoprotein apheresis) but is ineffective in patients with two null LDLR mutations.6,7 Lomitapide therapy requires adherence with a very low-fat diet (<20% of energy from fat) which is difficult for patients; in addition, side effects that may include hepatic steatosis are problematic.8

As the extent of cholesterol reduction is a major determinant of risk for cardiovascular complications and survival in homozygous FH,9,10 it is evident that additional approaches are needed to address this gap in management. Evinacumab, a fully human monoclonal antibody inhibitor of angiopoietin-like 3 protein (ANGPTL3), offers promise according to a recent report.11

ANGPTL3 inhibits lipoprotein lipase, the main enzyme involved in hydrolysis of triglyceride-rich lipoproteins. Carriage of loss-of-function variants in the gene encoding ANGPTL3 are associated with reduced serum lipid levels (triglycerides, LDL-C and high-density lipoprotein cholesterol) and about 40% lower risk of coronary artery disease.12 The underlying mechanism for the reduction in LDL-C levels is not clear, although studies in LDLR-deficient mice suggest that this is independent of the LDL receptor.13 In addition, functional analyses of LDLR mutations in lymphocytes of homozygous FH patients showed that evinacumab had no effect on LDLR activity.14

In a small proof-of-concept study in nine homozygous FH patients, evinacumab reduced LDL-C levels by 49% (mean absolute reduction from baseline ~4 mmol/L or 157 mg/dL),15 providing the impetus for further study. Recently, the efficacy and safety of evinacumab was tested in 65 adults with homozygous FH with LDL-C levels ≥1.8 mmol/L (70 mg/dL) on stable maximally tolerated lipid lowering therapy including lipoprotein apheresis.11 Genotyping was performed for all patients; 44 (68%) had one mutation with defective LDLR activity and one null mutation, and the remainder had null/null mutations (including mutations with <2% LDL receptor activity). Baseline lipid lowering therapy included a PCSK9 inhibitor (77%), lomitapide (22%) and/or lipoprotein apheresis (34%). Patients were randomized (2:1) to double-blind treatment with evinacumab 15 mg/kg intravenously every 4 weeks (n=43) or matching placebo (n=22), for 24 weeks, followed by open-label treatment with evinacumab for a further 24 weeks.

At the end of the double-blind treatment period, evinacumab reduced LDL-C by 49% (representing an absolute reduction of 3.4 mmol/L or 132 mg/dL) after correction for placebo, consistent with results from the proof-of-concept study.11,15 Importantly, nearly half of evinacumab-treated patients attained LDL-C levels <2.6 mmol/L or <100 mg/dL compared with about one in five in the placebo group. Evinacumab treatment was also associated with 50% reduction in triglycerides but had no effect on lipoprotein(a) levels. Safety findings were unremarkable, with no increase in the incidence of adverse events compared with placebo.

The results of this study are encouraging; however, outstanding questions remain regarding the long-term safety of evinacumab, given the relatively short duration of the current trial. Evinacumab, against a background of maximal LDL-lowering therapy including lipoprotein apheresis may offer the possibility of attaining LDL-C goal in these extremely-hard-to manage patients. Furthermore, while triple therapy (statin, PCSK9 inhibitor and evinacumab) attenuated atherosclerosis in experimental models,16 the impact of this combination on outcome in homozygous FH patients is unknown.

New understanding of the heterogeneity of genotype and phenotype in homozygous FH has driven the development of novel approaches to improve the management of patients. Will novel adjunctive therapies such as evinacumab offer opportunities to improve LDL-C control and prognosis, and be safe? There may be light at the end of tunnel, pending longer-term study. 


1. Vallejo-Vaz AJ, Kondapally Seshasai SR, Cole D, et al. Familial hypercholesterolaemia: A global call to arms. Atherosclerosis 2015;243:257-9.

2. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J 2016;37:1384-94.

3. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid lowering therapy. Circulation 2011;124: 2202-7.

4. Hartgers ML, Cuchel M, Hovingh GK, et al on behalf of the HoFH International Clinical Collaborators. Clinical, demographic and genetic characteristics of homozygous familial hypercholesterolemia patients worldwide: Interim results from the Homozygous FH (HoFH) International Clinical Collaborators (HICC) registry. 86th Annual Congress of the European Atherosclerosis Society, May 5-8, 2018, Lisbon, Portugal.

5. 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.

6. Raal FJ, Honarpour N, Blom DJ, et al for the 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.

7. Blom D, Harada-Shiba M, Rubba P, et al. Alirocumab efficacy and safety in adults with homozygous familial hypercholesterolemia (ODYSSEY HoFH). Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials V Session, ACC.20/WCC Virtual meeting. https://virtual.acc.org/?utm_campaign=acc20&utm_medium=email&utm_source=direct&utm_content=A20343

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. Thompson GR, Blom DJ, Marais AD, et al. Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol. Eur Heart J 2018;39:1162-8.

10. Bruckert E, Kalmykova O, Bittar R, et al. Long-term outcome in 53 patients with homozygous familial hypercholesterolaemia in a single centre in France. Atherosclerosis 2017;257:130-7.

11. Raal FJ, Rosenson R, Reeskamp LF, et al. Evinacumab significantly reduces LDL-C in patients with homozygous familial hypercholesterolemia. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials V Session, ACC.20/WCC Virtual meeting. https://virtual.acc.org/?utm_campaign=acc20&utm_medium=email&utm_source=direct&utm_content=A20343

12. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377: 211–21.

13. Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res 2015;56:1308–17.

14. Banerjee P, Chan KC, Tarabocchia M, et al. Functional analysis of LDLR (Low-Density Lipoprotein Receptor) variants in patient lymphocytes to assess the effect of evinacumab in homozygous familial hypercholesterolemia patients with a spectrum of LDLR activity. Arterioscler Thromb Vasc Biol 2019;39:2248-60.

15. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017;377:296-7.

16. Pouwer MG, Pieterman EJ, Worms N, et al. Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice. J Lipid Res 2020;61:365-75.