Efficacy and safety of statins, ezetimibe and statins-ezetimibe therapies for children and adolescents with heterozygous familial hypercholesterolaemia: Systematic review, pairwise and network meta-analyses of randomised controlled trials

Alexis Llewellyn; Mark Simmonds; David Marshall; Melissa Harden; Beth Woods; Steve E Humphries; Uma Ramaswami; Lorraine Priestley-Barnham; Mark Fisher; Laila J Tata; Nadeem Qureshi

doi:10.1016/j.atherosclerosis.2024.118598

Efficacy and safety of statins, ezetimibe and statins-ezetimibe therapies for children and adolescents with heterozygous familial hypercholesterolaemia: Systematic review, pairwise and network meta-analyses of randomised controlled trials

Atherosclerosis. 2024 Sep 28:118598. doi: 10.1016/j.atherosclerosis.2024.118598. Online ahead of print.

Authors

Affiliations

¹ Centre for Reviews and Dissemination, University of York, UK. Electronic address: alexis.llewellyn@york.ac.uk.
² Centre for Reviews and Dissemination, University of York, UK.
³ Centre for Health Economics, University of York, UK.
⁴ Centre for Cardiovascular Genetics, University College London, UK.
⁵ Royal Free Hospital and Genetics and Genomic Medicine, University College London, UK.
⁶ Royal Brompton and Harefield Hospital, Guy's and St Thomas NHS Trust, UK.
⁷ Lifespan and Population Health Unit and Centre for Perinatal Research, School of Medicine, University of Nottingham, UK.
⁸ NIHR School of Primary Care Research, University of Nottingham, UK.

PMID: 39343641
DOI: 10.1016/j.atherosclerosis.2024.118598

Abstract

Background and aims: Statins, ezetimibe and statins-ezetimibe combination therapy are recommended lipid-lowering therapies (LLTs) in children with heterozygous familial hypercholesterolaemia (HeFH). However, their relative effectiveness is not well understood. We aimed to compare the safety and efficacy of these therapies using direct and indirect comparisons.

Methods: We conducted systematic review, pairwise and network meta-analyses (NMAs) of randomised-controlled trials (RCTs) of statins, ezetimibe and statins-ezetimibe combination therapy in people <18 years with HeFH. Comprehensive bibliographic searches were conducted in December 2022, and a Medline update in January 2024. NMA models accounted for drug class, statin type and dosage.

Results: Thirteen RCTs were included (n = 1649, median age 13 years, follow-up 6 weeks-2 years). All LLTs reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol; statins led to increases in high-density lipoprotein cholesterol and reductions in triglycerides. Statins reduced LDL-C by 33.61 % against placebo (95 % CI 27.58 to 39.63, I² = 83 %). Adding ezetimibe to statins reduced LDL-C by an additional 15.85 % (95 % CI 11.91 to 19.79). NMAs showed intermediate-dose statins reduced LDL-C by an additional 4.77 % compared with lower-doses statins (95 % CrI -11.22 to 1.05); higher-dose statins and intermediate-dose statins + ezetimibe may be similarly effective and are probably superior to ezetimibe, intermediate-and lower-dose statins. There was no evidence of differences in maturation, safety or tolerability between LLTs and placebo.

Conclusions: Statins, ezetimibe and statins-ezetimibe are all effective treatments for children with HeFH, but the magnitude of LDL-C reductions varies and may depend on treatment dosage and combination. No safety or tolerability issues were found. Longer-term safety and effectiveness are uncertain.

Keywords: Adolescents; Children; Ezetimibe; Familial hypercholesterolaemia; Network meta-analysis; Statins; Systematic review.