Abstract
Introduction
Statins, ezetimibe and statins+ezetimibe combination therapy are recommended lipid-lowering therapies 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
A systematic review was undertaken, including 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. To explore the impact of statins dosage on %low-density lipoprotein-cholesterol (LDL-C) change, and in the absence of specific paediatric guidelines on dose-intensity, statins were grouped by dosage according to adult guidance on dose-intensity. 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). Statins reduced LDL-C by 33.61% compared to placebo (95% CI 27.58-39.63, I2=83%). Adding ezetimibe to statins reduced LDL-C by an additional 15.85% (95% CI 11.91 to 19.79). NMAs showed that 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. Statins, when compared to placebo, also led to reductions in serum total cholesterol (26.6%; 95% CI 21.5 to 31.8); a decrease in serum triglycerides (8.0%; 95%CI 3.1 to 12.9); and an increase in serum high-density lipoprotein cholesterol (3.5%; 95% CI 1.0 to 6.1). A similar pattern was seen in a placebo-controlled trial of ezetimibe monotherapy and a trial comparing simvastatin+ezetimibe against simvastatin+placebo. There was no evidence of a difference in safety and tolerability between statins, ezetimbe 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 issues were found. This review supports the ESC/EAS and UK HEART recommendations for managing paediatric HeFH, including statin initiation at low doses.1,2 It provides further evidence to support statin dose-escalation and/or addition of ezetimibe where safe, tolerated, and age-appropriate.
Statins, ezetimibe and statins+ezetimibe combination therapy are recommended lipid-lowering therapies 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
A systematic review was undertaken, including 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. To explore the impact of statins dosage on %low-density lipoprotein-cholesterol (LDL-C) change, and in the absence of specific paediatric guidelines on dose-intensity, statins were grouped by dosage according to adult guidance on dose-intensity. 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). Statins reduced LDL-C by 33.61% compared to placebo (95% CI 27.58-39.63, I2=83%). Adding ezetimibe to statins reduced LDL-C by an additional 15.85% (95% CI 11.91 to 19.79). NMAs showed that 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. Statins, when compared to placebo, also led to reductions in serum total cholesterol (26.6%; 95% CI 21.5 to 31.8); a decrease in serum triglycerides (8.0%; 95%CI 3.1 to 12.9); and an increase in serum high-density lipoprotein cholesterol (3.5%; 95% CI 1.0 to 6.1). A similar pattern was seen in a placebo-controlled trial of ezetimibe monotherapy and a trial comparing simvastatin+ezetimibe against simvastatin+placebo. There was no evidence of a difference in safety and tolerability between statins, ezetimbe 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 issues were found. This review supports the ESC/EAS and UK HEART recommendations for managing paediatric HeFH, including statin initiation at low doses.1,2 It provides further evidence to support statin dose-escalation and/or addition of ezetimibe where safe, tolerated, and age-appropriate.
| Original language | English |
|---|---|
| Title of host publication | Atherosclerosis Plus |
| Publisher | Elsevier B.V. |
| Number of pages | 2 |
| Volume | 57 |
| Edition | Supplement |
| Publication status | Published - Sept 2024 |