This review provides an overview of pediatric dyslipidemia emphasizing screening and treatment recommendations. The presence of risk factors for cardiovascular disease in childhood poses significant risk for the development of atherosclerotic cardiovascular disease and cardiovascular events in adulthood. While atherogenic dyslipidemia is the most common dyslipidemia seen in children and can be suspected based on the presence of risk factors (such as obesity), familial hypercholesterolemia can be found in children with no risk factors. As such, universal cholesterol screening is recommended to identify children with these disorders in order to initiate treatment and reduce the risk of future cardiovascular disease. Treatment of pediatric dyslipidemia begins with lifestyle modifications, but primary genetic dyslipidemias may require medications such as statins. As pediatric lipid disorders often have genetic or familial components, it is important that all physicians are aware that cardiovascular risk begins in childhood, and can both identify these disorders in pediatric patients and counsel their adult patients with dyslipidemia to have their children screened.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a genetic disease characterized by high levels of low-density lipoprotein cholesterol (LDL-C) present from birth, leading to early-onset and progressive atherosclerotic cardiovascular disease. Early treatment initiation is crucial for cardiovascular risk reduction; however, many patients do not reach LDL-C treatment goals. Inclisiran, a small interfering RNA targeting hepatic PCSK9 (proprotein convertase subtilisin/kexin type 9), is effective and well tolerated in adult patients with hyperlipidemia; however, it has not yet been studied in pediatric patients. METHODS: Herein we report results of the 1-year, double-blind, placebo-controlled part of the phase 3 study ORION-13 (Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia) in adolescents with HoFH. This 2-part multicenter study included 13 patients ≥12 to 130 mg/dL) on maximally tolerated statin treatment, with or without other lipid-lowering therapies. Eligible patients were randomized 2:1 to receive either 300 mg of inclisiran sodium or placebo, administered on days 1, 90, and 270. The primary end point was the mean percentage change in LDL-C from baseline to day 330. RESULTS: The mean age of patients was 14.8 years, and mean baseline LDL-C was 272 mg/dL. The placebo-adjusted mean (95% CI) percentage change in LDL-C from baseline to day 330 was −33.3% (−59.2% to −7.3%). Six of 9 (66.7%) inclisiran-treated patients (versus 1 of 4 [25%] on placebo) achieved a >15% reduction in LDL-C, and 5 of 9 (55.6%) inclisiran-treated patients (versus none on placebo) achieved a >20% reduction. The placebo-adjusted mean (95% CI) percentage change in PCSK9 from baseline to day 330 was −60.2% (−79.8% to −40.7%); corresponding changes in apolipoprotein B, non–high-density lipoprotein cholesterol, and total cholesterol were −23.0%, −32.7%, and −27.8%, respectively. No serious adverse events, treatment discontinuations because of adverse events, or deaths occurred. No new safety findings were reported. CONCLUSIONS: In a 1-year randomized controlled study (part 1 of ORION-13), inclisiran was effective in lowering LDL-C in adolescents with HoFH and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HoFH and a minimum of LDLR residual activity. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04659863.

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Heterozygous familial hypercholesterolemia (HeFH) is a common, treatable genetic disorder characterized by premature atherosclerosis and cardiovascular disease, yet the majority of affected individuals remain undiagnosed. Newborn screening could play a role in identification of at-risk individuals and provide an opportunity for early intervention, prior to the onset of symptoms. The objective of this study was to develop and validate assays for quantification of candidate HeFH biomarkers in dried blood spots (DBS). Commercially available enzyme assay kits for quantification of serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) were modified for high-throughput analysis of DBS. Apolipoprotein B (ApoB) concentrations in DBS were measured using an immunoassay with modifications from published studies. All three assays were validated according to the College of American Pathologists guidelines for clinical laboratories. The performance of TC, LDL-C, and ApoB assays was assessed by precision, recovery, limit of quantification (LOQ) and linearity. Precision studies yielded coefficients of variation (CV) of less than 15%, with recovery greater than 75% for all three assays. The determined LOQ and linearity were comparable to serum-based assays. In a direct comparison between serum and DBS concentrations, positive correlations were demonstrated for TC, LDL-C, and ApoB. Additionally, the initial evaluation of the three biomarker concentrations within the unaffected population was similar to values obtained in previous published studies. This study reports on methods for quantification of TC, LDL-C, and ApoB in DBS. Assay validation results were within acceptable limits for newborn screening. This is an important first step toward the identification of newborns with HeFH.