Management of Children with Heterozygous Familial Hypercholesterolemia Worldwide: A Meta-Analysis.

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Management of Children with Heterozygous Familial Hypercholesterolemia Worldwide: A Meta-Analysis.

https://doi.org/10.21203/rs.3.rs-5224358/v1

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Heterozygous familial hypercholesterolemia (HeFH) is one of the most frequent monogenic disorders in the world, leading to premature atherosclerotic cardiovascular diseases (ASCVD). The aim of this meta-analysis was to evaluate the efficacy and safety of lipid lowering therapy (LLT) and achievement of low-density lipoprotein cholesterol (LDL-C) goal in children with HeFH. The main endpoint was efficacy of goal achievement for LDL-C and other lipid parameters: total cholesterol [TC], triglycerides [TG], high density lipoprotein cholesterol [HDL-C], apolipoprotein B [apo B] and lipoprotein(a) [Lp(a)]), and the LLT safety (adverse events [AEs], including endocrine function, and growth indices). The secondary endpoint was an effect of LLT on attainment of LDL-C goal treatment (<3.5 mmol/L/130 mg/dL). A total of 41 studies with 4667 pediatric patients at mean age 12.08±2.4 years were included. 17 reported the efficacy and safety of LLT therapy compared to control, while the remaining assessed LLT through pre- and post-treatment. At median follow-up of 18.8 months, the group on LLT had significantly higher mean reductions of TC, LDL-C, TG, and increased HDL-C compared to control (-1.75 [-67,7 mg/dl], -1.84 [-71.2 mg/dl], -0.11 [-9.74 mg/dl], 0.08 mmol/L [3.1 mg/dl], respectively, p<0.001 for all). In the subgroup analysis according to different types of LLT we observed a significantly higher mean reduction of LDL-C by statin combined with ezetimibe treatment, followed by PCSK9 inhibitors, statins in monotherapy, and monotherapy with ezetimibe (-2.48 [-95.9 mg/dl], -2.16 [-83.5 mg/dl], -2.03 [-78.5 mg/dl], and -1.50 mmol/L [-58 mg/dl], respectively, test for overall effect: p<0.001). The pooled LDL-C was reduced by 33.44% (-2.14 mmol/L [-82.8 mg/dl], p<0.001) and failed to reach the goal treatment (<3.5 mmol/L) by 12.6% (95%CI, 12.4 – 12.9%). 38.7% of children achieved the LDL-C goal, 23.9% fell short by up to 10%, 10.7% experienced moderate failure (were over the LDL-C target between >10-20%), and 26.7% failed by more than 20% to reach the LDL-C target. When comparing different regions, only Sweden and Greece achieved the LDL-C goal <3.5 mmol/L in the follow-up, followed by the Netherlands, Norway, Poland, USA, UK, France, Spain, Belgium, and Austria (with the following additional required LDL-C reduction to be on the goal: 2.2%, 3.4%, 3.5%, 8.9%, 10.2%, 11.2%, 11.2%, 15%, 19.4%, respectively). For other investigated countries over 20% mean LDL-C reduction was required. All parameters related to endocrine function and demographic indices were unaffected by LLT therapy (p>0.05). The adverse events were not reported significantly higher when compared to the control and the prevalence of therapy discontinuation was only 0.8%. In conclusion, despite the efficacy of LLT in children with HeFH and the low occurrence of discontinuation-related adverse events, achieving LDL-C treatment goals was relatively rare, with large differences between the investigated countries. These results underscore the importance of considering early combination therapy of statins and ezetimibe, and PCSK9 inhibitors (if available) to attain LDL-C goals effectively.

Health sciences/Diseases/Cardiovascular diseases/Dyslipidaemias

Health sciences/Health care/Disease prevention/Preventive medicine

heterozygous familial hypercholesterolemia

children

efficacity

safety

LDL-C target

Heterozygous familial hypercholesterolemia (HeFH) is the most common genetic metabolic disorder globally, with even 30 million patients affected with raised elevated low-density lipoprotein cholesterol (LDL-C) levels [1, 2]. If left untreated, it can lead to premature atherosclerotic cardiovascular disease (ASCVD), even early coronary heart disease (CHD) deaths [1, 2]. HeFH has a high prevalence, affecting approximately 1 in 250 individuals worldwide (therefore it does not meet the criteria for rare disease with the prevenance less than 1:2000), and the mortality rate related to circulatory system diseases in these patients is even 100 times higher compared to the general population [3, 4]. While the prevalence likely underestimates the actual numbers, given that cardiovascular disease (CVD) is the primary global cause of death [5], the true extent of underdiagnosis and undertreatment among individuals in the general population with HeFH remains largely undetermined. Nevertheless, individuals with these conditions frequently go undetected in most countries [6, 7].

Because most individuals with HeFH may not exhibit symptoms of CHD until adulthood, prolonged exposure to elevated LDL-C levels leads to cumulative damage of the CV system [8, 9]. In addition, despite compelling evidence of clinical benefits, HeFH poses a significant burden, with the majority of cases remaining undetected due to the asymptomatic nature of the disease until clinical manifestations become overt. Certainly, there remains a very low awareness, detection and treatment of severe hypercholesterolemia even among adults [10, 11]. This delayed detection often results in underestimating the documented benefits of statin treatment, especially the impact of early treatment on early mortality [12]. Furthermore, the detection and management of HeFH in children have been shown to be cost-effective from both healthcare and societal perspectives across various countries [6, 9]. Consequently, it is crucial to initiate treatment for high LDL-C levels from childhood to prevent premature morbidity and mortality in people with HeFH [13, 14].

Regarding the treatment of FH in children, conflicting opinions remain among healthcare professionals about strategic management (including intensity) with lipid-lowering therapy (LLT), their safety and efficacity (what makes it ineffective in high proportion of children heFH patients) [15, 16]. Thus, in this meta-analysis we aimed to evaluate the efficacy and safety of LLT as well as the achievement of lipid treatment goals in children with HeFH in different regions and with different types of LLT.

Study selection and patient population

A total of 6782 articles were retrieved from the search after removing duplicates from the various databases. These articles underwent initial screening based on title and abstract, resulting in 98 articles that underwent a full-text review. Following a rigorous selection process, 41 studies with 4667 patients and a median follow-up of 18.8 months were included in the analysis [23-63]. Out of the 41 articles, 22 were randomized controlled trials (RCTs), and 19 were cohort studies. Seventeen articles reported the efficacy and safety of LLT therapy compared to control (25, 28-33, 37, 39, 41, 46, 49, 53, 55-57, 63), while the remaining 24 assessed LLT pre- and post-treatment (23, 24, 26, 27, 34-36, 38, 40, 42-45, 47, 48, 50-52, 54, 58-62). The PRISMA flow diagram is depicted in Figure S1, and the key characteristics of the included studies are presented in Table 1. The mean age of patients was 12.08 ± 2.4 and 46% were females. Out of 41 studies, 7 (16.7%) used low intensity LLT, 9 (21.4%) low to moderate, 10 (23.8%) moderate, 7 (16.7%) moderate to high, and 7 (16.7%) high intensity or combination therapy (Table 1).

Efficacy of LLT on lipidic profile and lipoproteins

The pooled analysis showed that the group commenced on LLT had higher baseline TC with a WMD of 0.25 mmol/L (9.7 mg/dl) (95%CI: 0.02 to 0.49, p = 0.04) and LDL-C of 0.23 mmol/L (8.9 mg/dl) (95% CI: 0.05 to 0.41, p = 0.01) compared to control (Figure S2). TG and HDL did not differ between the groups (p>0.05 for all, Figure S3), as did Lp (a), apoB, and apoA (p>0.05 for all, Figure S4). At median follow-up of 18.8 months, the group on LLT had significantly higher mean TC reduction -1.75 mmol/L (67.7 mg/dL) (95%CI: -1.95 to -1.55; p<0.001), LDL-C reduction -1.84 mmol/L (71.2 mg/dL) (-2.13 to -1.54; p<0.001), increased mean HDL-C by 0.08 mmol/L (3.1 mg/dL) (0.01 to 0.15; p=0.03) and reduced TG -0.11 mmol/L (9.74 mg/dL) (-0.16 to -0.07; p<0.001), compared to control (Figure S5 & S6). In addition, the LLT significantly reduced apoB (-0.32 g/L; p<0.001), while apoA and Lp(a) were not affected significantly compared to control (p>0.05, for both). The same results were achieved the inverse analysis we applied (Figure S7, S8). A summary of efficacity of LLT is shown on Figure 1.

In the subgroup analysis according to different types of LLT, using an inverse analysis model, we observed s significantly higher mean reduction of TC with statins combined with ezetimibe (WMD -2.73 [-105.6 mg/dl], 95%CI, -3.12 to -2.34 mmol/L)) followed by PCSK9is (-2.27 [-87.8 mg/dl], -2.39 to -2.15 mmol/L), statins in monotherapy (-2.21 [-85.5 mg/dl], -2.45 to -1.98 mmol/L), and only ezetimibe (-1.50 [-58 mg/dl], -1.68 to -1.32 mmol/L; test for overall effect: p<0.001; Figure S9). According to the above order of treatment, a mean reduction of LDL-C was similar: statins plus ezetimibe (WMD -2.48 [-95.9 mg/dl], 95%CI, -3.13 to -1.83 mmol/L), statin monotherapy (-2.16 [-83.5 mg/dl], -2.33 to -1.99 mmol/L], PCSK9is (WMD -2.03 [-78.5 mg/dl], -2.39 to -2.15 mmol/L] and ezetimibe monotherapy (-1.50 [-58 mg/dl], -1.71 to -1.29 mmol/L; test for overall effect: p<0.001, Figure 2). LLT also significantly affected TG, from -0.07 mmol/L (-6.2 mg/dl) for ezetimibe, through -0.15 mmol/L (-13.3 mg/dl) for statin in monotherapy, to -0.35 mmol/L (-31 mg/dl) for statins and ezetimibe in combination; no significant effect was observed for PCSK9 inhibitors (Figure S10). The overall test for subgroup differences was not statistically significant for HDL-C (p=0.76, respectively; with only statins that showed significant increase of HDL-C by 0.05 mmol/L [2 mg/dl], Figure S11).

LDL-C goal achievement using different types of LLT

At median follow-up of 18.8 months the pooled LDL-C was reduced for 33.44% (-2.14 [--2.30, - 1.98], p<0.001) and failed to reach the goal (LDL-C <3.5 mmol/L) for all investigated heFH children by 12.6% (95%CI, 12.4 – 12.9%) (Table 1). Among the 3522 children treated with LLT (1145 were on the dietary interventions), 1362 (38.7%) achieved the LDL-C goal, while 843 (23.9%) fell short by up to 10%, 377 (10.7%) experienced moderate failure (additional 10-20% overall LDL-C reduction was required), and 940 (26.7%) failed by more than 20% to reach the LDL-C target (Figure S12A).

When comparing different regions, only Sweden and Greece achieved the LDL-C goal, followed by the Netherlands, Norway, Poland, USA, UK, France, Spain, Belgium, and Austria (with the following additional required LDL-C reduction to be on the goal: 2.2%, 3.4%, 3.5%, 8.9%, 10.2%, 11.2%, 11.2%, 15%, 19.4%, respectively). Australia, Canada, Italy, Finland, and Japan experienced more than a 20% mean LDL-C reduction failure (Figure 3). Similarly, when comparing different types of LLT, the heFH children that were administered moderate to high dose of statins, high dose of statins, high-dose statins combined with ezetimibe, and PCSK9 inhibitors most often achieved the LDL-C goal while groups using only statins (low, moderate, low to moderate and moderate) and ezetimibe as monotherapy did not reach the treatment goal (Figure S12B).

Safety and tolerability of LLT in children

All parameters related to endocrine function, including cortisol, DHEA-S, FSH, LH, estradiol in girls, and testosterone in boys, were unaffected by LLT therapy (p>0.05 for all; Figure S13). Similarly, demographic indicators such as height, weight, body mass index (BMI), and surface area of the children increased comparably in both the LLT and control groups (p>0.05 for all; Figure S14). At the end of the follow-up period, no significant differences were observed in changes from baseline for ALT, AST, and CK (p>0.05 for all; Figure S15). A summary of LLT safety profile for demographic, endocrine, and liver/muscle enzyme parameters is provided in Figure 4.

The prevalence of treatment-emergent adverse events (TEAEs) was 4.6%, with a discontinuation rate of only 0.8%. Apart from headaches (10.2%), the prevalence of other adverse events was below 8.0%, including gastrointestinal effects, myalgia, sleep disorders, influenza-like disease, skin reactions, temporary increases in ALT, AST, CK, as well as ALT >3 x ULN, AST >3 x ULN, and CK >3 x ULN (8.41%, 3.18%, 2.54%, 5.62%, 3.71%, 1.89%, 1.50%, 0.52%, 0.83%, 0.51%, 0.67%, respectively; Figure 5A). Finally, the adverse events were not reported significantly higher when compared to the control group (Figure 5B, Figures S16-S19).

Risk of bias assessment

The assessment of risk of bias in the included studies using RoB2 for RCTs and NOS for cohort studies showed that most studies had moderate to high quality level in defining objectives and the main outcomes (Tables S4, S5).

To the best of our knowledge, the present meta-analysis is the first to evaluate the efficacy and safety of various types of LLT in children with HeFH, as well as the achievement of LDL-C treatment goals in children with HeFH globally and across different regions. This large analysis not only assesses the efficacy of lipid parameters reduction with the therapy, goal achievement for different therapy intensification and combination, but also presents strong safety of the lipid lowering therapy in children, one of the most important reasons of therapy nonadherence in heFH children. This also perfectly completes the results of the recent cross-sectional study from the Familial Hypercholesterolemia Studies Collaboration (FHSC) registry [64].

The results from our meta-analysis, encompassing 41 studies and involving 4667 children with HeFH and at mean age of 12 years, showed a significant efficacy of LLT on lipid profile. Subgroup analysis indicated a substantial mean reduction in LDL-C with statin combined with ezetimibe treatment, followed by PCSK9 inhibitors, statins, and sole ezetimibe treatment, strongly emphasizing the need to use combination LLT and/or PCSK9 inhibitors as the most effective method to achieve a therapeutic target for LDL-C. Overall, LDL-C was reduced by 33.44%, with insufficient reduction by 12.6% to reach the treatment goal for the whole pooled heFH cohort. Approximately 38.7% of children achieved the LDL-C goal, for 23.9% additional LDL-C reduction by up to 10% was required, 10.7% experienced moderate failure, and 26.7% failed by more than 20% to reach the LDL-C target. Regional comparisons showed that only Sweden and Greece achieved the LDL-C goal and many countries fell up to 10 or more than 20% mean LDL-C reduction failure.

Prior systematic reviews and meta-analyses addressing dietary interventions for individuals with HeFH have indicated insufficient efficacy, particularly in managing HeFH among children [65, 66]. The efficacy and safety of LLT especially statins, has been continuously debated with some studies suggesting that that statins are safe only in the short term [67, 68]. In contrast, other research recommends statins as the preferred pharmacological agents for treating HeFH, in conjunction with dietary and physical activity management, across all age groups [44,67, = 68]. For children unable to attain the LDL cholesterol goal with the initially prescribed statin dosage, higher statin doses or the addition of another lipid-lowering agent may be necessary [69, 70] In our meta-analysis, the effectiveness of high doses of statins, statins combined with ezetimibe, and/or PCSK9 inhibitors demonstrated significantly greater efficacy in lipid control compared to low-dose statins, low-to-moderate statins, moderate statins, and ezetimibe in monotherapy [71, 72].

In the recently published analysis from the FHSC registry with 11,848 heFH children or adolescents included (50.2% were female; median age 9.6 years; 89.9% genetic diagnosis) the authors showed that at registry entry 28.5% of children and adolescents were taking LLT, which increased with age in both sexes. 29.1% of children and adolescents were prescribed statins (from 10% for those younger than 5 years to 41.0% for those at age 15–18 years), and only 5.7% were prescribed ezetimibe (to less than 8% for those aged 15–18 years). The most common prescribed statins were atorvastatin (43.2%), simvastatin (24.4%), and rosuvastatin (18.4%). Only 0.4% individuals were taking PCSK9 inhibitors. Median LDL-C concentration among heFH children and adolescents on LLT was 4.35 mmol/L (168 mg/dl), compared with 5.00 mmol/L (193 mg/dl) for those not taking any medication. We have shown here that more than every third child with heFH achieved their goal of 3.5 mmol/L (135 mg/dl), with worse results in the real-word cohort from the FHSC registry, where among those taking statins or ezetimibe, every 4th boy and every fifth girl had LDL-C less than 3.4 mmol/L (131 mg/dl). Similarly to our results, compared with monotherapy with statins or ezetimibe, the combination therapy of statin and ezetimibe was associated with an increased likelihood of having LDL-C less than 3.4 mmol/L (131 mg/dl) (age-adjusted and sex-adjusted OR 1.83, 95%CI 1.19–2.82) compared with no therapy [66].

However, despite the results of LLT efficacy, the LDL-C target was not achieved in the majority of children (61.3% vs. 38.7%; p < 0.001) globally, with a lack of success in the majority of countries. To anticipate the risk of non-adherence, it is critically important to consider initiating treatment as early as possible, even with a low dose (with detailed dietary and lifestyle recommendations). During each visit, closely monitoring LDL-C levels until the target is reached and gradually increasing the dose of LLT while assessing for therapy tolerability. Our results also confirmed large efficacy and safety of the lipid lowering combination therapy of statins and ezetimibe, which is severely underused in heFH children worldwide. Furthermore, our findings underscore the significance of PCSK9 inhibitors, which are already available (or during evaluation) in many countries for children with FH. Novel therapeutic options, such as monoclonal antibodies, may be considered a substantial advancement in pediatric FH treatment (also in case of statin intolerance). However, our data is limited to two clinical trials, and further trials are still necessary to establish their safety profile and long-term effects [59, 60, 72]. Finally, despite being the most prevalent metabolic genetic disorder, HeFH remains underrecognized and undertreated. There should be a strong emphasis on early diagnosis and therapy. Implementing a multidisciplinary, family-centric approach as early as possible is crucial, as studies indicate that early-stage treatment with high dose of LLT significantly reduces future CVD risks in pediatric patients.

In last decades there is unjustified fear of parents to treat their heFH children with statins and other LLT, what is the main reason of therapy nonadherence, and in the consequence cardiovascular and vascular complications observed in children, adolescents, and young adults with heFH [14, 73]. Thus, despite LLT being the gold standard for dyslipidemia treatment and managing high CV risk, ensuring safety and tolerability in children is of paramount importance. Our findings indicate that LLT did not adversely affect parameters related to endocrine function, demographic indicators, and liver/muscle enzymes. Adverse events were not significantly higher in the heFH compared to the control group, and the prevalence of discontinuation was only 0.8%. The prevalence of treatment-emergent adverse events was also low. Apart from headaches, the prevalence of other adverse events was very low, encompassing gastrointestinal effects, myalgia, sleep disorders, influenza-like disease, skin reactions, and temporary increases in liver/muscle enzymes. Importantly, adverse events were not reported significantly higher when compared to the control group.

Strength and limitations

Our meta-analysis has some limitations. Moderate heterogeneity between studies was observed in several analyses, although the random-effects method was employed to mitigate the impact of this heterogeneity. The examination of potential publication bias using Egger and funnel plots was not conducted for studies with fewer than 100 patients, which were excluded from this type of analysis. The available data do not allow us to draw robust conclusions regarding the effectiveness and safety of new drugs, particularly PCSK9 inhibitors, and the varied doses used, mainly due to the limited number of trials. Subsequent studies may be necessary to determine the optimal dosage and timing of PCSK9 inhibitor therapy in children. Additionally, we cannot draw definitive conclusions regarding the benefits of initiating LLT in children at 8 years compared to 10 years, as different protocols are utilized in various regions. Finally, many countries, especially those with lower income, did not report the management of HeFH in children, potentially indicative of underrecognition and undertreatment.

In conclusions, in children with HeFH, LLT therapy significantly reduced lipid levels without impacting growth, hormones, or liver/muscle enzymes. Despite the low occurrence of discontinuation-related adverse events, achieving LDL-C treatment goals proved challenging in most of the investigated countries. These findings emphasize the significance of considering high-dose statins, lipid lowering combination therapy or PCSK9 inhibitors, to attain LDL-C goals effectively.

Search strategy and selection criteria

We followed to the methodology recommended by the Cochrane Collaboration, and the reporting standards outlined in the 2020 Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guideline [69]. A PECOS (population, exposure, comparison, outcomes, study design) model, as outlined in Table S1, was used to shape the clinical question, and devised the search strategy.

Our comprehensive search covered databases from their inception through December 31, 2023, including PubMed-Medline, EMBASE, Scopus, Google Scholar, the Cochrane Central Registry of Controlled Trials, and ClinicalTrial.gov. Key search terms included: ‘heterozygous familial hypercholesterolemia’, ‘HeFH’, ‘pediatric familial hypercholesterolemia’, ‘children’, ‘adolescents’, ‘pediatrics’, ‘treatment’, ‘lipid-lowering therapy’, ’statins’, ‘PCSK9 inhibitors’, ‘ezetimibe’, ‘dietary regimens’, ‘dietary interventions’, and ‘outcomes’ (Table S2). Furthermore, we conducted a thorough review by examining the references cited in the selected articles and relevant review articles. Additionally, abstracts from selected congresses, including scientific sessions of the European Society of Cardiology (ESC), the American Heart Association (AHA), European Atherosclerosis Society (EAS), American College of Cardiology (ACC), and National Lipid Association (NLA), were screened to identify any additional relevant articles. To enhance the search strategy’s sensitivity, the wild-card term ‘‘*’’ was used.

Articles were eligible if they reported the treatment with LLT in paediatric patients with HeFH and met the following inclusion criteria: i) trials or cohorts reporting treatment with LLT compared to control or comparison before-after treatment in the same group, ii) available mean change of lipidic profile and/or adverse events, and iii) genetically confirmed diagnosis of heFH. Exclusion criteria were as follows: i) studies with unclear methodologies to obtain the estimates of the LLT efficacy and safety, ii) ongoing trials (unless they reported relevant interim results), iii) studies only investigating diet regiments without LLT treatment, and iv) articles not published in English.

The search, screening, and data extraction were carried out independently by two reviewers (J.L. and S.S.). Any disagreements were resolved through discussions with senior investigators (I.B. and M.B.), while the analysis and interpretation of the data were performed by two different researchers (S.B. and I.B.). Irrelevant articles were excluded based on screening of titles and abstracts. Each trial underwent an independent assessment of the risk of bias by the same investigators using the revised Cochrane RoB2 tool, which includes five domains (randomization process, deviation from intended interventions, missing outcome data, outcome measurement, and selection of reported results). The risk of bias in each study was categorized as “low,” “high,” or “unclear” [70]. To assess the risk of bias in cohort studies, the Newcastle-Ottawa Scale (NOS) was employed. The three domains were evaluated based on the following criteria: a) selection, b) comparability, and c) exposure. The risk of bias in each study was categorized as “good,” “fair,” or “poor.” [71].

Outcome measures

The primary endpoint was the efficacy and safety of LLT in children with HeFH. The secondary endpoint was the effect of LLT on the achievement of lipid treatment goals. The efficacy parameters of LLT therapy (statins, ezetimibe, statin combined with ezetimibe, and PCSK9 inhibitors) on lipid profiles included total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB), apolipoprotein A (apoA), and lipoprotein(a) (Lp(a)). Safety parameters included endocrine function (cortisol, dehydroepiandrosterone sulfate [DHEA-S], follicular stimulating hormone [FSH], luteinizing hormone [LH], estradiol in girls, and testosterone in boys), demographic indices (weight, height, body mass index [BMI], and body surface area [BSA]), and adverse events (AE) compared to the control group and its prevalence.

The effect of LLT on the achievement of low-density lipoprotein cholesterol (LDL-C < 3.5 mmol/L [< 130mg/dL]) and to identify the LDL-C treatment goal variations in different regions were the main outcome. We determined the number of patients who achieved LDL-C < 3.5 mmol/L (< 130mg/dL), and in addition we classified the percent of failed to reached the target of LDL-C using the value of LDL-C < 3.5 mmol/L (< 130mg/dL) as reference line: low failure (1–10% not reached the target/additional reduction of LDL-C by 1–10% was required), moderate failure (> 10–20% not reached the target/additional reduction of LDL-C by > 10–20% was required) and high failure (> 20% not reached the target/additional reduction of LDL-C by > 20% was required). Furthermore, based on the dose of lipid-lowering therapy (LLT) that was used, we have classified patients into several groups: low intensity, moderate intensity, high intensity, and combined lipid lowering therapy. In cases where the LLT doses used were different and were not able to be included to the above groups, the groups of low to moderate and moderate to high have been also employed [72].

Data synthesis and statistical analyses

The meta-analysis was conducted using R Statistical Software (v3.5.1, Boston, MA, USA), using the packages ‘meta’ and ‘metafor’ for meta-analysis and the RevMan (Review Manager [RevMan] Version 5.1, The Cochrane Collaboration, Copenhagen, Denmark), with two-tailed p < 0.05 considered significant.

Weighted mean difference (WMD) with 95% confidence interval (CI) are presented as summary statistics, and for categorical variable relative risk (RR) ratio with the 95% CI was used. Mean and standard deviation (SD) values were estimated using the method described by Hozo et al [70]. A random-effects model (Der Simonian and Laird method) was applied to estimate the pooled prevalence of adverse events across the studies. The 95% confidence intervals (CIs) for the prevalence reported in the individual studies were estimated from the proportion of cases of adverse events and sample size using the binomial exact method (Clopper-Pearson method). An inverse variance method was used for weighting each study in the meta-analysis. Analysis is presented in forest plots, the standard way for illustrating the results of individual studies and meta-analysis.

Likewise, we calculated the effect of different type of LLT on lipid profile and safety parameters using sub-analysis. The meta-analyses were performed with the random-effects model. Heterogeneity between studies was assessed using Cochrane Q test and I² index. As a guide, I² < 25% indicated low, 25–50% moderate and > 50% high heterogeneity [73]. To assess the additive (between-study) component of variance, the reduced maximum likelihood method (tau²) incorporated the occurrence of residual heterogeneity into the analysis [74]. Publication bias was assessed using visual inspections of funnel plots and Egger’s test.

ACKNOWLEDGMENT:

The results of the meta-analysis were first released at the ESC Congress 2024 in London during the moderated session entitled “Cardiovascular Disease in Special Populations: Paediatric Cardiology”, 30 August 2024.

Funding: None.

Authorship: All authors contributed to the writing of this manuscript and approved the submitted version. No outside editorial/medical writing support was provided.

Declaration of interest: Maciej Banach: speakers bureau: Amgen, Daiichi Sankyo, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer, Sanofi-Aventis, Teva, Zentiva; consultant to Adamed, Amgen, Daiichi Sankyo, Esperion, NewAmsterdam, Novartis, Novo-Nordisk, Sanofi-Aventis; Grants from Amgen, Daiichi Sankyo, Mylan/Viatris, Sanofi and Valeant;

Ioanna Gouni-Berthold: speakers bureau: Amgen, Akcea Therapeutics, Daiichi-Sankyo, Novartis, Sanofi, Ultragenyx; Consultant to Amgen, Regeneron, Aegereon, Akcea Therapeutics, Daiichi-Sankyo, Novartis, Sanofi, Amarin and Ultragenyx. Dan Gaita: research grants, speaker honoraria or travel reimbursement from: Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Egis, Galenica, Gedeon Richter, GSK, MSD, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, Terapia, Viatris, Vifor, Zentiva. Francesco Paneni: is a consultant to Vectura Fertin Pharma and has received personal fees for lectures from Novo Nordisk. Arrigo FG Cicero: scientific consultant for Viatris and Edmond Pharma; research grants received by Viatris and IBSA pharmaceuticals; all other authors do not declare any conflict of interest in relation to the results of this paper.

McGowan, M.P., et al. Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia.J Am Heart Assoc.8, e013225 (2019).
Watts G.F., et al. International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolemia. Nat Rev Cardiol.20: 845–869 (2023).
Sturm A.C., et al. Convened by the Familial Hypercholesterolemia Foundation. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol.72: 662–680 (2018).
Goldberg A.C., et al. Familial Hypercholesterolemia: Screening, Diagnosis and Management of Pediatric and Adult Patients Clinical Guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J. Clin. Lipidol.5, S1–S8 (2011).
Mensah G.A., er al.; Global Burden of Cardiovascular Diseases and Risks Collaborators. Global Burden of Cardiovascular Diseases and Risks, 1990-2022. J Am Coll Cardiol.82, 2350-2473 (2023).
Nordestgaard B.G., et al.; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.Eur Heart J.34, 3478-90a (2013).
Marquina C., et al. Health economics of detection and treatment of children with familial hypercholesterolemia: to screen or not to screen is no longer the question.Curr Opin Endocrinol Diabetes Obes.31, 84-89 (2023).
Marks D., et al. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis.; 168, 1–14 (2003).
Banach M., Penson P.E. Homozygous familial hypercholesterolaemia: shedding new light on a rare but deadly condition.Eur J Prev Cardiol.29, 815-816 (2022).
Miles J., et al. Long-Term Mortality in Patients With Severe Hypercholesterolemia Phenotype From a Racial and Ethnically Diverse US Cohort. Circulation.149, 417-426 (2024).
Sayed A., et al. Prevalence, Awareness, and Treatment of Elevated LDL Cholesterol in US Adults, 1999-2020. JAMA Cardiol. Dec 8, 1185-1187 (2023).
Ray K.K., et al. Premature morbidity and mortality associated with potentially undiagnosed familial hypercholesterolemia in the general population. Am J Prev Cardiol. 15, 100580 (2023).
Representatives of the Global Familial Hypercholesterolemia. Reducing the clinical and public health burden of familial hypercholesterolemia: a global call to action. JAMA Cardiol.5, 217–29 (2020).
Podgórski M., et al. "Apple does not fall far from the tree" - subclinical atherosclerosis in children with familial hypercholesterolemia.Lipids Health Dis.19, 169 (2020).
EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Lancet.398, 1713-1725 (2021).
Mainieri F., et al. Recent Advances on Familial Hypercholesterolemia in Children and Adolescents.Biomedicines.10, 1043 (2022).
Ducobu J., et al. Simvastatin use in children. Lancet.339, 1488 (1992).
Sinzinger H., et al. Treatment of hypercholesterolaemia in children. Lancet. 340, 548–9 (1992).
Knipscheer H.C., et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Pediatr Res.39, 867–71 (1996).
Lambert M., et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group. Pediatrics. 97, 619–28 (1996).
Couture P., et al. Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol.18, 1007–12 (1998).
Stein E.A., et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia. A randomized controlled trial. JAMA. 281, 137–44 (1999).
Stefanutti C., et al. Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood. Drugs Exp Clin Res.25, 23–8 (1999).
McCrindle B.W., et al. A randomized crossover trial of combination pharmacologic therapy in children with familial hyperlipidemia. Pediatr Res.51, 715-21 (2002).
McCrindle B.W., et al. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.J Pediatr.143, 74-80 (2003).
de Jongh S., et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia. A randomized, double-blind, placebo-controlled trial with simvastatin. Circulation.106, 2231–7 (2002).
de Jongh S., et al. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol.40, 2117-21 (2002).
Vohl M., et al. Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia. Atherosclerosis.160, 361–8 (2002).
Dirisamer A. The effect of low-dose simvastatin in children with familial hypercholesterolaemia: a 1-year observation. Eur J Pediatr.162, 421–5 (2003).
Hedman M., et al. Pharmacokinetics and pharmacodynamics of pravastatin in children with familial hypercholesterolemia. Clin Pharmacol Ther.74, 178–85 (2003).
Wiegman A., et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia. A randomized controlled trial. JAMA.292, 331–7 (2004).
Koeijvoets K.C.M.C., et al. Low-density lipoprotein receptor genotype and response to pravastatin in children with familial hypercholesterolemia: substudy of an intima-media thickness trial. Circulation.112, 3168–73 (2005).
Hedman M., et al. Efficacy and safety of pravastatin in children and adolescents with heterozygous familial hypercholesterolemia: a prospective clinical follow-up study. J Clin Endocrinol Metab.90, 1942–52 (2005).
Clauss S.B., et al. Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics. 116, 682–8 (2005).
Rodenburg J., et al. Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings. J Am Coll Cardiol.47, 1803–10 (2006).
van der Graaf A., et al. Efficacy and safety of fluvastatin in children and adolescents with heterozygous familial hypercholesterolaemia. Acta Paediatr.95, 1461-6 (2006).
van der Graaf A., et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol.; 52, 1421-1429 (2008).
Yeste D., et al. Ezetimibe as monotherapy in the treatment of hypercholesterolemia in children and adolescents. J Pediatr Endocrinol Metab.22: 487-92 (2009).
Clauss S., et al. Ezetimibe treatment of pediatric patients with hypercholesterolemia. J Pediatr.154, 869-72 (2009).
Avis HJ, et al. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J Am Coll Cardiol.55, 1121-6 (2010).
Gandelman K, et al. An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia. Pediatr Cardiol.32, 433-41 (2011).
Kusters D.M., et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA.312, 1055-7 (2014).
Kusters D.M., et al. Efficacy and safety of ezetimibe monotherapy in children with heterozygous familial or nonfamilial hypercholesterolemia. J Pediatr.166, 1377-84, e1-3 (2015).
Braamskamp M.J.A.M., et al. Efficacy and safety of rosuvastatin therapy in children and adolescents with familial hypercholesterolemia: Results from the CHARON study. J Clin Lipidol. 9, 741-750 (2015).
Harada-Shiba, M., et al. & NK-104-PH 01 study registration group. Efficacy and safety of pitavastatin in Japanese male children with familial hypercholesterolemia. Journal of Atherosclerosis and Thrombosis.23, 48–55 (2016).
Langslet, G., et al. A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia. Journal of Clinical Lipidology. 10, 1153–1162.e3 (2016).
Hennig M., et al. When do paediatric patients with familial hypercholesterolemia need statin therapy?Dev Period Med. 21, 43-50 (2017).
Saltijeral A., et al; SAFEHEART Investigators. Attainment of LDL Cholesterol Treatment Goals in Children and Adolescents With Familial Hypercholesterolemia. The SAFEHEART Follow-up Registry. Rev Esp Cardiol (Engl Ed).70, 444-450 (2017).
Ramaswami U., et al., Group FHPRS. The UK Paediatric Familial Hypercholesterolaemia Register: preliminary data. Arch Dis Child.102, 255-60 (2017).
Humphries S.E., et al.; FH Paediatric Register Steering Group. The UK Paediatric Familial Hypercholesterolaemia Register: Statin-related safety and 1-year growth data. J Clin Lipidol.12: 25-32 (2018)
Bogsrud M.P., et al. Treatment goal attainment in children with familial hypercholesterolemia: A cohort study of 302 children in Norway. J Clin Lipidol.12, 375-382 (2018).
Pang J., et al. Parent-child genetic testing for familial hypercholesterolaemia in an Australian context.. J Paediatr Child Health.54, 741-747 (2018).
Daniels S., et al. PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study.J Clin Lipidol.14, 322-330.e5 (2020).
Santos R.D., et al.; HAUSER-RCT Investigators. Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia. N Engl J Med.383, 1317-1327 (2020).
Benekos T., et al. Nine-year overview of dyslipidemia management in children with heterozygous familial hypercholesterolemia: A university hospital outpatient lipid clinic project in Northwestern Greece. J. Pediatr. Endocrinol. Metab.33, 533–538 (2020).
Lewek J, et al. Clinical Features of Familial Hypercholesterolemia in Children and Adults in EAS-FHSC Regional Center for Rare Diseases in Poland.J Clin Med.10: 4302 (2021).
Peretti N., et al.; French Registry of Familial Hypercholesterolemia (REFERCHOL) investigators. Factors Predicting Statin Initiation During Childhood in Familial Hypercholesterolemia: Importance of Genetic Diagnosis.J Pediatr.253: 18-24. e2. (2023).
European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration. Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study. Lancet.403, 55-66 (2024).
Malhotra A., et al. Dietary interventions (plant sterols, stanols, omega-3 fatty acids, soy protein and dietary fibers) for familial hypercholesterolaemia.Cochrane Database Syst Rev.2014, CD001918 (2014).
Barkas F., et al. Diet and Cardiovascular Disease Risk Among Individuals with Familial Hypercholesterolemia: Systematic Review and Meta-Analysis.Nutrients.12, 2436 (2020).
Avis H.J., et al. A systematic review and meta‐analysis of statin therapy in children with familial hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology.27, 1803‐10 (2007).
Ziółkowska S., et al. Familial hypercholesterolemia - treatment update in children, systematic review.Pediatr Endocrinol Diabetes Metab. 28, 152-161 (2022).
Vuorio A., et al. Statins for children with familial hypercholesterolemia.Cochrane Database Syst Rev.2019, CD006401 (2019).
Banach M., et al. PoLA/CFPiP/PCS/PSLD/PSD/PSH guidelines on diagnosis and therapy of lipid disorders in Poland 2021. Arch Med Sci.17, 1447-1547 (2021).
Banach M., et al.; endorsed by the International Lipid Expert Panel (ILEP). Individualized therapy in statin intolerance: the key to success. Eur Heart J.44, 544-546 (2023).
Banach M., et al. Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement. Int J Cardiol.225, 184-196 (2016).
Santos RD, et al. Paediatric patients with heterozygous familial hypercholesterolaemia treated with evolocumab for 80 weeks (HAUSER-OLE): a single-arm, multicentre, open-label extension of HAUSER-RCT. Lancet Diabetes Endocrinol.10, 732-740 (2022).
Bjelakovic B, et al. Risk Assessment and Clinical Management of Children and Adolescents with Heterozygous Familial Hypercholesterolaemia. A Position Paper of the Associations of Preventive Pediatrics of Serbia, Mighty Medic and International Lipid Expert Panel. J Clin Med.; 10, 4930 (2021).
Page M.J., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 372, n71 (2021).
Higgins J.P.T., et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.
Zeng X., et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 8, 2–10 (2015).
Grundy S.M., et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol.73, 3168-3209 (2019).
Hozo S.P., et al.. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol.5, 13 (2005).
Higgins J.P.T., Thompson S.G. Quantifying heterogeneity in a meta-analysis. Stat Med. 21, 1539-58 (2002)

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Table 1. Main characteristics of studies included in the meta-analysis.
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Management of Children with Heterozygous Familial Hypercholesterolemia Worldwide: A Meta-Analysis.

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