PCSK9 targeting therapies for familial hypercholesterolaemia: a meta-analysis of efficacy on lipid biomarkers and safety in adults and children across 23 RCTs

Abstract

Background

Familial hypercholesterolaemia (FH) is a hereditary disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels, substantially increasing the risk of atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting therapies, including monoclonal antibodies and small interfering RNA (siRNA) agents, have emerged as effective lipid lowering therapies.

Objective

To assess the efficacy and safety of PCSK9-targeting therapy on lipid biomarkers and adverse events in patients with FH, compared with placebo on the background of standard lipid-lowering therapy.

Methods

A systematic review and meta-analysis were conducted, incorporating data from 23 randomised controlled trials involving adult and paediatric FH patients treated with PCSK9 inhibitors (PCSK9i) or siRNA, including alirocumab, bococizumab, evolocumab, tafolecimab and inclisiran. Eligible studies reported changes in LDL-C, apolipoprotein B (ApoB), lipoprotein a (Lp(a)), triglycerides (TGL) and adverse effects. Pooled mean differences (MDs) and ORs with 95% CIs were calculated using random-effects models, and heterogeneity was assessed with I² statistic. This meta-analysis was registered on PROSPERO (CRD42025631510).

Results

A total of 4282 patients were included. PCSK9-targeting therapies significantly reduced LDL-C levels compared with control therapies (MD=−46.64%; 95% CI −50.77% to –42.52%; p<0.00001) and TGL (MD=−15.18%; 95% CI –19.34% to –11.03%; p<0.00001). Significant reductions were also observed for ApoB (MD=−34.94%; 95% CI –40.89% to –28.99%; p<0.00001) and Lp(a) (MD=−22.7%; 95% CI −25.95% to –19.44%; p<0.00001). LDL-C, TGL and ApoB reduction were more significant in heterozygous FH patients than in homozygous patients. The safety profile of these therapies was favourable, with adverse event rates comparable to those of the controls.

Conclusions

PCSK9i and Inclisiran demonstrate significant and sustained reductions in LDL-C, ApoB, Lp(a) and TGL in FH patients, especially in heterozygous FH patients. These agents are generally well-tolerated and represent effective treatment options for FH patients inadequately controlled by standard lipid-lowering therapies.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• PCSK9-targeting therapies have demonstrated strong low-density lipoprotein cholesterol (LDL-C)-lowering effects in adults with familial hypercholesterolaemia (FH), but prior meta-analyses focused mainly on LDL-C and did not include paediatric or homozygous FH populations.

WHAT THIS STUDY ADDS

• This meta-analysis offers the most comprehensive assessment to date, covering 23 randomised controlled trials and evaluating multiple lipid biomarkers (LDL-C, apolipoprotein B, lipoprotein a, triglycerides) and safety outcomes in both adult and paediatric FH populations, including novel therapies like inclisiran, tafelocimab and bococizumab.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Findings support broader use of PCSK9-targeting therapies across age groups and FH subtypes and suggest Asian patients may experience enhanced LDL-C reduction with inclisiran, highlighting the potential for personalised lipid-lowering strategies.

Introduction

Familial hypercholesterolaemia (FH) is a prevalent genetic disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C), leading to a significantly increased risk of premature and atherosclerotic cardiovascular disease (ASCVD). The prevalence of heterozygous FH (HeFH) is approximately 1 in 250 individuals, while homozygous FH (HoFH) occurs in about 1 in 300 000 individuals.¹ Mutations in genes such as the LDL-C receptor (LDL-R), apolipoprotein B (ApoB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) impair the clearance of LDL-C from the bloodstream, resulting in persistently elevated cholesterol levels.²

Early diagnosis and treatment are essential to reduce cardiovascular (CV) risk in FH patients.^{3 4} Lifestyle modifications have limited impact on LDL-C, making pharmacological therapy the cornerstone of treatment.⁵ However, standard therapies such as statins and ezetimibe often fail to achieve LDL-C targets in both adult and paediatric populations,^{6 7} prompting the development of novel therapeutic strategies.8,10

The advent of PCSK9 inhibitors (PCSK9i) as monoclonal antibodies has revolutionised the management of hyperlipidaemia, showing significant efficacy in lowering LDL-C levels and other atherogenic lipids, including triglycerides (TGL), Apo B and lipoprotein a (Lp(a)).11,17 Inclisiran, a small interfering RNA (siRNA) therapy targeting PCSK9 synthesis, offers a novel mechanism of action with convenient biannual dosing, further enhancing patient adherence and lipid control.¹⁸

This meta-analysis evaluates the efficacy and safety of PCSK9i and siRNA therapies in both adult and paediatric FH patients, focusing on their impact on key lipid biomarkers including LDL-C, TGL, ApoB and Lp(a). The findings aim to support clinical decision-making in FH management.

Methods

This systematic review and meta-analysis were performed following the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines¹⁹ and registered at the International Prospective Register of Systematic Reviews (PROSPERO; CRD42025631510).

Search strategy

We searched PubMed, Embase and Cochrane from inception to January 2025, using the following terms: “PCSK9”; “proprotein convertase subtilisin/kexin”; “PCSK9 inhibitors”; “Inclisiran”; “siRNA”; “small interfering RNA”; “ALN-PCSSC”; “Proprotein convertase subtilisin/kexin type 9 inhibitor”; “Anti-PCSK9 monoclonal antibodies”; “heterozygous familial hypercholesterolemia”; “HeFH”; “heterozygous FH”; “homozygous familial hypercholesterolemia”; “HoFH”; “homozygous FH”; “familial hypercholesterolemia”; “Evolocumab”; “AMG 145”; “Alirocumab”; “REGN727”; “SAR236553”; “Bococizumab”; “RN316”; “PF-04950615”; “LY3015014”. Two authors (VQTH and MD) independently screened titles and abstracts and evaluated the articles for eligibility based on prespecified criteria. Two authors (NBT and NN) independently extracted data related to the outcomes. Discrepancies were resolved through consensus. Data for baseline characteristics (table 1) were extracted by two authors (GSA and VZF).

Table 1. Baseline characteristics of included studies.

RCT name	Patient, n	FH subtype	Age, years	Male, %	White, %	HTN, %	DM, %	LDL, mg/dL	TG, mg/dL	Lp(a), mgdL*; nmol/l†	ApoB, mg/dL	HIS use, %	EZ use, %
Type of intervention
ODYSSEY ESCAPE 24	62	HeFH	58.7	58.0	96.8	NA	NA	181.11	196.87	32.76*	143.4	40.3	NA
Alirocumab (150 mg Q2W)
ODYSSEY FH I 16	486	HeFH	52.0	56.38	91.3	43.2	11.7	144.6	127.83	49.96*	114.3	83.54	57.2
Alirocumab (75 mg Q2W)
ODYSSEY FH II 16	249	HeFH	53.2	52.61	98.0	32.5	4.0	134.4	121.23	50.23*	107.9	88.35	66.26
Alirocumab (75 mg Q2W)
ODYSSEY HIGH FH 25	107	HeFH	50.55	53.27	87.85	57.0	14.0	197.85	129.83	27.0*	140.92	72.9	24.3
Alirocumab (150 mg Q2W)
ODYSSEY HoFH 26	69	HoFH	43.38	49.27	78.26	NA	NA	282.7	107.17	34.8*	186.93	85.5	72.46
Alirocumab (150 mg Q2W)
Santos 2024 22	153	HeFH	12.90	43.14	81.7	NA	NA	174.23	79.18	22.65*	117.41	15.03	13.72
Alirocumab (40 mg Q2W; 75 mg Q2W; 150 mg Q4W; 300 mg Q4W)
Stein 2012 #1 23	77	HeFH	53.4	61.0	95.0	NA	4.0	155.07	119.57	NA	127.0	77.0	71.0
Alirocumab (150 mg Q4W; 200 mg Q4W; 300 mg Q4W; 150 mg Q2W)
Stein 2012 #2 14	21	HeFH	40.43	80.86	85.71	NA	NA	133.56	NA	NA	112.0	52.38	NA
Alirocumab (50 mg; 100 mg; 150 mg)‡
Ridker 201820 (SPIRE trials)	1578	HeFH	57.60	58.11	NA	59.25	24.9	151.36	139.04	40.41*	116.46	80.9	46.94
Bococizumab (150 mg Q2W)
HAUSER-RCT 21	157	HeFH	13.7	43.7	85.0	3.35	0.66	184.32	86.26	44.9†	NA	16.6	13.4
Evolocumab (420 mg Q4W)
RUTHERFORD 27	167	HeFH	49.58	53.29	88.62	NA	NA	157.39	124.0	69.83†	123.0	89.82	64.67
Evolocumab (350 mg Q4W; 420 mg Q4W)
RUTHERFORD-2 28	329	HeFH	51.15	57.75	NA	NA	NA	155.84	116.91	93.61†	113.0	87.0	62.0
Evolocumab (140 mg Q2W; 420 mg Q4W)
TESLA 29	49	HoFH	31.0	51.22	90.0	NA	NA	348.03	106.28	92.67†	210.0	94.0	92.0
Evolocumab (420 mg Q4W)
CREDIT-2 30	148	HeFH	49.41	52	NA	NA	NA	164.35	138.17	28.0*	121.0	12.16	28.38
Tafolecimab (150 mg Q2W; 450 mg Q4W)
ORION-5 31	56	HoFH	42.7	39.3	NA	37.5	5.4	315.3	NA	85.0†	203.1	100.0	66.1
Inclisiran sodium (300 mg)§
ORION-9 32	482	HeFH	5m6.0	47.1	93.98	42.1	9.96	153.04	123.16	86.33†	124.15	73.86	52.9
Inclisiran sodium (300 mg)¶
ORION-15 33	56	HeFH	††	††	††	††	††	††	††	††	††	††	††
Inclisiran sodium (100 mg, 200 mg, 300 mg)**
ORION-18 34	36	HeFH	††	††	††	††	††	††	††	††	††	††	††
Inclisiran sodium (300 mg)§§

Values are mean or %.

^*Measured in mg/dL

^†Measured in nmol/L.

^‡Administered on days 1, 29 and 43.

^§Administered on days 1 and 90.

^¶Administered on days 1, 90, 270 and 450.

^**Administered on days 1, 90, 270.

^††Baseline characteristics of FH subgroup in ORION-15 and ORION-18 are not reported, only for the overall population.

ApoB, apolipoprotein B; DM, diabetes mellitus; EZ, Ezetimibe; FH, familial hypercholesterolaemia; HeFH, heterozygous familial hypercholesterolaemia; HIS, high-intensity statin; HoFH, homozygous familial hypercholesterolaemia; HTN, hypertension; LDL-C, low-density lipoprotein-cholesterol; Lp(a), lipoprotein(a); NA, not applicable; Q2W, administered every 2 weeks; Q4W, administered every 4 weeks; RCT, randomised controlled trial; TG, triglycerides.

Study eligibility

Studies were eligible if they (1) were RCTs; (2) compared PCSK9i and PCSK9-targeting siRNA to placebo on background of standard lipid-lowering therapies; (3) included HeFH or HoFH; (4) in adults or paediatric populations; (5) had at least one outcome of interest and (6)were published in the English language. We excluded (1) non-RCT (2) studies with overlapping populations; (3) studies with an absence of a control group and (4) studies involving head-to-head comparisons of PCSK9-targeting therapies.

Endpoints

Outcomes of interest included LDL-C, TGL, ApoB and Lp(a) percentage changes from baseline when comparing PCSK9-targeting therapies (PSCK9i and siRNA therapies) to the control group (placebo on the background of standard lipid-lowering therapies).

The primary safety endpoint was serious adverse events (defined as fatal, life-threatening, required admission to hospital or prolonged stay in hospital, persistent or significant disability or incapacity, congenital anomaly or birth defect, and growth negative impact in paediatric population) related to the drug, and adverse events with treatment discontinuation (injection-site reactions).

Statistical analysis

We used the Mantel-Haenszel random-effects model for all outcomes. We pooled ORs with 95% CIs for binary endpoints, and weighted mean differences (MDs) for continuous outcomes. All tests were two-tailed, and statistical significance was defined at a p<0.05. Means and SDs were estimated if necessary. Heterogeneity was assessed using Cochrane’s Q test and Higgins and Thompson’s I² statistics, with p≤0.10 indicating statistical significance. We determined the consistency of the studies based on I² values of 0%, ≤25%, ≤50% and >50%, indicating no heterogeneity, low heterogeneity, moderate heterogeneity and substantial heterogeneity, respectively. Statistical analyses were conducted using Review Manager (RevMan) V.5.4 (Cochrane Center, The Cochrane Collaboration, Denmark).

Subgroup analysis

Subgroup analyses were conducted to assess differences in treatment efficacy and safety across key clinical and therapeutic factors. Analyses were performed based on: (1) FH subtype (HeFH vs HoFH); (2) drug type and dosing regimen and (3) age group (paediatric vs adult patients). Studies were grouped accordingly, and separate pooled effect estimates were calculated for each subgroup. Statistical differences between subgroups were evaluated using the χ² test for subgroup differences, with significance defined as p<0.05.

Quality assessment

Two independent authors (VQTH and NBT) performed quality assessments of RCTs using the Cochrane Collaboration’s tool for assessing risk of bias in randomised trials (RoB-2). Any disagreements were resolved by consensus between the authors. Publication bias was investigated using a funnel-plot analysis of point estimates and study weights. Leave-one-out sensitivity analyses were performed to ensure the results were not dependent on a single study.

Certainty of the body of evidence

We assessed the certainty of evidence for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, considering five domains: risk of bias, inconsistency, indirectness, imprecision and publication bias. Two reviewers (VQTH and NN) independently rated each outcome, resolving discrepancies by consensus. The Summary of Findings table presents the key results, including effect estimates, CIs, study counts and GRADE ratings (online supplemental file 2).

Sensitivity analysis

We performed leave-one-out sensitivity analyses for all lipid biomarkers and adverse event outcomes to explore potential causes of heterogeneity and ensure no single study disproportionately influenced the pooled estimate. Meta-regression analysis was performed to examine the relationship between highly heterogeneous outcomes and baseline lipid biomarker levels, combined treatment and follow-up time. Small-study effects and publication bias were evaluated with Egger’s test and trim-and-fill adjustments. Analyses were conducted in accordance with the PRISMA guidelines.¹⁹

Patient and public involvement

Patients and the public were not involved in the design, conduct, reporting or dissemination plans of this study.

Results

Baseline characteristics

The search strategy yielded 762 results (figure 1). After removing duplicates and screening titles and abstracts, 26 studies were selected for full-text review. Based on eligibility criteria, 18 studies met all inclusion criteria.1416 20,34 One of the included studies reported pooled results from six RCTs of the SPIRE trial series (SPIRE-1, SPIRE-2, SPIRE-FH, SPIRE-HR, SPIRE-LDL, SPIRE-LL), comparing bococizumab versus placebo in FH patients, without overlapping populations.²⁰ Therefore, we included 23 RCTs. Of the 23 included RCTs, 3 studies were conducted exclusively in HoFH patients, including ODYSSEY HoFH, TESLA part B and ORION-5,^{26 29 31} while the remaining studies enrolled HeFH patients. The baseline characteristics are summarised in table 1. A total of 4282 FH patients were enrolled, receiving five types of PCSK9 targeting therapies, including alirocumab, bococizumab, evolocumab, tafolecimab and inclisiran. The mean age of the studies ranged from 12.9 to 58.7 years, with two RCTs, Santos 2024 and HAUSER-RCT, conducted in the paediatric population.^{21 22} The follow-up duration ranged from 12 weeks to 78 weeks, with the mean baseline LDL-C levels ranging from 133.56±25.31 to 348.03±135.34 mg/DL. In two studies ORION-15 and ORION-18, baseline characteristics specific to the FH subgroup were not reported.^{33 34} Therefore, the baseline characteristics for these studies are not included in table 1.

Figure 1. PRISMA flow diagram of study screening and selection. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Efficacy outcomes

In the included 23 RCTs, PCSK9-targeting therapy (PSCK9i and siRNA therapy) showed statistically significant LDL-C reduction (MD=−46.64%; 95% CI −50.77% to –42.52%; p<0.00001; I²=82%, figure 2) compared with placebo. Another notable finding was the significant reduction in ApoB levels (MD=−34.94%; 95% CI –40.89% to –28.99%; p<0.00001; I²=94%, figure 3), Lp(a) (MD=−22.70%; 95% CI −25.95% to –19.44%; p<0.00001, I²=47%, figure 4) and TGL (MD=−15.18%; 95% CI −19.34% to –11.03%; p<0.00001, I²=52%, (online supplemental figure S1).

Figure 2. LDL-C was statistically significantly reduced with PCSK9 targeting therapies when compared with control group (placebo on the background of standard lipid-lowering therapy) (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; LDL-C, low-density lipoprotein cholesterol; MD, mean difference; RCT, randomised controlled trial.

Figure 3. Apolipoprotein B was statistically significantly reduced with PCSK9 targeting therapies when compared with control group (placebo on the background of standard lipid-lowering therapy) (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; MD, mean difference; RCT, randomised controlled trial.

Figure 4. Lipoprotein (a) was statistically significantly reduced with PCSK9 targeting therapies when compared with control group (placebo on the background of standard lipid-lowering therapy) (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; MD, mean difference; RCT, randomised controlled trial.

Paediatric populations displayed a substantial reduction of LDL-C levels (MD=−38.15%; 95% CI –43.57% to –32.73%; p<0.00001; I²=0%, figure 2) as well as reduction in levels of ApoB (MD=−33.66%; 95% CI% –38.16 to –29.15%; p<0.00001; I²=0%, figure 3) and Lp (a) (MD=−17.1%; 95% CI –26.43% to –7.78%; p=0.0003; I²=0%, figure 4).

HeFH populations demonstrated a significantly greater response to treatment compared with HoFH populations in the reduction of LDL-C, ApoB and TGL. Among the studies reporting on HeFH patients, PCSK9-targeting therapies led to a significant mean reduction in LDL-C of (MD=–48.50%; 95% CI –52.49% to –44.50%; p<0.00001; I²=80 (online supplemental figure S2). In contrast, the pooled analysis of 3 studies involving HoFH patients showed a smaller LDL-C reduction (MD=−25.98%; 95% CI −41.68% to –10.27%; p=0.001; I²=62%, online supplemental figure S2). Similarly, for ApoB reduction, HeFH patients demonstrated a significantly greater treatment response (MD=−36.76%; 95% CI –43.02% to –30.50%; p<0.00001; I²=95%, online supplemental figure S3) compared with those with HoFH (MD=−21.47%; 95% CI −33.37% to −9.56%; p=0.0004; I²=55%, online supplemental figure S3). For TGL reduction, the effect was also more pronounced in the HeFH subgroup (MD=−16.50%; 95% CI −20.59% to –12.42%; p<0.00001; I²=47%, online supplemental figure S4). In contrast, the TGL reduction observed in HoFH patients was smaller and not statistically significant (MD=−5.67%; 95% CI −17.03% to 5.70%; p=0.33; I²=23%, online supplemental figure S4). The reduction in Lp(a) levels was comparable between HeFH and HoFH populations. In HeFH, the MD was −22.96% (95% CI –26.34% to –19.59%; p<0.00001; I²=48%, online supplemental figure S5), while in HoFH it was −20.04% (95% CI –36.30% to –3.77; p=0.02; I²=68%, online supplemental figure S5).

Safety outcomes

Injection site adverse effects were significant in PCSK9-targeting therapies vs the control group (OR=4.67; 95% CI 3.76 to 5.8; p<0.00001; I²=65%; figure 5). Serious adverse effects associated with PCSK9-targeting therapies vs the control group show no statistically significant difference between the two groups (OR=0.99; 95% CI 0.8 to 1.23; p=0.93; I²=0%; online supplemental figure S6). Similarly, adverse effects leading to treatment discontinuation showed no statistically significant difference between the PCSK9-targeting therapies and the control groups (OR=1.31; 95% CI 0.93 to 1.85; p=0.12; I²=0%; online supplemental figure S7).

Figure 5. Injection site adverse effects caused by subcutaneous injections periodically were statistically increased in the PCSK-9 targeting therapies group when compared with the control group (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; M-H, Mantel-Haenszel; RCT, randomised controlled trial.

In the paediatric populations, the analysis of height impact between PCSK9-targeting therapies and the control group showed no significant difference (MD=0.03 cm; 95% CI −0.41 to 0.47; p=0.89; I²=0%; online supplemental figure S8).

Heterogeneity analysis

Substantial heterogeneity with I² above 50% was observed for LDL-C (I²=82%), ApoB (I²=94%) and TGL (I²=52%), whereas Lp(a) showed moderate heterogeneity (I²=47%). Subgroup differences were significant in LDL-C (I²=73.5%), ApoB (I²=74.3%), Lp(a) (I²=47.8%) and TGL (I²=74.3%). All findings remained consistent across both fixed and random-effects models.

Injection site adverse events also showed substantial heterogeneity (I²=65%), with SPIRE trials and ODYSSEY FH I identified as major contributors. Their exclusion via leave-one-out analysis reduced I² to 10% and 41%, respectively (online supplemental figure S9a and b).

In the LDL-C outcome, leave-one-out analysis within the subgroups identified key sources of heterogeneity: excluding Stein 2012 (Alirocumab 150 mg Q2W) and TESLA Part B (Evolocumab 420 mg Q4W) reduced I² to 0% in their respective subgroups (online supplemental figure S10, S11). In the Inclisiran subgroup, excluding ORION-5 lowered I² from 80% to 63% (online supplemental figure 12). Moreover, including only ORION-15 and ORION-18 (both 300 mg, Asian cohorts) resulted in I²=0% and a larger LDL-C reduction (MD=−65.60%) compared with the full subgroup (MD=−46.64%; online supplemental figure S13).

Meta-regression analysis revealed that changes within the placebo cohorts and the year of publication were not significant contributors to the variability in LDL-C, ApoB, Lp(a) or TGL results. Similarly, for injection site adverse effects, year of publication did not significantly drive heterogeneity, with differences in sample size showing a borderline effect (p=0.0747). Influence diagnostic plots of all findings with high heterogeneity confirmed the results of the leave-one-out analysis, noting all the mentioned studies as prominent influential outliers that drove heterogeneity. Finally, trim-and-fill analysis detected no significant publication bias for LDL-C results. For ApoB and Lp(a), minor publication bias was detected. However, the adjusted effect size remained statistically significant. Four potentially missing studies on the left side of the funnel plot were identified for TGL results (online supplemental figure S14), suggesting that the actual effect may be more substantial than the calculated one. Finally, assessment of the OR for injection site adverse events estimated 10 missing studies on the right side of the funnel plot (online supplemental figure S15). After adjusting for bias, the OR increased, suggesting that smaller studies with non-significant or negative results may be under-represented.

Risk of bias assessment

Using the Cochrane Risk of Bias Tool (version 2), we identified 15 of the included studies as having a low risk of bias. Three studies, CREDIT-2, ODYSSEY HoFH and ODYSSEY ESCAPE, were rated as having some concerns regarding the risk of bias. The risk of bias assessment is detailed in online supplemental table S1.

Certainty of the body of evidence

Moderate certainty is reported in five outcomes, including the LDL-C, ApoB, injection site adverse effects, serious adverse effects and adverse effects leading to treatment discontinuation. Lp(a) reported high certainty of evidence, while TGL shows low certainty (Summary of Findings table, online supplemental file 4).

Discussion

This meta-analysis demonstrates that PSCK9-targeting therapies, such as PCSK9i and siRNA, in adults and paediatric patients with HeFH and HoFH are associated with significantly lower rates of LDL-C, ApoB, TGL and Lp(a) levels, with acceptable safety profiles maintained throughout the follow-up period. The substantial heterogeneity observed likely reflects variations in baseline characteristics, including LDL-C levels, comorbidities and ethnicities. Despite this variability, sensitivity analyses confirmed that LDL-C reductions remained consistently significant across subgroups, underscoring the robustness of PCSK9-targeting therapies. In the Alirocumab 150 mg Q2W subgroup, Stein 2012 emerged as a key source of heterogeneity. This may be attributed to its notably lower baseline LDL-C level (155.07 mg/dL) compared with ODYSSEY ESCAPE (181.11 mg/dL), ODYSSEY HIGH FH (197.85 mg/dL) and ODYSSEY HoFH (282.7 mg/dL), all of which demonstrated more consistent effect sizes (table 1). Similarly, in the Evolocumab 420 mg Q4W subgroup, TESLA Part B likely drove heterogeneity due to its exclusive inclusion of patients with HoFH, whereas RUTHERFORD and RUTHERFORD 2 enrolled HeFH patients. These distinct population profiles likely contributed to the observed between-study variability.

Sensitivity analysis also revealed that using Inclisiran 300 mg exclusively in Asian populations (ORION-15 and ORION-18) resulted in low heterogeneity (I²=0%) and significantly greater LDL-C reduction than the entire Inclisiran subgroup (MD=−65.6% compared with MD=−46.64%). This suggests that Asian FH patients may exhibit a particularly strong and consistent response to Inclisiran. Notably, this finding aligns with previous evidence showing that compared with other populations, Asian patients achieve greater LDL-C reductions with Alirocumab, a PCSK9 targeting therapy.³⁵ Our findings suggest that Inclisiran may offer greater LDL-C reduction in Asian FH patients, underscoring the potential for personalised therapy. Further research is needed to clarify the mechanisms behind this enhanced response.

Subgroup analyses revealed that patients with HeFH consistently experienced greater efficacy from PCSK9-targeting therapies compared with those with HoFH, including the reduction in LDL-C, ApoB and TGL. This may reflect the differences in underlying pathophysiology between the two conditions, as HoFH patients typically have minimal or absent LDL-R activity, potentially limiting the efficacy of PCSK9 inhibition.⁵ In contrast, Lp(a) reduction appeared similar between HeFH and HoFH populations, suggesting that the mechanism of PCSK9-targeting therapies on Lp(a) may be independent of LDL-R function. These findings support the use of PCSK9-targeting therapies as especially effective in HeFH patients.

FH is a genetic disorder marked by lifelong elevated LDL-C levels due to mutations in LDLR, LDLRAP1, APOB or PCSK9, which impair LDL-C clearance and accelerate ASCVD development. PCSK9 promotes LDL-R degradation, reducing clearance efficiency. Targeting PCSK9 with monoclonal antibodies or siRNA therapies has proven effective in lowering LDL-C levels. PCSK9 monoclonal antibodies inhibit the protein’s function extracellularly, whereas siRNA therapies reduce hepatic PCSK9 synthesis intracellularly, both resulting in increased LDL-R availability and enhanced LDL-C clearance (figures6 7).

Figure 6. Mechanism of action of PCSK9 inhibitors. Left panel: Without PCSK9 inhibitors, PCSK9 binds to LDL receptors (LDLR) on hepatocytes, promoting receptor degradation and reducing LDL clearance, leading to elevated LDL blood levels. Right panel: PCSK9 inhibitors block PCSK9 from binding to LDLR, promoting LDLR recycling and an increase in LDL clearance, resulting in lower LDL-C levels in the bloodstream. Image created with BioRender. LDL-C, low-density lipoprotein cholesterol.

Figure 7. Mechanism of action of Inclisiran for hypercholesterolaemia. Inclisiran, a small interfering RNA (siRNA) with a GalNAc tail, binds to asialoglycoprotein receptors (ASGPR) on hepatocytes, facilitating its uptake. Inside the cell, Inclisiran forms a RISC complex that binds to PCSK9 mRNA, leading to its degradation and reduced PCSK9 production. Lowered PCSK9 levels result in increased LDL receptor recycling and enhanced clearance of LDL from the bloodstream, causing reduction in LDL-C levels. Image created with BioRender. LDL-C, low-density lipoprotein cholesterol.

Statins and ezetimibe are cornerstone therapies for lowering LDL-C and reducing CV risk.⁶ However, their efficacy is often limited in patients with FH, particularly in HoFH, due to the genetic underpinnings of the disorder.⁵ Statins function by inhibiting HMG-CoA reductase, leading to upregulation of LDL-R and increased clearance of LDL-C.⁸ Ezetimibe inhibits intestinal cholesterol absorption, reducing the amount of cholesterol delivered to the liver and subsequently lowering LDL-C levels.⁸ Studies have demonstrated that while statin and ezetimibe can greatly reduce LDL-C levels in the general population, their impact is attenuated in FH patients.⁴ The limited efficacy of statins and ezetimibe in FH underscores the need for alternative or adjunctive therapies. PCSK9i, such as alirocumab and evolocumab, has emerged as effective options, offering significant LDL-C reductions even in HoFH populations.^{26 29} Additionally, Inclisiran, a siRNA therapy targeting PCSK9 synthesis, provides a novel mechanism of action with the convenience of biannual dosing, further enhancing patient adherence and lipid control.¹⁰

In addition to their potent LDL-C lowering effect, PCSK9-targeting therapies have shown promising results in improving vascular health. In a prospective observational study, treatment with PCSK9 inhibitors led to a significant reduction in pulse wave velocity (PWV), a marker of arterial stiffness, and in inflammatory markers such as the monocyte-to-HDL-cholesterol ratio, suggesting a beneficial impact on vascular function and systemic inflammation in patients with FH.³⁶ Another study evaluating inclisiran in a real-world setting found a 14.4% reduction in PWV over 6 months, further suggesting that this novel therapy may enhance vascular health together with its lipid-lowering effects.³⁷

Although PCSK9i have demonstrated strong efficacy in reducing LDL-C levels, real-world adherence and persistence remain relevant challenges. The AT-TARGET-IT study revealed that while overall adherence was high (95.2%), a small proportion of patients showed partial (1.6%) or poor adherence (3.1%).³⁸ These findings highlight that despite strong efficacy, patient adherence can be affected by injection concerns, side effects and a lack of understanding of LDL-C goals. In clinical practice, improving patient education, addressing injection-related concerns and ensuring consistent follow-up could enhance adherence and persistence with PCSK9-targeting therapies. Inclisiran, with its twice-yearly dosing regimen following initial loading doses, may offer a practical advantage in this regard. By reducing the frequency of administration, Inclisiran has the potential to enhance adherence compared with more frequently dosed monoclonal antibodies. Moreover, inclisiran’s favourable tolerability profile and infrequent dosing regimen also make it an attractive option for patients who are intolerant to statins, which is a common problem in routine clinical practice.³⁹

Compared with previous literature, this meta-analysis provides a more comprehensive and clinically relevant pooled analysis by incorporating 23 RCTs with 4282 patients in both adult and paediatric populations, including HeFH and HoFH patients. Notably, previous meta-analyses^{40 41} did not include paediatric and HoFH populations. Unlike prior studies,^{40 41} which focused primarily on monoclonal antibodies or LDL-C outcomes alone, our analysis evaluated a broader range of PCSK9-targeting therapies, including Inclisiran and less studied agents such as tafelocimab and bococizumab and examined multiple lipid biomarkers (LDL-C, TGL, ApoB and Lp(a)). We also included paediatric-specific outcomes such as height impact and assessed tolerability through adverse events leading to discontinuation, which were not addressed in earlier meta-analyses. By comparing these therapies to placebo on the background of standard lipid-lowering treatment, our findings better reflect real-world practice.

PCSK9-targeting therapies, including the recent addition of Inclisiran, have expanded treatment options for FH patients. Their favourable safety profile and ability to lower LDL-C, ApoB and Lp(a) support their role as a key therapy for CV risk reduction in FH patients. Additionally, emerging treatments like ANGPTL3 inhibitors show promise for difficult cases, such as HoFH and severe hypertriglyceridaemia.⁴²

Study limitations

Heterogeneity in trial designs and populations warrants cautious interpretation of pooled estimates. Furthermore, long-term CV outcomes associated with Inclisiran remain under investigation, particularly in ORION-5, which includes a more severely affected HoFH population. While ORION-15 and ORION-18 demonstrated promising short-term efficacy in LDL-C reduction, especially among Asian cohorts, both studies lack detailed reporting of baseline characteristics specific to FH patients. This limits the ability to fully contextualise the observed responses and assess the generalisability of findings to broader FH populations. ORION-15 and ORION-18 also lack report of safety outcomes specific to FH patients.

Conclusions

PCSK9i and Inclisiran are highly effective in lowering LDL-C levels in FH patients, demonstrating sustained efficacy across various subgroups, including the paediatric population. HeFH patients showed a greater response to PCSK9-targeting therapies compared with HoFH patients, particularly in reducing LDL-C, ApoB and TGL levels. Asian FH cohorts demonstrated a notably stronger LDL-C response to Inclisiran compared with the overall FH population. In addition to LDL-C reduction, these therapies significantly lower ApoB and Lp(a) levels, and to some extent, TGL levels, providing CV benefits by targeting multiple lipid biomarkers associated with ASCVD risk. Furthermore, these therapies have a favourable safety profile, with minimal significant adverse events reported, making them a well-tolerated and promising treatment option for patients with persistently high LDL-C levels despite standard lipid-lowering therapies. Long-term follow-up, especially with siRNA therapy, is necessary for a better understanding of this new and revolutionary drug class in the HF population.

Data availability statement

Data are available in a public, open access repository.