DISCUSSION
HoFH remains underdiagnosed and often identified too late, leading to suboptimal treatment despite the availability of several LLTs for reducing LDL-C [2, 34]. Also, guideline-recommended LDL-C targets are rarely achieved in these patients, largely due to the heterogeneous nature of the condition, which results from its diverse genetic and phenotypic presentations. Consequently, achieving optimal LDL-C levels is challenging, and newer therapies are typically added to existing treatments rather than replacing them. This practice complicates accurate evaluation of the individual efficacy of new therapies, as issues of external validity and generalizability arise from the wide variety of background treatments [1, 35, 36]. To our knowledge, this is the first meta-analysis that compares the efficacy and safety of PCSK9i and ANGPTL3i in HoFH patients. The results of our meta-analysis, which included 12 RCTs involving 392 early adult patients with HoFH and a median follow-up of 6 months, demonstrate a greater reduction in the lipid profile (TC, LDL-C, TG) and lipoproteins such as ApoB and Lp(a) in patients treated with ANGPTL3i compared to those receiving PCSK9i. Conversely, HDL-C showed a slightly greater increase in the PCSK9i groups, while Apo A levels remained unaffected in both treatment groups.
PCSK9 monoclonal antibody therapy (evolocumab or alirocumab, at approved doses for HoFH) has shown significant efficacy in reducing LDL-C levels for many patients with HoFH [22, 23, 24, 25, 26, 25, 37, 38]. However, the extent of LDL-C reduction can vary widely depending on the activity of the LDL receptor (LDLR), as well as individual genetic factors influencing response to treatment. Pharmacogenetic profiling may help predict the effectiveness of these therapies, and in some cases, the treatment response is best assessed through a trial of different therapeutic approaches [1, 2, 35]. Based on the 2023 European Atherosclerosis Society Consensus Statement on HoFH, if patients show continue [1, 7]. This variability underscores the importance of personalized treatment strategies for achieving optimal lipid control in HoFH patients. On the other hand, ANGPTL3 monoclonal antibody, targets angiopoietin-like protein 3, which plays an important role in regulating lipid-lipoprotein metabolism. Licensed for patients with HoFH aged ≥12 years, evinacumab gained approval based on results from the Phase 3 ELIPSE HoFH trial [1, 29]. Importantly, response to evinacumab was not dependent on LDL receptor (LDLR) genotype, with similar outcomes in patients with bi-allelic null variants or those with predicted residual LDL receptor function. Despite the difference in the pharmacokinetics of these two medications, at the end of the follow-up period, no significant differences were found between the treated groups in terms of the prevalence of treatment-emergent adverse events or treatment discontinuation.
The age-based subgroup analysis was of interest. It revealed a significantly greater reduction in mean LDL-C in adults compared to children, only in the PCSK9i resulted patients but not in the ANGPTL3i ones (p = 0.22). While the exact mechanism behind such differences remains incompletely understood, we hypothesize that the higher baseline LDL-C levels in the pediatric cohorts treated with PCSK9 inhibitors, compared to patients treated with ANGPTL3 inhibitors, may explain the difference in the age related treatment effect. The genotypic findings from our meta-analysis suggest a plausible higher reduction in LDL receptor (LDLR) activity, given that the cohort was relatively young and presented with markedly elevated LDL-C levels at baseline, potentially reflecting significant LDLR dysfunction. Furthermore, patients with baseline LDL-C levels greater than 13 mmol/L (500 mg/dL) did not achieve consistent lipid-lowering effects with PCSK9i, in contrast to those with lower baseline LDL-C levels (<13 mmol/L or <500 mg/dL), thus further supporting the hypothesis of LDLR impairment. In summary, the variability in responses to ANGPTL3i and the apparent discrepancies compared to other studies may be attributable to the LDLR genotype of the patient population [26, 27, 33, 35, 39, 40].