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].