LDL-C Targets in Patients with Heterozygous Familial Hypercholesterolemia

Even with maximum intensity statin/ezetimibe treatment, most of the patients with familial hypercholesterolemia (FH) do not achieve the latest low-density lipoprotein cholesterol (LDL-C) targets; highlighting the necessity for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and additional LDL-C lowering therapy.

• ESC/EAS 2019 guidelines recommend more aggressive LDL-C targets for patients with FH.
• PCSK9i are recommended in very high-risk patients with FH if the treatment goal is not attained on maximal tolerated statin plus ezetimibe and in FH patients who cannot tolerate statins.
• However, it is currently unknown how many patient with FH are candidates for PCSK9i under 2019 ESC/EAS guidelines and in how many of them a fourth LDL-C lowering agent will be required.

• In total, 1,694 adult patients (860 male) were enrolled in this analysis, mean age of 50.8 ± 14.7 years old.
  • A total of 430 patients had established atherosclerotic cardiovascular disease.
  • Among patients, 61.4% (n = 1,040) had a target LDL-C of ≤55 mg/dL and the rest (38.6%, n = 654) a target of ≤70 mg/dL
  • Most treated patients were receiving a statin (97.5%) and about half were receiving additional ezetimibe (46.3%) and 4.9% were treated with a PCSK9i

• On-treatment LDL-C was 130 ± 49 mg/dL (3.4 ± 1.3 mmol/L). Almost half of patients (47.3%) had an LDL-C reduction >50% than baseline.
  • When 2019 ESC/EAS guidelines were applied to an FH cohort, the LDL-C goals achievement was only 2.7%
  • In sub-group of patients with LDL-C targets of ≤55 mg/dL and ≤70 mg/dL, only 2.2% and 3.6% achieved target, respectively (P = 0.146 between groups)
• After theoretical optimization of therapy to rosuvastatin/ezetimibe 40/10 mg daily, mean LDL-C level was 90 ± 26 mg/dL (2.3 ± 0.7 mmol/L).
  • Increase of ESC/EAS 2019 target achievement rate was 5.9%
  • In sub-group of patients with LDL-C targets of ≤55 mg/dL and ≤70 mg/dL, 3.0% and 10.8% achieved target, respectively (P <0.001 between groups)
  • Significant percentage of patients (55.9%) would be eligible for PCSK9i treatment despite receiving rosuvastatin/ezetimibe 40/10 mg
• After theoretical administration of rosuvastatin/ezetimibe 40/10 mg plus PCSK9i (for those who were eligible):
  • LDL-C target achievement rate would rise to 57.6%
  • However, 42.4% of patients would still be eligible for further LDL-C lowering treatment
  • In sub-group analysis of patients with LDL-C targets of ≤55 mg/dL and ≤70 mg/dL, 86.3% and 10.8% achieved target, respectively (P < 0.001 between groups)
• In subgroup of patients (n = 337) with DLCN score ≥9 (i.e., definitive diagnosis of FH).
  • Untreated LDL-C levels were 310 ± 90 mg/dL (8.0 ± 2.3 mmol/L)
  • Among patients already on treatment (n = 266), mean LDL-C was 147 ± 60 mg/dL (3.8 ± 1.6 mmol/L) with only 2.6% patients achieving the 2019 ESC/EAS LDL-C target
  • On switching all these patients not reaching LDL-C target as well as untreated patients to rosuvastatin/ezetimibe 40/10 mg, mean LDL-C was 112 ± 33 mg/dL (2.9 ± 0.9 mmol/L) and 3.3% patients reached target
    • 60.2% of patients with definite FH would be eligible for PCSK9i therapy despite receiving rosuvastatin/ezetimibe 40/10 mg versus 55.9% in the whole population.

• Diagnosis of FH was made using the DLCN criteria.
• Participating sites were specialist outpatient lipid clinics.