PCSK9 Inhibitors for Familial Hypercholesterolemia Not Dependent on Gene Mutation

Ilenia Calcaterra, MD

PCSK9 inhibitor response does not appear to be correlated with mutation types among patients with familial hypercholesterolemia (FH), according to a new study which assessed evolocumab (Repatha) and alirocumab (Praluent) in patients with the common hereditary autosomal disease.

In new data presented virtually during the European Society of Cardiology (ESC) 2020 Congress this week, a team of investigators from Federico II University Hospital in Florence, Italy, reported new interpretations of PCSK9 inhibition among patients with differing mutations of FH.

Led by Ilenia Calcaterra, MD, the team sought to evaluate LDLR gene mutations relative to their response to evolocumab—an inhibitor agent which they noted has changed the approach to FH therapy.

Their observed population included 73 patients with FH. Mean patient age was 53.9 years old, with 33 (45.2%) women. Most patients (n = 46 [63%]) were in primary prevention at recruitment.

Regarding LDLR gene mutations, patients primarily reported heterozygotes for missense mutations (n = 31) or null mutations (n = 31). The remaining 11 patients reported compound heterozygotes or homozygotes.

All patients at baseline were being treated with maximally tolerated lipid lowering therapy without PCSK9 inhibitors. Just 16 patients reported intolerance to such therapy regimen. Investigators prescribed add-on alirocumab to 45 patients and evolocumab to 28 patients.

Calcaterra and colleagues evaluated the achievement of LDL cholesterol (LDL-C) <70 mg/dL among primary prevention and LDL-C <55 mg/dL among patients without diabetes mellitus at 160 days post-PCSK9 inhibitor initiation.

Among the PCSK9 inhibitor-treated patient group, 29 (39.7%) achieved the LDL-C goal at 160 days—split almost evenly among primary prevention (n = 14) and secondary prevention (n = 15) subpopulations.

LDL-C goals were achieved by 15 (48.3%) of FH patients with missense mutation and 14 (45.1%) of patients with null mutation, with no significant difference in clinical benefit observed across either group. None of the 11 patients with compound heterozygotes or homozygotes achieved the LDL-C goal at 160 days.

Just 3 (18.7%) of the patients with maximally tolerated lipid lowering therapy intolerance achieved the goal.

Calcaterra and colleagues concluded there was a lack of correlation among mutation types in patients with heterozygous FH being treated with evolocumab or alirocumab.

“Response was significantly poorest in patients with compound heterozygosis or homozygosis mutation as compared to heterozygotes,” they wrote. “The intolerance to maximally tolerated lipid lowering therapies was significant in the achievement of the goal of LDL-C.”

The study, “Changes in markers of subclinical atherosclerosis in patients with familial hypercholesterolemia treated with evolocumab: a prospective cohort study,” was presented at ESC 2020.