Treatment of a patient homozygous for familial defective apolipoprotein B-100 (FDB) with evolocumabRolf L. Andersen, MD, FACC, FNLA, Tina M. Davis, CRNP, Lars H. Andersen, BA, Heidi L. Testa, BSN, Joseluis Ibarra, MD, FACC
Lancaster General Health/Penn Medicine Research Institute
Familial defective apolipoprotein B (FDB) is an autosomal co-dominant
disorder of lipid metabolism characterized by elevated LDL-C and
generally considered to be a type of familial hypercholesterolemia
(FH).1-4 In contrast with autosomal dominant hypercholesterolemia
caused by mutations in LDLR, most cases of FDB identified to date
result from a single mutation in APOB known as R3500Q or
p.Arg3527Gln (rs5742904).5,6 R3500Q appears frequently among
genetically confirmed cases of FH in many European nations.7-11 To
date, relatively few patients homozygous for R3500Q have been
detected, and the phenotypic data and therapeutic responses of these
patients occurred before the release of monoclonal antibody inhibitors of
proprotein convertase subtilisin/kexin type 9 (PCSK9).12-17
We retrospectively analyzed the patient’s electronic health record
to determine the patient’s lipid levels before and after the
addition of PCSK9 inhibitor evolocumab to statin/ezetimibe
therapy. We further examined the subject’s cardiovascular
medical history, recorded lipid values, social history, family
history, genetic status, and concomitant medications.
Background
Objective
Methods
Results
The subject is a male aged 40 with a history of premature ST-elevated myocardial
infarction at age 37 followed by three coronary artery bypass grafts, as well as non-ST-
elevated myocardial infarction at age 39. The subject is a current every day smoker
with a family history of premature coronary artery disease. Prior to treatment, the
subject displayed a maximum LDL-C of 318 mg/dL which was reduced to 180 mg/dL
with atorvastatin 80 mg daily and ezetemibe 10 mg daily. Based on these lipid levels,
the subject was phenotypically diagnosed with heterozygous FH. The subject was
placed on 140 mg/mL evolocumab following its approval as indicated for prior ASCVD
requiring additional lipid-lowering therapy as well as heterozygous FH. The subject’s
LDL-C then dropped from 180 mg/dL to 108 mg/dL, a reduction of 40%. After beginning
evolocumab therapy, the subject received genetic testing demonstrating his status as
homozygous for R3500Q.
ConclusionSimilar to FDB homozygotes previously described, the subject presented with lipid
levels lower than those typically displayed by patients homozygous for mutations in
LDLR, leading to his initial identification as a heterozygote. The disparity between
phenotypic and genotypic diagnosis in the case of this subject demonstrates the
increasing relevance of genetic testing to dyslipidemia, as a diagnosis of homozygous
FDB/FH qualifies the subject for an increase in evolocumab monthly dosage as well as
other adjunct therapies such as mipomersen sodium and lomitapide. While the subject
did not reach NLA lipid goals for patients with prior ASCVD, there was an observed 40%
reduction in LDL-C after treatment with evolocumab 140 mg/mL.18 This may be due to
enhanced LDLR-mediated uptake of VLDL and IDL particles as well as larger LDL
particles as previously described in an FDB homozygote.13
Here we report the first known case study of the use of PCSK9
inhibitors in a patient homozygous for R3500Q. We sought to
determine the effect of PCSK9 therapy (140 mg/mL evolocumab) on the subject’s lipid profile related to goal lipid levels for a patient in secondary prevention. We also compare the subject’s baseline levels to other R3500Q homozygotes previously reported.
Lipid values
(mg/dL)
Off treatment 80 mg atorvastatin
10 mg ezetimibe
80 mg atorvastatin
10 mg ezetimibe
140 mg/mL evolocumab
LDL-C 318 180 108
Non-HDL-C 334 197 125
Triglycerides 87 83 85
HDL-C 44 44 39
VLDL-C 16 17 170
50
100
150
200
250
300
350
Off treatment 80 mg atorvastatin, 10 mgezetimibe
80 mg atorvastatin, 10 mgezetimibe, 140 mg/mL
evolocumab
LD
L-C
(m
g/d
L)
Figure 1. R3500Q homozygous subject lipid levels Figure 2. Lipid levels with increasing treatment intensity
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