The addition of ezetimibe to statin therapy in patients with homozygous familial hypercholesterolaemia
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Date
2016-10-17
Authors
Dello-lacono, Adriano Luke
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Abstract
Background: Homozygous Familial hypercholesterolaemia (HoFH) is a rare genetic
disorder affecting approximately one in every million people worldwide. It is
characterized by severely elevated LDL-cholesterol (LDL-C) levels usually as a
result of mutations in both LDL receptor alleles, and is associated with a markedly
increased risk of premature cardiovascular disease with death often occurring in the
first 3 decades of life. Standard treatment with statin therapy has been shown to
yield suboptimal results with additional therapy required to achieve lower LDL-C
levels. As not all centers worldwide have access to newer treatment modalities,
cheaper and more accessible therapy needs to be considered. The addition of
ezetimibe to statin therapy in HoFH individuals has only been reported in one
previous study, but in that study other factors which may have influenced the
response to ezetimibe such as body mass index (BMI), gender and the type of LDLR
mutation were not evaluated
Objectives: Firstly to assess whether the addition of ezetimibe to statin therapy can
result in further reduction in LDL-cholesterol in subjects with HoFH. Secondly, to
assess whether the reduction in LDL-C (response rate) is dependent on the
underlying LDLR mutations, gender and/or BMI. Lastly, to compare HoFH patients
which showed higher responses in LDL-C reduction to ezetimibe (“responders”) to
those who responded poorly (non-responders),
Study design: This was a retrospective study which evaluated HoFH patients known
to the Charlotte Maxeke Johannesburg Academic Hospital’s lipid clinic. All patients
were confirmed to have HoFH and were already on high intensity statin therapy prior
to initiating ezetimibe at a fixed dose of 10mg daily given orally. Their lipograms prior
to ezetimibe initiation were recorded and used as a baseline. In addition, their BMI,
gender, age, FH genotype and cardiovascular complications were recorded. Follow
up lipograms were recorded at 3 and 6 month after ezetimibe initiation.
Results: 48 patients who fulfilled the entry criteria were eligible for the study. Of the
48 patients, 24 were males and 24 females. The average BMI in males was 22.7 ±
6.9 kg/m2 and 24 ± 7.1 kg/m2 in females. The two commonest FH genotypes were
Afrikaner FH1/FH1 (17 patients) and Afrikaner FH1/FH2 (11 patients). Age ranged
between 3 and 48 years with a mean age of 25 years. 65% of patients had
documented coronary artery disease or aortic stenosis. 86% of patients were on high
intensity statin therapy (atorvastatin 80mg or rosuvastatin 40 mg daily) prior to
starting ezetimibe. Despite high intensity statin therapy, mean LDL-C at baseline was
12.1 ± 3.3 mmol/L, decreasing to 10 ± 3.4 mmol/L after 3 months of ezetimibe
therapy, and 10.4 ± 3.3 mmol/L at 6 months (p=0.0018). The mean percentage
reduction of LDL-C on ezetimibe was -18.9% after 3 months and -17.6% at 6
months. There was no significant change in HDL-C or triglyceride levels with the
addition of ezetimibe, p>0.05. Response of LDL-C based on BMI, gender and LDLR
mutation was evaluated at 3 months. Overweight patients had an overall better
response compared to normal weight patients, with a mean percentage reduction of -
20.5% vs -15.7% (p=0.02). A significant difference in response to ezetimibe was also
seen amongst different FH genotypes, with FH1/FH1 having a significant lower mean
LDL-C level at baseline (p=0.04), and a greater reduction in LDL-C following 3
months of ezetimibe therapy compared to FH1/FH2 (-17.5% vs -11.5%, p=0.027).
Lastly, there was no significant difference in LDL-C at baseline or 3 months between
gender. However females tended to show a slightly better mean percentage
reduction at 3 months (-20.7% vs -17%; p = 0.49).When patients were divided into
those who responded to ezetimibe (mean percentage reduction of > 20%), compared
to those with that did not (mean percentage reduction of < 20%), no identifiable
factor such as BMI, gender or FH genotype was shown to be significant in identifying
those patients who were more likely to respond.
Conclusion: Ezetimibe is effective in HoFH and, on top of statin therapy, can reduce
LDL-C by a further 18.9%. Ezetimibe should therefore be considered in all HoFH
patients in order to lower LDL-C levels further. BMI and FH genotype influenced the
response to ezetimibe. However, no single factor was able to predict response in the
individual patient.
Description
Submitted in fulfilment with the requirements for the degree Master in Medicine
(MMed)