The Addition of Ezetimibe to Statin therapy in Patients with Homozygous Familial Hypercholesterolaemia Submitted in fulfilment with the requirements for the degree Master in Medicine (MMed) Dr Adriano Luke Dello-Iacono Bsc (Hons), MBBCh (Wits) Registrar, Department of Medicine University of the Witwatersrand 0105531H i
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 ii
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/m 2 and 24 ± 7.1 kg/m 2 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 iii
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. iv
DECLARATION I, Dr Adriano Dello Iacono declare that this research report is my own work. It is being submitted for the degree of Master of Medicine in the Department of Internal Medicine, Faculty of Health Sciences, at the University of Witwatersrand, Johannesburg. It has not been submitted before for any degree or examination at this or any other University. Dr Adriano Dello Iacono BSc(Hons), MBBCh (Wits). v
DEDICATION To my supervisor, Professor Frederick Raal, whose guidance, wisdom and expertise were always available. He has been a role model for me throughout my under and post-graduate studies To my amazing girlfriend, Samantha Lake, for her love, understanding, motivation and inspiration. To my parents Antonio and Antoinette Dello Iacono for their constant support, love and encouragement. To my Sister Francesca Burger and brother in law Josh Burger, for their guidance and motivation. To all other members of my family and friends not mentioned above, for their support, love and encouragement. vi
TABLE OF CONTENTS pages ABSTRACT...ii DECLARATION v DEDICATION...vi LIST OF TABLES....ix LIST OF FIGURES..x ABBREVIATIONS....xi LITERATURE REVIEW Introduction.. 1 Homozygous Familial Hypercholesterolaemia (HoFH)...1 Diagnosis....4 Cholesterol..5 Lipid Metabolism....6 Exogenous pathway.. 6 Endogenous pathway...9 Treatment options. 13 Statins. 13 Ezetimibe...14 Lomitapide...14 Mipomersen...15 PCSK9 Inhibition...15 LDL Apheresis...15 STUDY OBJECTIONS:... 16 METHODS Study design.....17 Study population... 17 Inclusion criteria...18 Exclusion criteria......18 Ethics......18 Data collection and analysis... 18 Statistics..20 vii
Pages RESULTS....21 DISCUSSION.. 39 CONCLUSION....46 REFERENCES...48 APPENDIX..53 viii
LIST OF TABLES Pages TABLE 1: Demographics of patients in study.22 TABLE 2: Mean ± SD of total cholesterol, LDL-C, HDL-C, Median Triglycerides 27 at baseline, 3 months and 6 months in total study group TABLE 3: Mean LDL-C and mean percentage change between normal and...30 overweight groups at baseline and 3 months TABLE 4: Mean LDL-C and Mean LDL-C percentage change in FH1/FH1 and..31 FH1/FH2 at baseline and 3 months TABLE 5: Mean LDL-C percentage change and mean LDL-C at baseline and...33 3 months in males and females TABLE 6: Demographics between responders and non-responders...35 TABLE 7: Mean ± SD of LDL-C between responders and non-responders at 37 baseline, 3 months and 3 months. Mean percentage change of LDL-C, HDL-C, and triglycerides from baseline at 3 months and 6 months TABLE 8: Comparison of mean total cholesterol, LDL-C, HDL-C and TG at...40 baseline between current and previous study TABLE 9: Comparison of mean percentage change of LDL-C at 3 months..41 and mean total cholesterol, LDL-C, HDL-C and TG at 3 months, between current and previous study. ix
LIST OF FIGURES pages FIGURE 1: Exogenous pathway..8 FIGURE 2: Endogenous pathway...10 FIGURE 3: Reverse Cholesterol Transport 12 FIGURE 4: Total mean BMI for males and females.23 FIGURE 5: Mean BMI (body mass index) amongst males and females above the age of 20 years...23 FIGURE 6: Mean BMI (body mass index) amongst males and females below the age of 20 years 24 FIGURE 7: The percentage of smoking statuses amongst genders.25 FIGURE 8: Percentage of patients with both aortic stenosis and IHD..25 FIGURE 9: Percentage of patients with only based on gender....26 FIGURE 10: Percentage of patients with only aortic stenosis based on gender...26 FIGURE 11: Percentage break down of the statins and doses at baseline...27 FIGURE 12: Mean LDL-C at baseline, 3 months and 6 months...28 FIGURE 13: Mean total cholesterol at baseline, 3 months and 6 months 29 FIGURE 14: Graphical representation of mean LDL-C between normal and.30 overweight population groups FIGURE 15: Mean percentage change of LDL-C between normal and 31 overweight population at 3months FIGURE 16: Mean LDL-C at baseline and 3 months amongst..32 FH1/FH1 and FH1/FH2 population groups FIGURE 17: Mean percentage change from baseline of LDL-C between...33 FH1/FH1 and FH1/FH2 population groups FIGURE 18: Mean LDL-C between males and female. 34 at baseline and 3 months FIGURE 19: Mean percentage change from baseline in LDL-C between males 34 and females FIGURE 20: Pie chart illustrating percentage make up of each mutation group 36 FIGURE 21: Mean LDL-C at baseline, 3 months and 6 months between.. 38 responders and non-responders FIGURE 22: Mean percentage change of LDL-C between responders and..38 non-responders from baseline at 3 months and 6 months x
ABBREVIATIONS APOB Apolipoprotein B APOC2 Apolipoprotein C2 APOE Apolipoprotein E BMI Body Mass Index CAD Coronary artery disease CE Cholesteryl Esters CI Confidence Intervals CMJAH Charlotte Maxeke Johannesburg Academic Hospital FFA Free fatty Acids FH Familial Hypercholesterolaemia FH1 Afrikaner 1 mutation FH2 Afrikaner 2 mutation FH3 Afrikaner 3 mutation HDL-C High Density Lipoprotein-cholesterol HeFH Heterozygous Familial Hypercholesterolaemia HMG-COA Hydroxymethylglutaryl Co-enzyme A HoFH Homozygous Familial Hypercholesterolaemia IHD Ischaemic Heart Disease LCAT Lecithin Cholesterol Acyltransferase LDL-C Low Density Lipoprotein-cholesterol LDL Low Density Lipoprotein LDLR Low Density Lipoprotein Receptor LDLRAP1 Low Density Lipoprotein Receptor Adapter Protein 1 LPL Lipoprotein Lipase mrna Messenger Ribonucleic acid MTP Microsomal triglyceride transfer protein NPC1L1 Niemann Pick C1 Like 1 PCSK9 Proprotein Convertase Subtilisin/Kexin type 9 PLTP Phospholipid transfer protein RCT Reverse Cholesterol Transport SD Standard Deviation SR-B1 Scavenger Receptor B1 SREBP Sterol Regulatory Element Binding Protein TG Triglycerides TIA Transient Ischaemic Attack VLDL Very Low Density Lipoprotein xi