23rd ANNUAL CONGRESS Lebanese Society of Endocrinology, Diabetes, and Lipids Cardio-metabolic, Thyroid and Pituitary Diseases 10-11 July 2020 Hilton Habtoor- Beirut - Lebanon Hypercholesterolaemia: a step towards achieving optimal treatment targets and cardiovascular prevention Professor Frederick Raal FCP(SA),FRCP, Cert Endo, MMED, PHD Head, Division of Endocrinology & Metabolism Director Carbohydrate and Lipid Metabolism Research Unit University of the Witwatersrand Presenter Disclosure Information Frederick J. Raal FCP(SA), FRCP, Cert Endo, MMed(Wits), PhD Professor Raal has received research grants, honoraria, or consulting fees for professional input and/or delivered lectures from Sanofi, Regeneron, Amgen, Novartis and The Medicines Company. A case of severe hypercholesterolaemia Mrs. TDK 50 year old female. Well. Non smoker and no other risk factors for ASCVD. Serum cholesterol measured because of positive family history of coronary artery disease, her father having undergone coronary bypass surgery at age 52. Fasting lipid profile Total cholesterol: 15.6 mmol/L (604 mg/dL) Triglycerides: 1.34 mmol/L HDL-cholesterol: 1.8 mmol/L LDL-cholesterol 13.2 mmol/L (510 mg/dL) Familial Hypercholesterolaemia (FH) One of the most common and serious single gene disorders, affecting approximately 1 in every 311 persons or over 30 million people worldwide Beheshti SO, et al. J Am Coll Cardiol 2020:75:2553-2566 Hu P, et al. Circulation 2020:141:1742-1759 Familial hypercholesterolaemia (FH) Is not a rare genetic disorder: Prevalence is at least 5x other inherited conditions 5.0 4.5 4.0 3.5 3.2 3.0 2.5 births Frequency per 1,000 births of 2.0 common genetic disorders Frequency per 1,000 Frequency 1.5 1.0 1.0 0.8 0.5 0.5 0.5 0.5 0.5 0.4 0.4 0.3 0.0 FH Dominant Adult Sickle cell Multiple Huntington’s Fragile X Neuro- Cystic Duchenne otosclerosis PCKD disease exostoses disease syndrome fibromatosis fibrosis muscular dystrophy Wiegman R, et al. European Heart Journal. 2015;36:2423-2437 Familial hypercholesterolaemia Mother Father Offspring X X X X X X LDL receptor X locus on chromosome 19 FH Heterozygote FH Homozygote . 1 in 200- 500 in population . 1 in 300000 to 1 million in population . Half normal number of LDL receptors . Few or no LDL receptors . 2-fold increase in plasma LDL-C . 4 to 6-fold increase in plasma LDL-C . ASCVD manifests at age 35 . ASCVD manifests in childhood Cuchel M et al. Eur Heart J 2014;35:2146-57 Genetics and genetic heterogeneity of FH A B x LDLRAP1 x PCSK9 APOB x x x x LDLR Normal subject Normal allele x Chr 1 Chr 2 Chr 19 FH heterozygote FH mutation- FH homozygote bearing allele LDLRAP1=Low-density lipoprotein receptor adapter protein 1 PCSK9=Proprotein convertase subtilisin/kexin type 9 APOB=Apolipoprotein B LDLR=Low-density lipoprotein receptor Cuchel M et al. Eur Heart J 2014;35:2146-57 Phenotypic variability in FH LDL cholesterol Clinical Mutation diagnosis diagnosis mmol/L mg/dL Homozygous LDL-receptor negative 20 770 Homozygous FH Homozygous LDL-receptor Compound heterozygous defective or homozygous LDL-receptor APOB/PCSK9 15 580 LDLRAP1/ARH 13 500 Homozygous APOB defect/PCSK9 gain of 10 390 Heterozygous FH function 5 190 Common or polygenic hypercholesterolemia 0 0 Adapted from Cuchel M, Eur Heart J 2014;35:2146-57 Therapy for severe FH . Pharmacotherapy - lipid modifying drugs . Extracorporeal removal of LDL - LDL apheresis . Surgical therapy - portacaval shunt - partial ileal bypass . Methods to restore LDL receptor activity - liver transplantation - gene therapy Gidding S. The agenda for FH; Circulation 2015;132:2167-2192 STATIN THERAPY FOR FH Despite the absence of randomised clinical trial in subjects with FH, since their introduction in the late 1980’s statins have become the mainstay of therapy. Gidding, S. The agenda for FH; Circulation 2015;132:2167-2192 Compensatory increase in Synthesis of Hepatic LDL Receptors LDL in plasma LDL Synthesis uptake HMG-CoA HMG-CoA Blocked By statins Cholesterol Cholesterol Brown and Goldstein.Science.1986;232:34. High Dose Simvastatin and Atorvastatin in Homozygous FH % LDL-C Reduction Simvastatin 80 mg/d - 25% Simvastatin 160 mg/d - 31% Atorvastatin 40 mg/d - 20% Atorvastatin 80 mg/d - 33% Raal et al. Atherosclerosis 1997;135:249-56. Raal et al. Atherosclerosis 2000;150:421-8. Low-density lipoprotein-cholesterol levels in homozygous autosomal dominant hypercholesterolaemia patients after LLT 25 Two null alleles One null and one defective allele Two defective alleles 20 15 10 C levels (mmol/L) C levels - LDL 5 0 Prior to LLT After LLT Sjouke B. Eur Heart J. 2015;36:560-565 Mechanisms of action of high dose statins in HoFH Receptor Receptor defective negative HoFH HoFH Upregulation of Reduction in LDL hepatic apo-B receptors lipoprotein synthesis Raal et al. Atherosclerosis 2000;150:421-8. Mean percentage reduction in LDL-C for patients with HoFH receiving ezetimibe plus statin Entire Study Cohort (n=48) Genotype Confirmed HoFH (n=35)) Ezetimibe + Ezetimibe + Statin-80 Statin 80 Statin-80 Statin 80 0% 0% -5% -5% -5.6% -7.0% -10% -10% -15% -15% Cholesterol Reduction Cholesterol Cholesterol Reduction Cholesterol - - -20% -20% % % LDL -25% LDL % -25% -26.6% -27.5% -30% -30% Gagne C. Circulation 2002;105:2469-2475 Reduction in LDL-C in FH with combination lipid-lowering therapy 15 LDL-C 10 -50% mmol/L 55 - 70 % reduction 10-20% In LDL-C 5 5-10% Adapted from Nordestgaard B.G. et al. Eur Heart J 2013;34:3478-3490 and Hovingh G.K et al. Eur Heart J 2013;34, 962–971 Mrs TDK, a case of severe hypercholesterolaemia Treated with Rosuvastatin 40mg daily x 3 months Lipid profile Total cholesterol: 9.4 mmol/L (364 mg/dL) Triglycerides: 1.20 mmol/L HDL-cholesterol: 1.9 mmol/L LDL-cholesterol 7.0 mmol/L (270 mg/dL) Mrs TDK, a case of severe hypercholesterolaemia Ezetimibe 10mg daily added Lipid profile Total cholesterol: 7.6 mmol/L (294 mg/dL) Triglycerides: 1.30 mmol/L HDL-cholesterol: 1.8 mmol/L LDL-cholesterol 5.2 mmol/L (201 mg/dL) SAFEHEART study: Proportion of FH patients at LDL-C target 100 CVD (+) / LDL-C Target <1.8 mmol/L (70mg/dL) 90 80 70 60 50 40 target (%) target Attainment of Attainment 30 20 10 0 1.8 2.6 100 CVD (-) / LDL-C Target <2.6 mmol/L (100mg/dL) 90 80 70 60 50 40 target(%) Attainmentof 30 20 10 0 0 1.3 2.6 3.9 5.2 6.5 7.8 LDL-C Target (mmol/L) Perez de Isla et al. J Am Coll Cardiol. 2016;67((11):1275-85 Current/Emerging therapies for severe FH . While statins and ezetimibe constitute first-line therapy, they provide less than optimal LDL-C reduction in severe FH . in particular HoFH requires combination therapy: high-dose statin, ezetimibe, with or without apheresis Therapies for severe FH: Emerging therapies New therapies . PPAR delta agonists . Mipomersen (apoB inhibitor) . Acetyl CoA carboxylase inhibitor (Gemcabene) . Lomitapide (MTP inhibitor) . ACL/AMP kinase modulator (ETC-1002 or . PCSK9 inhibitors Bempedoic acid) . ANGPTL3 inhibitors - mAbs, Inclisiran . Others e.g. CETP–inhibitors, probucol . AAV-8 LDLR gene replacement therapy Stein EA, Raal FJ. Curr Cardiol Reports 2015;17:1-11 INHIBITION OF PCSK9 in FH 1. How effective is PCSK9-inhibitor therapy in FH? 1. In patients with HoFH with either no (<2%) or little (2-25%) LDL-receptor activity will PCSK9 inhibition be effective? Ch a n g e i n S e r u m C h o l e s t e r o l e With Concentration ( ) % in a further in - - - 75 50 25 25 0 ach doubling of statin dose only results only dose statin of doubling ach 0 6% reduction 6% 20 LDL cholesterol with statin with cholesterol LDL Statin (mg/day) 4 Rule of 6! Rule 0 in cholesterol 60 Davidson M, M, Davidson J Am Cardiol Am Coll J 80 . 2003;42:398 . - 399 Statin therapy and upregulation of PCSK9 Statins SREBP-2 PCSK9 LDLR LDLC SREBP2 = Sterol regulatory element-binding protein -2 Zhang L. Int J Biol Sci 2012;8:310-327 Serum PCSK9 levels in subjects with heterozygous and homozygous familial hypercholesterolaemia 600 PCSK9 500 Controls HeFH HoFH 400 300 200 PCSK9(ng/mL) 100 R=0.68 p>0.001 0 0 5 10 15 20 LDL-Cholesterol (mmol/L) Raal FJ. J Am Heart Assoc 2013;2:e000028 RCTs (Phase III trials) with PCSK9 inhibitors published or presented RCT Study Design Net LDL-C reduction (%) DESCARTES Long-term efficacy & safety -49 to -62 LAPLACE-2 Combination therapy with statins -63 to -75 GAUSS-2 Statin intolerance -37 to -39 MENDEL-2 Monotherapy -39 to -40 RUTHERFORD 2 Heterozygous FH -60 to -66 TESLA Homozygous FH -31 ODYSSEY MONO Monotherapy -32 ODYSSEY COMBO II Comparison with ezetimibe -51 to -58 ODYSSEY FH I and II Heterozygous FH -62 ODYSSEY Long-term Combination with statins including HeFH -30 ODYSSEY ALTERNATIVE Statin intolerance -39 ODYSSEY HIGH FH Severe heterozygous FH -24 to -49 ODYSSSEY OPTIONS Different strategies in high risk subjects -20 to -37 De Backer et al. Eur Heart J 2015;36:214-218 ODYSSEY FH I and FH II - Results over 52 Weeks Achieved LDL-C over time on background of maximally tolerated statin with or without other LLT 4.5 174 4.0 mmol/L 4.0 mmol/L Placebo FH I 4.0 155 3.3 135 3.5 mmol/L 3.7 mmol/L mg/dL 3.0 Placebo FH II 116 2.5 Alirocumab FH I 97 1.8 mmol/L 1.9 mmol/L 2.0 77 C, C, LS mean (SE), mmol/L - 1.5 1.8 mmol/L Alirocumab FH II 1.7 mmol/L 58 LDL 1.0 39 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Dose if LDL-C > 1.8 mmol/L at W8 Time (weeks) Kastelein JP et al.