High Cholesterol Treatment (2017) PDF

COMMONWEALTH OF AUSTRALIA Copyright Regulation WARNING This material has been reproduced and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The m...

COMMONWEALTH OF AUSTRALIA Copyright Regulation WARNING This material has been reproduced and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice Primary Prevention of Vascular Disease - high cholesterol for treatment Presented by Professor Leonard Kritharides Head of Cardiology Concord Hospital Clinical School Department of Cardiology, University of Sydney The University of Sydney Page 2  Learning Outcomes – Risk factors – Identification, severity, complications – Risk stratification – Absolute risk and its limitations – Lipid pathways and drug targets – Established drugs, emerging therapies – Treating high blood pressure and Diabetes The University of Sydney Page 3  Burden of CV disease – Between 1990 and 2013 total CV deaths in Australia A. Decreased by 50% B. Increased by 5% C. Increased by 50% The University of Sydney Page 4  Burden of CV disease – Between 1990 and 2013 total CV deaths in Australia A. Decreased by 50% B. Increased by 5% C. Increased by 50% – Although age-adjusted rates fell by over 50%, because our population has increased and is older, our overall rate has increased. In parts of the world where age adjusted declines did not occur- eg South East Asia, a massive increase in burden of disease has occurred. (see next slide) The University of Sydney Page 5  Roth et al NEJM 2015 The University of Sydney Page 6  Risk factors interact with age - Life time risk CVD according to Risk factors at 50y Lloyd Jones Circulation 2006. The University of Sydney Page 7  Lifetime risk and LDL cholesterol Q: In people with inherited 50% reduction of LDL due to loss of function in PCSK9 their lifetime risk of coronary disease is reduced by: A. 20% B. 30% C. 50% D. 80% The University of Sydney Cohen, J. et al. N Engl J Med 2006;354:1264-1272 Page 8  Lifetime risk and LDL cholesterol Q: In people with inherited 50% reduction of LDL due to loss of function in PCSK9 their lifetime risk of coronary disease is reduced by: A. 20% B. 30% C. 50% D. 80% Cohen NEJM 2006 The University of Sydney Cohen, J. et al. N Engl J Med 2006;354:1264-1272 Page 9  Lifetime risk - Genes and environment are additive Khera NEJM 2016 The University of Sydney Page 10  Modifiable environmental factors and CV risk Interheart Study Yusuf et al Lancet 2004; 364: 937–52 increase risk smoking apoB/A-I ratio (includes LDLc, nonHDLc, HDLc) diabetes hypertension abdominal obesity psychosocial stress decrease risk fruit and vegetable intake alcohol exercise 9 risk factors explain 90% of population attributable risk The University of Sydney Page 11  Quantifying absolute risk - Framingham risk score - FRS BP Age Sex Smoking Total:HDL cholesterol Diabetes High >15%/5y Intermediate 10-15% Low risk 60 years microalbuminuria chronic kidney disease (persistent proteinuria or eGFR< 45 mL/min/1.73 m2) familial hypercholesterolaemia** systolic BP≥ 180 mmHg or diastolic BP≥ 110 mmHg Serum total cholesterol > 7.5 mmol/L – calculator includes New Zealand Calculator and LVH on ECG +PBS guidelines include BP, Aboriginal population, diabetes, family history, HDL The University of Sydney Page 19  Coronary-Artery Calcium predicts coronary events Detrano R et al. N Engl J Med 2008;358:1336-1345 The University of Sydney Page 20  Framingham Risk Score interacts with coronary calcium to predict events Valenti JACC 2015 The University of Sydney Page 21  Lipoprotein Nomenclature and Composition CM VLDL IDL LDL HDL Major apoB48 apoB100 apoB100 apoB100 apoA-I Protein Major TG TG CE CE CE Lipid Non HDL cholesterol The University of Sydney Page 22  Overview of Cholesterol Transport NPC1 IDL-C = intermediate-density lipoprotein cholesterol Adapted from Champe PC, Harvey RA Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994. The University of Sydney Page 23  Sites of action of lipid Lomitapide lowering drugs Mipomersen Bile-acid sequestrants Bile acids X CE VLDL DIET X Free cholesterol Statins Fibrates Unstirred LPL water PCSK9inh Cholesterol layer CE (CII+, CIII-) Border Brush ENTEROCYTE Remnants Sterols/ XX FC FC biosynthesis Cholesteryl Ester (CE) BLOOD stanols Micelles ACAT X CE Cholesterol Absorption Chylomicrons Inhibitors (e.g., ezetimibe) Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 2004; 303: 1201-1204l; Klett EL, Patel SB. Will the Real CholesterolTransporter Please Stand Up. Science 2004; 303: 1149-1150 The University of Sydney Page 24  Drugs commonly used to lower lipids (symbols ✓✓ refer to quality of outcome data) Common Statins lowers LDL (30-50%), lowers TG ✓✓✓ Ezetimibe lowers LDL (10-15%) ✓✓ Fibrates lowers TG (20-50%), raises HDL ✓ Fish oil lowers TG, elevates LDL ± Less common Bile acid sequestrants lowers LDL, raises TG ✓ Nicotinic acid lowers TG, LDL, raises HDL x Emerging PCSK9 inhibitors lowers LDL and Lp(a) ✓✓ Dietary Plant sterols, soluble fibre, beta glucan-oats, lower LDL ± The University of Sydney Page 25  Total cholesterol and risk of CHD The University of Sydney Page 26  Risk predicts statin benefit Cholesterol trialists’ collaboration NNT to avoid 1 vascular event for 1mmol LDL drop Baseline risk >30%/5y- 61/1000= 16 30%/5y- 20/1000= 50 40 repeats LDL-like particle apolipoprotein(a) Koschinsky et al. Cur Opin Lipidol 2004;15:167-174 The University of Sydney Page 32  Lp(a) increases risk of myocardial infarction aortic stenosis Inherited phenotype effects proportional to plasma concentration No standard agents effectively lower Lp(a) Is lowered by 30-40% by PCSK9 antibodies Nordestgaard 2016 JLR The University of Sydney Page 33  Risk predicts statin benefit Cholesterol trialists’ collaboration The University of Sydney Page 34  Benefit Risk predicts relatesCholesterol statin benefit to degreetrialists’ of BP lowering collaboration The University of Sydney Page 35  Contemporary Issues in BP management – Ambulatory BP or home BP more predictive than office BP – Combined low doses of medications more efficacious than high dose monotherapy – Labile blood pressure is also a risk factor for events – Most patients who warrant BP treatment warrant treatment with statin to – maximise reduction in absolute risk – There is a lower limit to which BP should be treated- but this varies with – at risk population. As rule of thumb, 120/80 for most (see Sprint study), 140/80 for diabetics – And even higher for those with postural hypotension,