LDL-Cholesterol : Old Story but New Insights & Emerging Evidence The 10th. Central Vietnam Open Congress of Cardiology Choo Gim Hooi MD Cardiac Vascular Sentral KL (CVSKL) 12th. July, 2019 Disclosure • No conflicts with regards to this presentation / meeting Sypnosis : • Myth & Fallacies about LDL-C & Statins • Brief historical facts • Genetic, Epidemiological & Interventional Evidence • New Frontiers in LDL-C management : Low & Ultra-low LDL-C targets, Plaque regression • ?Cure for atherosclerosis Atherosclerosis : Ancient Disease Atherosclerosis in Ancient Egyptian Mummies: The Horus Study. JACC Apr 3, 2011; Adel H. Allam, Randall C. Thompson, L. Samuel Wann, Michael I. Miyamoto, Abd el-Halim Nur el-Din, Gomaa Abd el-Maksoud, Muhammad Al-Tohamy Soliman, Ibrahem Badr, Hany Abd el-Rahman Amer, M. Linda Sutherland, James D. Sutherland, and Gregory S. Thomas Vietnam Health Statistics 2016 World Health Organization - Noncommunicable Diseases (NCD) Country Profiles, 2018. Atherosclerosis timeline Modified from Stary HC et al, Circulation 92:1355, 1995 Fatty Streak in Epicardial Coronary Artery of a 3 year old boy Slide courtesy of Dr.Peter Lansberg, Amsterdam Medical Centre Prevalence of Atherosclerosis by Donor Age Tuzcu. Circ 2001. 103:2075-10 Factors Contributing to Atherosclerosis Factors contributing to Atherosclerosis • High LDL-C • Low HDL-C • Obesity (Central, Visceral) • Diet • Physical inactivity • Hypertension • Smoking • Diabetes mellitus • Genetics • Environment 1856 Rudolf Ludwig Carl Virchow 1821-1902 Atherosclerosis, Inflammation [endarteritis deformans] & Cholesterol deposit Cholesterol & Atherosclerosis model, 1913 Healthy Volunteers Carrots & Salads Egg Yolk Fortified Food Nikolaj Nikolajewitsch Anitschkow (1885-1964) Adolf Otto Reinhold Windaus • Organic Chemistry Professor – one of the 1st. to Study Cholesterol structure 1910s • Nobel Laureate in Chemistry 1928 for Research on Sterols & its connection to Vitamins 1964: Nobel Laureate for Physiology or Medicine : Elucidation of Cholesterol & Fatty Acid Metabolism Pathway Konrad Emil Bloch Feodor Lynen Joseph Goldstein & Michael Brown : Nobel Laureate 1985 1974 Circulating LDL-C controlled by LDL-C Receptor activity Goldstein JL, Brown MS. Cell 2015;161-161 1976 : Dr.Akira Endo Discoverer of 1st. HMG Co-A Reductase inhibitor • 1970s: Focus of Drug Companies – Antibiotics • 1971 : Fungi Research Project started - >6000 experiments over 2 years - Initial experiments in rats unsuccessful - Later Dog experiments were successful • Initially no Pharma interest, until Sankyo Co took notice • Mevastin (Compactin) – 1st statin derived from Penicillium citinium Developers [Merck] of Clinically useful Statins : Lovastatin & Simvastatin Roy Vagelos Alfred W. Alberts Constant Battle with the Myths & Fallacies about LDL-C and Statins ! http://www.tbyil.com/Lowering_Chole sterol.htm Various myths about LDL-C and Statins ? • No cause & effect relationship between cholesterol and Atherosclerosis • Cholesterol is necessary for bodily function and should not be lowered • Statins damage my kidney, liver • Statins cause heart failure, cancer • I can lower cholesterol without statins • Once LDL-C is lowered, I can stop the statin or reduce the dose • I need to take Coenzyme Q10 if I’m on a statin Your physician is prescribing you unnecessary Statins because of ‘Corruption/Greed’? Physicians Pharma Industry DONATION ? Let’s debunk the Myths : Show me the evidences - LDL-C is important in atherosclerosis Framingham Heart Study 1948-1951 1980 men / 2421 women First publication in 1961 Epidemiological link – Risk factor concept INTERHEART Study LDL accounted for ~50% of the Population Attributable Risk Slide courtesy of MJ Chapman S. Yusuf et al. Lancet 2004; 364:937-52 Genetic studies ARIC: LDL-Cholesterol & CHD among Black Subjects with PCSK9 LOF Mutations (PCSK9142X or PCSK9679X Allele) No Nonsense 30 50th Mutation Percentile 88 % reduction in the risk 20 (N=3278) 12 of CHD p=0.008 10 0 8 0 50 100 150 200 250 300 PCSK9142x or 679X Frequency (%) Frequency PCSK9 30 (N=85) 4 20 28 % reduction in mean LDL-C (%) Disease Heart Coronary 10 0 0 No Yes 0 50 100 150 200 250 300 PCSK9142x or LDL Cholesterol in Black Subjects (mg/dL) PCSK9679X Adapted from Cohen JC. N Engl J Med 2006;354:1264-72; ARIC=Atherosclerosis Risk in the Community Therapeutic developments to lower LDL-C Early Primary-Prevention Trials: Overview TC * CHD events * 0 -5 Oslo: Diet/smoking cessation N=1,232, P=0.02 -10 -9 -9 -8.5 WHO: Clofibrate -11 -15 -14 N=15,745, P<0.05 Upjohn: Colestipol -20 -19 -20 N=2,278, P0.02 %+ -25 -23 LRC-CPPT: -30 Cholestyramine -35 N=3,806, P<0.05 -34 HHS: Gemfibrozil -40 N=4,081, P<0.02 -45 -50 -47 N=number enrolled. * Net difference between treatment and control groups (P values are for events). Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521. Early Secondary-Prevention Trials: Overview TC * CHD events * %+ CDP: Clofibrate (n=1,103) N=8,341, P=ns CDP: Niacin (n=1,119) N=8,341, P=ns Stockholm: Clofibrate + niacin N=555, P=ns POSCH: Partial ileal bypass N=838, P<0.001 N=number enrolled; ns=not significant. * Net difference between treatment and control groups (P values are for events). Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521. Partial Ileal Bypass to lower LDL-C Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Statin Trials 10 8 Nonfatal 5 5 MI/CHD CHD All-cause 5 TC LDL-C death death mortality 0 HDL-C -5 -10 -9 %+ -15 -20 -20 -20 -20 -22 -25 -24 -25 -26 -30 -28 -31 -30 -35 -33 -35 -34 -40 -45 -42 WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159) 1o prevention 2o prevention 2o prevention N=number enrolled. Achieved LDL-C (mmol/l) : 2.3 3.2 2.9 2.5 (3.9mmol/l) (3.4mmol/l) (3.1mmol/l) (2.8mmol/l) (2.9mmol/l) (2.0mmol/l) (2.1mmol/l) (1.9mmol/l) (1.6mmol/l) (1.6mmol/l) 49% 33% 42% 40% 39% On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials – Lower is Better 30 4S - Placebo 25 Rx - Statin therapy Secondary Prevention PRA – pravastatin ATV - atorvastatin 4S - Rx 20 LIPID - Placebo 15 LIPID - Rx CARE - Placebo CARE - Rx Primary Prevention HPS - Rx TNT – ATV10 HPS - Placebo 10 TNT – ATV80 PROVE-IT - PRA WOSCOPS – Placebo PROVE-IT – ATV AFCAPS - Placebo 6 5 AFCAPS - Rx WOSCOPS - Rx ASCOT - Placebo ASCOT - Rx 0 40 60 (1.8) 80 100 120 140 160 180 200 (1.0) (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) LDL-C achieved mg/dL (mmol/L) Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279 LaRosa JC et al. N Engl J Med 2005;352:e-version <64 mg/dl 65-77 mg/dl (<1.7mmol/l) (1.7-2.0mmol/l) 78-90mg/dl 91-106mg/dl >106mg/dl (2.0-2.3mmol/l) (2.3-2.7mmol/l) (>2.7mmol/l) (2.1-2.6mmol/l) (1.6-2.1mmol/l) (1.0-1.6mmol/l) ≤40 (1mmol/l) IMProved Reduction of Outcomes: Vytorin Efficacy International Trial A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome Study Design Patients stabilized post ACS ≤ 10 days: *3.2mM LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx) **2.6mM N=18,144 Standard Medical & Interventional Therapy Uptitrated to Simvastatin Simva 80 mg Ezetimibe / Simvastatin if LDL-C > 79 40 mg (adapted per 10 / 40 mg FDA label 2011) Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (≥ 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12 LDL-C and Lipid Changes Baseline LDL 2.5mM (IQR) 1 Yr Mean LDL-C TC TG HDL hsCRP (2.6mM) Simva 69.9 145.1 137.1 48.1 3.8 (1.8mM) (3.8mM) (1.5mM) (1.2mM) EZ/Simva 53.2 125.8 120.4 48.7 3.3 (2.3mM) (1.4mM) (3.3mM) (1.4mM) (1.3mM) Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5 (2.1mM) (-0.4mM) (0.5mM) (-0.2mM) (0.1mM) (1.8mM) Median Time avg 69.5 mg/dL (1.8mmol/L) vs. 53.7 mg/dL (1.4mmol/L) (1.6mM) (1.3mM) (1.0mM) Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489. Primary Endpoint — ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke HR 0.936 CI (0.887, 0.988) Simva — 34.7% p=0.016 2742 events NNT= 50 EZ/Simva — 32.7% 2572 events 7-year event rates Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489. CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 Simva — 22.2% NNT= 56 1704 events EZ/Simva — 20.4% 1544 events 7-year event rates Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489. Pushing the Boundaries: Targeting Ultra- Low LDL-C Territory Unchartered ? PCSK9 reduces LDLR recycling LDL particles PCSK9 routes LDL-R for lysosomal LDL-R degradation LDL-R recycling blocked PCSK9 secretion Horton et al. J Lipid Res 2009;50:S172–S177.