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2/7/2013 Disclosure Statement of Financial Interest • I, (Jack Whitaker), DO have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation, they are: Grant/Research Support: AstraZeneca Boehringer Ingelheim F.Hoffmann-La Roche GlaskoSmithKline Johnson and Johnson Janssen Lantheus Medical Imaging Novartis Schering-Plough Research Institute 1 2/7/2013 Disclosure Statement of Financial Interest • I, (Jack Whitaker), DO have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation, they are: Speaker's Bureau: Amarin Boehringer Ingelhiem Daiichi Sankyo Lilly Sanofi Aventis Disclosure Statement of Financial Interest • I, (Jack Whitaker), DO have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation, they are: Employment: Wellmont Disclosure Statement of Unapproved/Investigative Use I, (Jack Whitaker), DO anticipate discussing the unapproved/investigative use of a commercial product/device during this activity or presentation. 2 2/7/2013 LIPID MANAGEMENT CARDIOVASCULAR MORTALITY & MORBIDITY 3 2/7/2013 CARDIOVASCULAR MORTALITY & MORBIDITY Explaining the Decrease in U.S. Deaths from Coronary Disease 1980 - 2000 • Reductions in Major Risk Factors • Evidence Based Therapies N Engl J Med 2007 ; 356:2388-98 4 2/7/2013 Clinical Trials This image cannot currently be display ed. CLARIT Y TIMI 23 TIMI 28 PCI- CU RE CAPRIE 5 2/7/2013 LIPID MANAGEMENT LIPID MANAGEMENT 6 2/7/2013 7 2/7/2013 JNC ATP 4 GUIDELINES “PROBABLY IN THE SPRING…” National Heart, Lung, and Blood institute. Clinical practice guidelines aid reports in the development. Available on website NCEP - III • < 100 mg / dL Optimal • 100 - 129 mg / dL Near Optimal / Above Optimal • 130 - 159 mg / dL Borderline High • 160 - 189 mg / dL High • > 190 mg / dL Very High Diabetic or other Risk Factors for Ischemic Heart Disease VA/DOD Practice Guideline Goal for LDL < 100 8 2/7/2013 9 2/7/2013 LIPID MANAGEMENT • LDL CHOLESTEROL • HDL CHOLESTEROL • TRIGLYCERIDES • Other LDL Cholesterol 10 2/7/2013 LDL Cholesterol • HMG-CoA reductase inhibitors ( “statins” ) • PCSK9 inhibitors (antibody therapy) • Microsomal Triglyceride Transfer Protein inhibitors ( MTP ) LDL Cholesterol HMG – CoA Reductase Inhibitors “Statins” LDL Cholesterol 11 2/7/2013 LDL Cholesterol • < 100 mg / dL Optimal • 100 - 129 mg / dL Near Optimal / Above Optimal • 130 - 159 mg / dL Borderline High • 160 - 189 mg / dL High • > 190 mg / dL Very High Trig > 400 dLDL Performed Diabetic or other Risk Factors for Ischemic Heart Disease VA/DOD Practice Guideline Goal for LDL < 100 LDL Cholesterol LDL Cholesterol • HMG-CoA reductase inhibitors ( “statins” ) • PCSK9 inhibitors (antibody therapy) • Microsomal Triglyceride Transfer Protein inhibitors ( MTP ) 12 2/7/2013 LDL Cholesterol PCSK9 Inhibitors Proprotein Convertase Subtilisin Kexin Type 9 LDL Cholesterol PCSK 9 Inhibitors LDL Cholesterol PCSK 9 Inhibitors 13 2/7/2013 LDL Cholesterol PCSK9 Inhibitors Early trials LDL Cholesterol • HMG-CoA reductase inhibitors ( “statins” ) • PCSK9 inhibitors (antibody therapy) • Microsomal Triglyceride Transfer Protein inhibitors ( MTP ) LDL Cholesterol Microsomal Triglyceride Transfer Protein inhibitors ( MTP ) Familiar Hypercholesterolemia 14 2/7/2013 LDL Cholesterol MTP Inhibitors Familiar Hypercholesterolemia • Lomitapide • Mipomersen 15 2/7/2013 HDL Cholesterol HDL Cholesterol • < 40 mg / dL Low • > 60 mg / dL High HDL Cholesterol HDL for CVD PREVENTION: HOPE or HYPE ? 16 2/7/2013 Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 1% National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation. 2002;106(25):3143-3223; Barter et al. Eur Heart J. 2004;6(suppl A):A19-A22. Framingham Heart Study: CHD Risk CHD Risk After 4 Years 3 2 25 (0.7) 45 (1.2) 65 (1.7) 85 (2.2) 1 0 100 (2.6) 160 (4.1) 220 (5.7) LDL-C, mg/dL (mmol/L) Men aged 50-70; Castelli. Can J Cardiol. 1988;4(suppl A):5A-10A. HDL Cholesterol Current Approaches to Raising HDL - C • Diet and exercise up to 10% • Fibrates 5 – 20% • Statins 3 – 15% • Niacin up to 30% 17 2/7/2013 HDL Cholesterol • Is niacin ineffective? Or did AIM-HIGH miss its target? • HPS – 2 THRIVE study HDL Cholesterol Is niacin ineffective? Or did AIM-HIGH miss its target? • Perhaps niacin is no good as a preventative agent • Perhaps raising raising HDL-C is flawed as a preventive strategy • Perhaps AIM-HIGH had methodological flaws • Perhaps statins are so good that, once you prescribe one, anything else you do will not make much of a difference Cleveland Clinic Journal of Medicine January 2012 vol. 79 1 38-43 HDL Cholesterol HPS – 2 THRIVE study • After nearly four years of follow-up , the combination of extended-release niacin / laropiprant added to statin therapy did not significantly reduce the risk of CV events compared to statin therapy but did significantly increase the risk of nonfatal but serious side effects Merck. Merck announces HPS-THRIVE study of Tredaptive (extended-release niacin / laropiprant) did not achieve primary endpoint. December 20, 2012. 18 2/7/2013 HDL Cholesterol NOVEL Approaches to Raising HDL - C • Cholesteryl Ester Transfer Protein (CETP) Inhibition • Infusions of ApoA1 • LXR Antagonists HDL Cholesterol CETP inhibition 19 2/7/2013 Effect of CETP Inhibition on Plasma Cholesterol Transport Liver LDL-R CE CE SR-B1 SR-B1 VLDL-C/ LDL-C FC CETP Bile HDL-C CE LCAT FC Extrahepatic tissues FC Adapted from Barter et al. Arteriosclerosis Thromb Vasc Biol. 2003;23(2):160-167. Relationship Between CETP and Atherosclerosis Animal Studies (Rodents) • Rodents naturally deficient in CETP • Rodents naturally resistant to development of atherosclerosis • Expression of CETP in transgenic mice and rats increases atherosclerosis in most (but not all) models Barter et al. Arterioscler Thromb Vasc Biol. 2003;23(2):160-167. Relationship Between CETP and Atherosclerosis Animal Studies (Rabbits) • Rabbits have high level of activity of CETP • Rabbits naturally highly susceptible to the development of atherosclerosis • Inhibition of CETP in rabbits decreases atherosclerosis in all models Barter et al. Arterioscler Thromb Vasc Biol. 2003;23(2):160-167. 20 2/7/2013 Relationship Between CETP and Atherosclerosis CV Risk in Human Population Studies • Presence of CETP deficiency associated with elevated HDL-C levels • Genetic CETP mutations are highly prevalent in individuals with HDL-C > 100 mg/dl • CETP deficiency associated with less vascular events only when accompanied by higher HDL-C levels CETP Inhibitor Differentiation • CETP inhibitors differ by: –Their chemical structures –Physicochemical properties –Binding site on CETP Stroes et al. Poster presented at: ACC Annual Scientific Session. March 29 - April 1, 2008; Chicago, Illinois. CETP Inhibitors • Torcetrapib • Dalcetrapib • Anacetrapib • Evacetrapib 21 2/7/2013 Relationship Between CETP and Atherosclerosis Human Studies • Torcetrapib inhibits CETP and raises HDL-C by about 60 to 70% and lowers LDL-C by more than 20 to 25% • In human studies torcetrapib had no effect on atherosclerosis in 3 imaging trials • In human studies torcetrapib increased both mortality and major CV events in a large endpoint trial Barter et al. N Engl J Med. 2007;357:2109-2122. Off-Target Pharmacological Effects of Torcetrapib • Torcetrapib has off-target (non-CETP inhibitor) effects – In patients receiving torcetrapib in the ILLUMINATE trial there was a significant: • Increase in blood pressure • Decrease in serum potassium • Increase in serum bicarbonate • Increase in serum sodium • Increase in serum aldosterone • The adverse outcome in the ILLUMINATE trial may thus have been the consequence of off-target actions of torcetrapib and not related to CETP inhibition Barter et al. N Engl J Med. 2007;357:2109-2122. CETP Inhibitors • Torcetrapib • Dalcetrapib • Anacetrapib • Evacetrapib 22 2/7/2013 Dalcetrapib Dalcetrapib N ENGL J MED 367:22 Dalcetrapib N ENGL J MED 367:22 23 2/7/2013 Dalcetrapib N ENGL J MED 367:22 Relationship Between CETP and Atherosclerosis Human Studies • Dalcetrapib inhibits CETP and raises HDL-C by about 31 to 40% and had minimal effect on LDL-C • Dalcetrapib had no significant effect on any component of the primary endpoint or total mortality in a large endpoint trial (halted due to futility) • Dalcetrapib had a generally acceptable side-effect profile Schwartz et al. N Engl J Med. 2012;367:2089-2099. CETP Inhibitors • Torcetrapib • Dalcetrapib • Anacetrapib • Evacetrapib 24 2/7/2013 TRIGLYCERIDES TRIGLYCERIDES • 40 - 160 mg / dL TRIGLYCERIDES “the association between triglyceride levels and cardiovascular disease is more uncertain” Lars Berglund, John D. Brunzell, Anne C. Goldberg, Ira J. Goldberg, Frank Sacks, Mohammad Hassan Murad, and Anton F. H. Stalenhoef Clinical Practice Guideline: Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline JCEM 2012 97: 2969-2989; 25 2/7/2013 TRIGLYCERIDES • FIBRATES • NIACIN • OMEGA - 3 FATTY ACIDS TRIGLYCERIDES ICOSAPENT ETHYL Indications and Usage VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. • The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. • The effect of VASCEPA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined. TRIGLYCERIDES Indications and Usage VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. • The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. • The effect of VASCEPA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined. 26 2/7/2013 TRIGLYCERIDES ICOSAPENT ETHYL INFLAMMATION and ATHEROSCLEROSIS INFLAMMATION and ATHEROSCLEROSIS • Cardiovascular Inflammation Reduction Trial (CIRT) • Canakinumab Antiinflammatory Thrombosis Outcomes study (CANTOS) • The Stabilization of Plaques using Darapladib ( SOLID TIMI 52 ) 27 2/7/2013 INFLAMMATION and ATHEROSCLEROSIS Cardiovascular Inflammation Reduction Trial (CIRT) INFLAMMATION and ATHEROSCLEROSIS Cardiovascular Inflammation Reduction Trial (CIRT) • Methotrexate • Trial to evaluate efficacy in preventing recurrent cardiovascular events in patients with MI prior to study entry INFLAMMATION and ATHEROSCLEROSIS Canakinumab Anti-inflammatory Thrombosis Outcomes study (CANTOS) 28 2/7/2013 INFLAMMATION and ATHEROSCLEROSIS Canakinumab Anti-inflammatory Thrombosis Outcomes study (CANTOS) • Anti- IL -1B monoclonal antibody • Trial to evaluate efficacy in preventing recurrent cardiovascular events in patients with MI prior to study entry and elevated hsCRP INFLAMMATION and ATHEROSCLEROSIS The Stabilization of Plaques using Darapladib ( SOLID TIMI 52 ) INFLAMMATION and ATHEROSCLEROSIS The Stabilization of Plaques using Darapladib ( SOLID TIMI 52 ) • Selective inhibitor of lipoprotein - associated phospholipase A2 ( Lp – PLA2 ) • Trial to evaluate the efficacy in preventing cardiovascular death, nonfatal MI and nonfatal stroke in patients following acute coronary syndrome 29 2/7/2013 Case History: A 69 year old man is referred to your service for routine evaluation. He has a history of hypertension, dyslipidemia, prior 25 pack year Tobacco use, obesity, and non-insulin dependent diabetes mellitus. He admits to poor dietary compliance. He has a prior history of stable exertional angina and underwent cardiac catherization six years ago , which revealed an 90% mid-LAD occlusion that was treated with a percutaneous coronary intervention and bare metal stenting. Current medications consist of aspirin, lisinopril, metformin, and metopropol. On examination his BP is 155/95 mmHg, pulse is 85 bpm and regular. Cardiovascular exam is unremarkable. On laboratory testing, he is found to have a creatinine of 0.6 mg/dl, fasting glucose of 112 mg/dl, liver function test within normal limits, and a fasting lipid panel of triglycerides 194 mg/dl, HDL 42 mg/dl, and a calculated LDL of 158 mg/dl. He inquires as to the benefit of cholesterol lowering therapy? 30 2/7/2013 Lowering this patient’s LDL-C level from 158 mg/dl (4.0 mmol/L) to 116 mg/dl (3.0 mmol/L) with a statin medication would result in which of the following? A. No change in this patient’s long-term future cardiovascular risk B. 20% - 25% decrease in relative risk of future CV events C. 12% increase in risk of worsening glucose intolerance D. 10% decrease in relative risk of future CV event E. It is unknown whether statin medication alters the risk of major CV events in patients with known coronary artery disease answer There is clear evidence that in patients with underlying coronary disease, the use of statin medications results in substantial reduction in risk of future cardiovascular events due to lowering of LDL cholesterol levels. Prior work has suggested that lowering LDL cholesterol on average 1 mmol/L (~40 mg/dL), reduces the relative risk of cardiovascular events 20-30% (CTT Collaboration, Lancet, 2010; LaRosa, NEJM, 2005). While a slight increase in risk of glucose intolerance has been observed in patients treated with statin medications, this overall risk is quite low (Sattar N, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 375: 735–42. 2010) Thank you! 31