Personalized Lipidology: How genomics is changing the management of dyslipidemia

Transcription

1 Personalized Lipidology: How genomics is changing the management of dyslipidemia Michael Davidson M.D. FACC, Diplomate of the American Board of Lipidology Clinical Professor, Director of Preventive Cardiology The University of Chicago Pritzker School of Medicine

2 Presenter Disclosure Information Research Support None for the past 24 months Consulting Fees Amgen, Atherotech,, Lipidemix, sanofi-aventis, Modest Level DSMB Aegerion, Merck, Modest Level Grants None for the past 24 months Equity Founder of Omthera now owned by Astra-Zeneca Significant

3 Unmet Medical Need for Patients with Dyslipidemia and Atherosclerosis 1) Statin Intolerance 2) Refractory Hypercholesterolemia 3) Hypertriglyceridemia (elevated non-hdl-c) 4) Low HDL-c 5) Elevated Lp(a) 6) Progressive Atherosclerosis despite maximal therapy

4 Only One Volume in an Encyclopedia of Guidelines 13 Guidelines 11/13 have lipid targets 10/11 target LDL C 1/11 target non HDL C 1/11 target non HDL C or apo B as a secondary target Multiple Risk Calculators: Framingham, Modified Framingham, Reynold s, SCORE, KDIGO, Pooled Cohort Risk Equations

5 Metanalysis demonstrating that the lower the LDL c the better J Am Coll Cardiol 2014;64:485 94)

6 A Treasure Trove of Information for Lipoprotein Biology Dietary fat, cholesterol Intestine Phospholipid (PL) A I A V A IV PNLIP CEL Protein B48 Chylomicron Fatty Lipolysis acids ABCG5 ABCG8 NPC1L1 Cholesteryl ester (CE) Triglycerides (TG) A I Nascent HDL Cholesterol, PL Bile salts, cholesterol E C Lipolysis LCAT PLTP Remnant All E B48 Lipolysis HDL A I E LDLR TG CE CETP VLDL Fatty acids LPL B100 C E B100 IDL LDLR GCKR LIPC LP (a) LDL Liver MLXILP CYP7A Lipogenesis MEV-MMAB HMGCR LRP1 SCABR1 Cholesterol LPA B100 B100 LPL CD36 ABCA 1 ABCG1 Inhibition transporters ANGPTL3 GALNT2 Peripheral tissues LIPG CD36 Glycosylation CELSR2-PCRC1-SORT1 TRIB1 NCAN-CLIP2-PBX4 LDLR PCSK9 Degradation Adapted from Lusis AJ, et al. Nat Genet. 2008;40:

7 Genome Wide Association Study (GWAS) in >100,000 Individuals of European Ancestry In 2010, 95 loci across the human genome were reported to harbor common variants associated with plasma lipid traits LDL-C (newly identified loci in red) HDL-C Triglycerides ABCG5/8 HFE SORT1 ABCA1 HNF4A PDE3A ABO HMGCR ST3GAL4 ABCA8 IRS1 PGS1 GCKR ANGPTL3 HNF1A TIMD4 KLF14 PLTP ANGPTL3 IRS1 APOA HPR TOP1 ANGPTL4 LACTB PPP1R3B ANKRD55 JMJD1C APOB TRIB1 APOA LCAT SBNO1 APOA LIPC APOE IRF2BP2 APOB LILRA/B SCARB1 APOB LPL BRAP LDLR APOE LIPC SLC39A8 APOE LRP1 LDLRAP1 ARL15 LIPG STARD3 MLXIPL LPA C6orf106 LPA TRIB1 CAPN3 MSL2L1 CETP MAFB CETP LPL TRPS1 CETP NAT2 CILP2 MOSC1 CITED2 LRP1 TTC39B CILP2 PINX1 CYP7A1 NPC1L1 CMIP LRP4 UBASH3B COBLL1 PLA2G6 DNAH11 OSBPL7 COBLL1 UBE2L3 CTF1 PLTP FADS PCSK9 MC4R ZNF648 CYP26A1 TIMD4 FRK PLEC1 FADS MLXIPL ZNF664 FADS TRIB1 GPAM PPP1R3B GALNT2 MMAB TYW1B Total Cholesterol ZNF664 ERGIC3 EVI5 RAB3GAP1 RAF1 SPTY2D1 Note, the loci shown may have different traits associated with them, and therefore may appear in more than one category for LDL-C, HDL-C, Triglycerides, and Total Cholesterol. Teslovich TM, et al. Nature. 2010;466:

8 PCSK9: Rapid Progress From Discovery to Clinic Adenoviral expression in mice PCSK9 KO mouse LDL-C PCSK9 LOF mutations found with 28% LDL-C and 88% CHD risk First subject treated with PCSK9 mab PCSK9 (NARC-1) discovered PCSK9 GOF mutations associated with ADH Humans null for PCSK9 have LDL-C ~15 mg/dl Plasma PCSK9 binds to LDLr LDL-C in mice and nonhuman primates treated with anti-pcsk9 mab First patients with FH & nonfh treated with PCSK9 mab First publication POC in patients Seidah NG. Proc Natl Acad Sci USA 2003;100(3):928-33, Abifadel M. Nat Genet 2003;34(2):154-6, Maxwell KN. Proc Natl Acad Sci USA 2004;101(18):7100-5, Rashid S. Proc Natl Acad Sci USA 2005;102(15): , Lagace TA et al. JCI 2006;116: Cohen JC. N Engl J Med 2006;354(12): , Zhao Z. Am J Hum Genet 2006;79(3):514-23, Hooper AJ. Atherosclerosis 2007;193(2):445-8, Chan JC. Proc Natl Acad Sci USA 2009;106(24):9820-5; Stein et al N Engl J Med 2012;366: Stein modified from Swergold, Regeneron

9 Recycling of LDL-Rs Enables Efficient Clearance of LDL Particles The ability of hepatic LDLRs to be recycled is a key determinant of hepatic efficacy in lowering plasma LDL levels 1. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29: Brown MS, et al. Science. 1986;232: Steinberg D, et al. Proc Natl Acad Sci USA. 2009;106: Brown MS, et al. Proc Natl Acad Sci USA. 1979;76:

10 Proprotein convertase subtilisin/kexin type 9 (PCSK9) Is a Key Regulator of LDL-R Recycling PCSK9 mediates degradation of the LDL R by interacting with the extracellular domain and targeting the receptor for degradation 1 PCSK9 is highly expressed in the liver, small intestine, and kidney 4 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S Qian YW, et al. J Lipid Res. 2007;48: Zhang DW, et al. J Biol Chem. 2007;282: Lopez D. Biochim Biophys Acta. 2008;1781:

11 Impact of an PCSK9 mab on LDL Receptor Expression For illustration purposes only mab 11 11

12 Pharmacokinetics and pharmacodynamics of evolocumab: changes in PCSK9 and LDL-C levels in response to evolocumab (AMG 145) Free PCSK9 concentration (ng/ml) Free AMG 145 concentration (ng/ml x 0.01) Total AMG 145 (evolocumab) Free PCSK9 LDL-C Study Day LDL-C Mean Change (%) Stein EA & Raal FJ Annu. Rev. Med :

13 ODDYSSY Outcomes: Long term LDL-C reduction with alirocumab 150 mg Q2W Achieved LDL-C Over Time All patients on background of maximally-tolerated statin ±other lipid-lowering therapy LDL-C, LS mean (SE), mmol/l Placebo Alirocumab 3.1 mmol/l mg/dl 1.3 mmol/l 48.3 mg/dl 3.2 mmol/l mg/dl 1.4 mmol/l 53.1 mg/dl mg/dl Week Intent-to-treat (ITT) analysis Robinson J et al ESC hotline session Barcelona Aug 31, 2014

14 DESCARTES: Long term stability of LDL-C reduction UC LDL-C Percent Change from Baseline, Mean (± SE) Number of patients: 57.5% 6.0% % 51.5% Baseline Week 12 Week 52 Study Week Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599) FAS = Full analysis set, UC = Ultracentrifugation Blom et al NEJM 2014:370:

15 Impact Of Evolocumab vs SOC on MACE in 4465 Patients in the Osler Study Osler: Open label study of 4465 pts randomized to evolocumab 140 mg SC Q2W or 420 mg SC QM + standard of care (SOC) or SOC for 48 wks CV Events Death MI UA requiring hospitalization CVA TIA Hosp w CHF CV Events SOC = 2.18% Evolocumab = 0.95% Kaplan Myer estimates at 1 yr Hazard ratio, 0.47; 95% CI, p=0.003 Sabatine et al NEJM 2015; 372:1500 9

16 Impact Of Alirocumab vs Placebo on MACE in 2341 Patients in the Odyssey Long Term Study Odyssey Long Term: Blinded study of 2341 high risk pts on max tolerated statin with LDL C > 70 randomized receiving alirocumab 150 mg or placebo SC Q2W for 78 weeks Placebo + maximally tolerated statin + other LLT Alirocumab + maximally tolerated statin + other LLT MACE CHD death Nonfatal MI Fatal/nonfatal ischemic CVA UA requiring hospitalization MACE Placebo = 3.3% Alirocumab = 1.7% Cox model analysis Hazard ratio, 0.52, 95% CI Nominal p=0.02 Robinson et al NEJM 2015; 16;372:

17 Adjusted MACE Rate by Average Achieved non-hdl-c During Treatment Multivariate analysis adjusted on baseline characteristics; pool of Phase 3 trials 4.0 Event rate % CI LDL-C Adjusted rate of MACE (per 100 patient-years) Average non-hdl-c during the treatment period (mg/dl) HR [95% CI]: 0.77 [0.65 to 0.93] per 42 mg/dl difference; p=

18 Physical Exam

19 35-Year-Old Indian Male Post MI

20 Laboratory Values Laboratory Test Notes High Risk Intermediate Risk Optimal High Risk Range Intermediate Risk Range Optimal Range Previous Results 7/22/2015 Total Cholesterol (mg/dl) <200 Lipids LDL-C Direct (mg/dl) CHD & CHD risk eq. > CHD & CHD risk eq <100 CHD & CHD risk eq. <70 HDL-C (mg/dl) 35 <40 40 Triglycerides (mg/dl) 255 > <150 Non-HDL-C (mg/dl) (calculated) <130 Apo B (mg/dl) <60 Lipoprotein Particles and Apolipoproteins LDL-P (nmol/l), by NMR > <1020 Small LDL-P (nmol/l), by NMR 2360 > <501 sdldl-c (mg/dl) 74 > <21 Apo A-I (mg/dl) 81 < >131 HDL-P ( mol/l) >38.0 HDL2-C (mg/dl) Apo B:Apo A-I Ratio (calculated) Lp(a)-P (nmol/l) 136 > <75

21 Labs Post Alirocumab 75 mg SC Q2W After Switching to Rosuvastatin 40 mg Plus Ezetimibe Laboratory Test Notes High Risk Intermediate Risk Optimal High Risk Range Intermediate Risk Range Optimal Range Previous Results 7/22/2015 Total Cholesterol (mg/dl) < Lipids LDL-C Direct (mg/dl) CHD & CHD risk eq. > CHD & CHD risk eq <100 CHD & CHD risk eq. <70 HDL-C (mg/dl) 28 < Triglycerides (mg/dl) 273 > < Non-HDL-C (mg/dl) (calculated) < Apo B (mg/dl) < Lipoprotein Particles and Apolipoproteins LDL-P (nmol/l), by NMR < Small LDL-P (nmol/l), by NMR 744 > < sdldl-c (mg/dl) 38 > <21 55 Apo A-I (mg/dl) 89 < > HDL-P ( mol/l) > HDL2-C (mg/dl) Apo B:Apo A-I Ratio (calculated) Lp(a)-P (nmol/l) 55 > <

22 65 yo male s/p CABG X2 on pitavastatin 2 mg qd Pre and post evolcumab 140mg q2w ^

23 Ongoing Outcomes trials

24 Potential concerns Outcomes RCTs not available till How we lower LDL matters (CETP inhibitors, niacin) Long term safety (neurocognitive effects) Compliance In which patient subsets is the cost justifiable? ICER, 9/8/15

25 Ridker et al, Eur Ht Journal 2016 JUPITER: which pts likely to benefit?

26 GAUSS 3 Study Compared evolocumab and ezetimibe and in patients with SI history. Differed from earlier SI studies in that treated patients failed an atorvastatin challenge with cross over (N= 492 screened; 218 randomized). Evolocumab beat ezetimibe in LDL C lowering. Oral versus percutaneous treatment drop out rates provides insight to challenge of this population. SI, statin intolerance JAMA Apr 19; 315 (15) Cardiometabolic Health Congress October 5 8, 2016 Boston MA

27 Residual Risk 60-70% Risk persists

28 ODYSSEY Outcomes

29 c

30 Genetics of LDL-Mediated Cardioprotection It was uncertain if lowering LDL through ezetimibe would reduce risk for MI. A human genetics experiment was designed address this issue.

31 Ezetimibe

32

33

34

35 Figure 4 American Heart Journal , e1DOI: ( /j.ahj ) Copyright 2014 The Authors. Terms and Conditions

36 IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit IMPROVE-IT CTT Collaboration. Lancet 2005; 366: ; Lancet 2010;376:

37 Conclusions IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES: Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dl at 1 year) YES: Confirms ezetimibe safety profile Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events Results could be considered for future guidelines

38 Ference, B.A. et al. J Am Coll Cardiol. 2015; 65(15):

39 Effect of Random Allocation to Lower LDL-C on the Risk of Coronary Heart Disease Mediated by Polymorphisms in NPC1L1, HMGCR, or Both. A 2X2 Factorial Mendelian Randomization Study: Randomization Worked! Ference, B.A. et al. J Am Coll Cardiol. 2015; 65(15):

40 Ference, B.A. et al. J Am Coll Cardiol. 2015;

41 Lifelong genetically low LDL confers much greater CV risk reduction than shortterm drug treatment Ference, B.A. et al. J Am Coll Cardiol. 2015;

42 Two men who died of a MI at age vs 2008

43 Justification for lowering Non-HDL-c to reduce CHD Risk Reduction Assertions Hypertriglyceridemia is correlated with increased CV risk Risk of hypertriglyceridemia is contained within non-hdl-c rather than triglycerides per se VLDL-C triglyceride risk lipoprotein cholesterol is an atherogenic component of non-hdl-c Reduced VLDL-C is associated with decreased CV events Pharmacologic treatment of high VLDL-C has potential to reduce CV risk

44 Non-HDL-C: Cholesterol Carried by All Apolipoprotein (Apo) B Lipoproteins Triglyceride Cholesterol All atherogenic lipoproteins HDL LDL IDL VLDL Chylomicron remnant Apo AI Apo B Apo B Apo B Apo B48 non-hdl Non-HDL-C = Total-C HDL-C

45 Terminology LDL-c = Total Cholesterol ( HDL-c + Triglycerides/5) Non-HDL-C = LDL-C + TRL-C TRL-C = triglyceride-rich lipoprotein cholesterol The term remnant cholesterol is sometimes used for TRL-C VLDL-C is a surrogate for TRL-C VLDL-C is highly correlated with TRL-C, but does not fully account for total TRL-C, which includes: VLDL-C IDL-C Chylomicron remnant-c

46 Meta-analysis of Risk for Major CV Events with Statin Therapy: Discordance Analysis When discordant, risk follows non-hdl-c, not LDL-cC Boekholdt SM, et al. JAMA. 2012;307:

47 High hepatic TG production results in elevated triglyceride-rich lipoprotein cholesterol (TRL-c) and low LDL-c ApoA5 Very Small VLDL LPL Large LDL TG Production ApoB TRL-c ApoE ApoB LDL-C High Low Non-HDL-C TG Renal clearance CETP HDL HL shdl ApoB Large VLDL ApoC-III ApoE LPL Triglyceride-rich lipoprotein-c Cholesterol CE LPL/HL HL Remnants Small slow LDL ApoB ApoB ApoB ApoE ApoC-III ApoC-III Non-HDL-C Triglycerides TG TG LDL-C Very Smal LDL ApoC-III

48 CHD Risk with Triglyceride Elevation Risk Contained within Non-HDL-C and HDL-C Analyses of log e TG were adjusted for HDL-C and non-hdl-c. Analyses of HDL-C were adjusted for non-hdl-c and log e TG. Analyses of non-hdl-c were adjusted for HDL-C and log e TG. Emerging Risk Factors Collaboration. JAMA. 2009;302:

49 Non-HDL Cholesterol Discordance Meta-Analysis Risk of Major CV Events during Statin Therapy HRs adjusted for sex, age, smoking, diabetes, systolic BP and trial When discordant, risk follows non-hdl-c, not LDL-C Boekholdt SM, et al. JAMA. 2012;307:

50 The effects of high vs low hepatic lipogenesis on lipid metabolism ApoA5 Very Small VLDL LPL Large LDL TG Production ApoB ApoE Remnant Cholesterol ApoB LDL-C High Low Non-HDL-C TG Renal clearance CETP HDL HL shdl ApoB Large VLDL ApoC-III ApoE LPL CE Remnants ApoB ApoE ApoC-III Remnant Cholesterol LPL/HL slow TG Small LDL HL TG ApoB ApoB ApoC-III LDL-C Very Smal LDL ApoC-III Cholesterol Non-HDL-C Triglycerides

51 more VLDL-C and less LDL-C within non- HDL-C associated with Increasing CV Risk (VLDL-C) Varbo A, et al. J Am Coll Cardiol. 2013;61:

52 Lipoprotein Cholesterol Levels and IHD Copenhagen Studies (n = 73,513): Risk of Ischemic Heart Disease By Lipoprotein Cholesterol Levels Varbo et al. JACC 2013;61:

53 Lipoprotein Genotypes and IHD Copenhagen Studies: Causal vs Observational Risk Estimates HRs for 1 mmol/l or a 1 ratio unit increase or decrease in plasma lipoprotein levels Varbo et al. JACC 2013;61:

54 Fibrates, EPA, Niacin CV Outcome Trials - The STRENGTH trial with Epanova is targeting the high TG/low HDL-C segment which is the population at greatest risk due to non-hdl-c elevation on statin therapy Larger Risk Reductions in with Patients with Hypertriglyceridemia and Low HDL-C Trial (drug) HHS (gemfibrozil) BIP (bezafibrate) VA-HIT (gemfibrozil) FIELD (fenofibrate) ACCORD (fenofibrate) JELIS (ethyl-epa) AIM-HIGH (niacin) Entire cohort HR (95% CI) Subgroup Subgroup HR (95% CI) 0.66 (0.47, 0.92) TG 184 mg/dl BMI >27.5 kg/m (0.15, 0.58) 0.91 (NR) TG 200 mg/dl 0.60 (NR) 0.78 (0.65, 0.93) TG 151 mg/dl 0.73 (0.58, 0.93) 0.89 (0.75, 1.05) TG 204 mg/dl HDL-C <42 mg/dl 0.92 (0.79, 1.08) TG 204 mg/dl HDL-C 34 mg/dl 0.81 (0.69, 0.95) TG >150 mg/dl HDL-C <40 mg/dl 1.02 (0.87, 1.21) TG >198 mg/dl HDL-C <33 mg/dl 0.73 (0.58, 0.91) 0.69 (NR) 0.47 (0.23, 0.98) 0.74 (0.50, 1.09) Maki et al. J Clin Lipidol. 2012;6:413. Guyton et al. JACC 2013;62:1580.

55 Meta-regression Demonstrates that VLDL-C Lowering is Highly Correlated with a Reduction in the Hazard Ratio for a Major CV Event Each 8.9 mg/dl reduction in VLDL-C (equivalent to 0.5 mmol/l for TG) in the fibrate outcome trials is associated with a reduction of 26% in the hazard for a CV event 1.0 Y = *X ; r = -0.93, P = Y = *X ; r = -0.93, P = HR for CV Events BIP ACCORD FIELD VA-HIT SIHD HHS VLDL-C Reduction (mg/dl) Calculated from: Nordestgaard BG, Varbo A. Lancet. 2014;384: Maki KC, et al. J Clin Lipidol. 2012;6: SIHD is Carlson LA, Rosenhamer G. Acta Med Scand. 1988;223:

56 VLDL-C and LDL-C Changes in ACCORD in Subgroups with Dyslipidemia and Others Change in VLDL-C with Fenofibrate (mg/dl) High TG/Low HDL-C Others Change in LDL-C with Fenofibrate (mg/dl) High TG/Low HDL-C Others Fenofibrate Placebo Difference High TG was defined as TG 204 mg/dl and low HDL-C was defined as HDL-C 34 mg/dl. High TG/Low HDL-C subgroup: fenofibrate n = 316 and placebo n = 287 Others: fenofibrate n = 1465 and placebo n = 1495 FDA Briefing Document. Endocrinologic and Metabolic Drugs Advisory Committee Meeting. October 16, Available at: EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM pdf

57 VLDL-C is causal for atherosclerosis greater than LDL-C: Each VLDL particle carries 5-20X more cholesterol than LDL with unregulated uptake by macrophages VLDL VLDL Adapted from Nordestgaard BG, Varbo A. Lancet. 2014;384:

58 Cumulative incidence curves for risk of coronary heart disease (CHD) by small dense lowdensity lipoprotein-cholesterol (sdldl-c) and large buoyant LDL-C (lbldl-c) quartiles, adjusted for age, race, and sex. Hoogeveen R C et al. Arterioscler Thromb Vasc Biol. 2014;34: Copyright American Heart Association, Inc. All rights reserved.

59 Cumulative incidence of cardiovascular events in subgroups with low-density lipoproteincholesterol (LDL-C) <100 mg/dl (<25th percentile) and small dense LDL-C (sdldl-c) <27.8 mg/dl (<25th percentile), from proportional hazards models adjusted for age, sex, and race. Hoogeveen R C et al. Arterioscler Thromb Vasc Biol. 2014;34: Copyright American Heart Association, Inc. All rights reserved.

60 TG Cholesterol Triglycerides ApoA5 ApoB ApoC-III ApoE CETP HDL HL HDL-C shdl Renal clearance TG production + OM3-CA (EPA, DHA) TG high TG low VLDL LPL CE Remnants VLDL and remnant cholesterol LPL/HL (slow) TG Non-HDL-C LPL Small LDL HL TG Very small LDL LDL-C VLDL (-25.77*) Remnants (-19.85*) VLDL and remnant cholesterol Non-HDL-C Large LDL (+10.04*) LDL-C Small LDL (-7.75*) * Least-squares mean difference relative to olive oil. Apo, apolipoprotein; CE, cholesterol ester; CETP, cholesterol ester transfer protein; DHA, docosahexanoic acid; EPA, eicosapentanoic acid; HDL, high-density lipoprotein; HL, hepatic lipase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; TG, triglyceride; VLDL, very-low-density lipoprotein

61 The Effects of 10 lbs of weight loss

62 Hill s Criteria for Causation of ASCVD: LDL-C vs. TRL-C LDL-C TRL-C Strength Consistency Temporality Dose response Biologic plausibility Coherence/experiment* Rating of available evidence: + Fair, ++ Good, +++ Excellent *Coherence with other types of evidence, particularly experimental studies Analogy and specificity are less relevant for this type of exposure Bradford Hill A. Proc Royal Soc Med. 1965;58:

63 The importance of understanding the causal role of TRL-c vs LDL-c Elevated TRL-c explains the superiority of non-hdl-c over LDL-c as a predictor of CV risk Focusing only on LDL-c rather than both LDL-c and TRL-c (ie non-hdl-c) misses a potential opportunity to further lower CV events with therapy The primacy of LDL-c over non-hdl-c as a target of therapy raises inappropriate concerns regarding the increase in LDL-c with triglyceride lipoprotein lowering therapies Since TRL-c is at least as atherogenic as LDL-c, non-hdl-c should be the preferred target of therapy 63

64 ) Old vs new paradigm for CV risk assessment T- Chol = HDL-c (good) + VLDL-c (uncertain) + LDL-c (bad) T-Chol= HDL-c (uncertain)+ TRL-c (bad)+ LDL-c (bad) 64

65 STRENGTH (Epanova) vs. REDUCE-IT (Vascepa) Outcomes Trials Clinical factors STRENGTH REDUCE-IT Number of patients ~13,000 ~8000 Inclusion criteria TG 200 mg/dl, <500 mg/dl HDL-C <40 mg/dl (men) HDL-C <45 mg/dl (women) 4 weeks on statin Established CVD or at high risk for development CVD TG 200 mg/dl, <500 mg/dl (started with TG 150 mg/dl) 4 weeks on statin Established CVD or at high risk for development of CVD Primary endpoint MACE MACE Dosing regimen 4 g/d 4 g/d Placebo Corn oil Mineral oil

66 Of 15 variants that alter HDL-C, 6 also affect MI risk

67 Of 15 variants that alter HDL-C, 6 also affect MI risk

68 Of 15 variants that alter HDL-C, 6 also affect MI risk All 6 are HDL-C Plus (alter HDL-C & at least one other lipid fraction)

69 Odds Ratio for Coronary Artery Disease According to Selected Risk factors including Flux Capacity Khera AV et al. N Engl J Med. 2011;364:

70 HDL Metabolism Bile Mature HDL-C A-I SR-BI Liver FC LDL-C Receptor CE SR-BI CE E CETP LCAT HL, EL A-I FC Nascent HDL-C FC B CE VLDL/LDL-C Cuchel et al. Arterioscler Thromb Vasc Biol. 2003;23: Copyright 2003 American Heart Association, Inc.

71 HDL Metabolism with SRBI Blocked Bile Mature HDL-C A-I SR-BI Liver FC LDL-C Receptor CE SR-BI CE E CETP LCAT HL, EL A-I FC Nascent HDL-C FC B CE VLDL/LDL-C Cuchel et al. Arterioscler Thromb Vasc Biol. 2003;23: Copyright 2003 American Heart Association, Inc.

72 62 yo male with preclinical atherosclerosis

73 Particle shape HDL Can Be Subdivided into Various Subpopulations Apolipoprotein composition Discoidal Spherical A-I HDL A-I/A-II HDL E HDL Particle size Lipid-poor ApoA-I HDL 2b HDL 2a HDL 3a HDL 3b HDL 3c Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39 47.

74 HDL Structure and Composition Pre-beta Discoidal Shaped HDL Alpha Spherical Shaped HDL Initial Cholesterol Acceptor Delivers Cholesterol to Liver

75 The HDL Proteome Vaisar et al. J Clin Invest. 2007;117: American Society for Clinical Investigation.

76 Cholesterol Efflux Capacity and ASCVD Events: Dallas Heart Study 10% Low efflux 8% Q1 ASCVD Events: MI Stroke PCI/CABG CV death n=132 6% 4% 2% Log rank p=0.002 Q2 Q3 Q4 High efflux Rohatgi et al. NEJM 2014;371: % Years

77 HDL/RCT - Reason to believe Failures cast doubts on the HDL/RCT concept Human population studies show that plasma levels of high-density lipoprotein (HDL) cholesterol correlate inversely with cardiovascular risk. LXR agonists Safety issues BET BDi RVX 208 positive data HDL Biogenesis Small HDL Niacin AIM-high failed HPS-Thrive failed LXR agonists Safety issues ApoA1 RCT Large HDL ABCG5/G8 ABCA1/G1 Cholesterol excre on into bile CETPi Torcetrapib failed Dalcetrapib failed Anacetrapib? Evacetrapib? CETP LDL Plaque Macrophages 77

78 JUPITER: CVD Event Rates by Quartiles of HDL-C and Apo A-I Incidence Per 100 Person-Years Placebo Rosuvastatin 20 mg 0.0 Q1 Q2 Q3 Q4 Quartile of On-treatment HDL Cholesterol Concentration Q1 Q2 Q3 Q4 Quartile of On-treatment Apolipoprotein A1 Concentration Median LDL-C with rosuvastatin: 55 mg/dl Ridker PM, et al. Lancet. 2010;376(9738):

79 Testing for concordance Lower LDL-C concentration Observational epidemiology Genetic epidemiology Statin trials Implications for compounds LDL-C lowering Lower circulating Lp-PLA 2 activity Observational epidemiology Genetic epidemiology X Darapladib Higher circulating lipoprotein(a) Observational epidemiology Genetic epidemiology Various Circulating interleukin-6 receptor Observational epidemiology Genetic epidemiology?? IL-6 inhibitors Odds ratio (95% CI) LSC, Lancet 2010 ERFC, JAMA 2009 IL6R Genetics Consortium, Lancet 2012 Clarke, NEJM 2009

80 Superior doctors prevent the disease. Mediocre doctors treat the disease before evident. Inferior doctors treat the full blown disease. Huang Dee: Nai-Ching (2600 BC; first Chinese medical text).

81 INTERVENTIONAL LIPIDOLOGIST