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Tues 07 Anderson Dyslipidemia 0.5 0.75 1 1.25 1.5 Statin/more better Control/less better

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Text of Tues 07 Anderson Dyslipidemia 0.5 0.75 1 1.25 1.5 Statin/more better Control/less better

  • Contemporary  management  of  Dyslipidemia

    Todd  Anderson            Feb  2018

  • www.ccs.ca Dyslipidemia  Guidelines

    Disclosure  Statement

    Type  of  Relationship Organization  Name  

    Modest (less  than  $10K)  

    Significant (greater  than  $10K)  

    A  -­ Consulting  Fees/Honoraria   Amgen,  Sanofi,  Bayer

    B  -­ Officer,  Director,  Or  In  Any  Other  Fiduciary  Role  

    C  – Clinical  Trials   Merck,  Amgen,  Dal-­cor

    D  -­ Ownership/Partnership/Principal

    E  -­ Intellectual  Property  Rights  

    F  -­ Other  Financial  Benefit  

    I  have  not  had  an  affiliation  (financial  or  otherwise)  with  a  commercial  organization   that  may  have  a  direct  or  indirect  connection  to  the  content  of  my  presentation.

    I  have  had an  affiliation  (financial  or  otherwise)  with  a  commercial  organization  that   may  have  a  direct  or  indirect  connection  to  the  content  of  my  presentation.    Details   below.

    Does  your  presentation  describe  the  off-­label  use  of  a  device,  product,  or  drug  that  is   approved  for  another  purpose? No Yes If  you  answered  YES,  you  must  disclose  this  to  the  audience  within  

    your  presentation

    Within  the  past    two  years:

  • Approach  to  Risk   Management  

    Who,  how  when  to  screen

    How  to  evaluate   risk

    When  to  initiate  what   treatment

    Monitoring  and  surveillance

  • • Target  levels  of  LDL-­C

    • Role  of  Combination  therapy

    • Risk  assessment  strategies

    Areas  to  consider  guideline  change

  • Category Consider  Initiating   pharmaco-­therapy  if

    Target NNT

    Primary  prevention High  FRS  (≥20%)   all LDL-­C  <  2.0  mmol/L  or  

    >  50%  ↓

    Or

    Apo  B  <  0.8  g/L

    Or  

    non-­HDL-­C  <  2.6  

    mmol/L

    35

    Intermediate  FRS  (10-­ 19%)   LDL-­C  ≥  3.5  mmol/L   or  Non-­HDL  ≥  4.3   mmol/L   or  Apo  B  ≥  1.2  g/L   or  Men  ≥  50  and   women  ≥  60  yrs  and   one  additional  CVD  RF

    40

    Statin  indicated   conditions

    Clinical   atherosclerosis*

    20Abdominal  aortic   aneurysm Diabetes  mellitus >40  yrs 15  yrs  duration  for  age   >30  yrs  (DM  1) Microvascular  disease Chronic  kidney  disease   (age  ≥  50  y) eGFR  <  60   mL/min/1.73  m2 or ACR  >  3  mg/mmol LDL-­C  ≥  5.  0  mmol/L >50%  ↓  in  LDL-­C

    FRS  – modified  Framingham  Risk  Score;  ACR  – albumin:creatinine  ratio;  *  consider  LDL-­‐C  <  1.8  mmol/L  for  subjects  with  ACS  within last  3  months

  • www.ccs.ca Dyslipidemia  Guidelines

    The  Case  for  Lower  is  Better • Biological  plausibility  – Apo  B  lipoproteins  linked  to   atherogenesis

    • Epidemiology  data  – Mendelian  randomization

    • On  Rx  LDL-­‐C  related  to  events

    • CTT  meta-­‐analysis  – 22%  reduction  per  1  mmol/L  ↓

    • IVUS  trials

    • Emerging  randomized  trial  data  with  new  meds

  • www.ccs.ca Dyslipidemia  Guidelines

    Biological  Plausibility

    Labos  et  al.  ATVB  2018;;  ahead  of  press

    Statin  effect  is  mediated  entirely  by  change  in  LDL-­C

  • www.ccs.ca Dyslipidemia  Guidelines

    CHD  Reduction  from  Earlier  LDL-­C   Lowering:  Lifetime  low  LDL

    Ferrence BA,  et  al.  J  Am  Coll Cardiol.  2012;60(25):2631-­‐9.

    Association  between  1mmol/L  lower  LDL-­C  and  risk  of  CHD

    Lifetime  lower  LDL-­C  due  to  genetics  resulted  in  a  3-­fold   greater  reduction  in  the  risk  of  CHD  per  unit  lower  LDL-­C   than  that  observed  during  treatment  with  a  statin  started   later  in  life

  • 0.5 0.75 1 1.25 1.5

    Statin/more better Control/less better

  • Primary  Endpoint  — ITT  (2014)

    Simva  — 34.7%   2742  events  

    EZ/Simva  — 32.7%   2572  events  

    HR  0.936  CI  (0.887,  0.988) p=0.016  

    Cardiovascular  death,  MI,  documented  unstable  angina  requiring   rehospitalization,  coronary  revascularization  (≥30  days),  or  stroke

    7-­year  event  rates

    NNT=  50

  • An  Academic  Research  Organization  of   Brigham  and  Women’s  Hospital  and  Harvard  Medical  School

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

    LD L   C ho le st er ol  (m

    g/ dl )

    Weeks

    LDL  Cholesterol

    Evolocumab (median  30  mg/dl,  IQR  19-­46  mg/dl)

    Placebo

    59%  mean  reduction  (95%CI  58-­60),  P

  • An  Academic  Research  Organization  of   Brigham  and  Women’s  Hospital  and  Harvard  Medical  School

    0%

    2%

    4%

    6%

    8%

    10%

    12%

    14%

    16%

    Primary  Endpoint

    Evolocumab

    Placebo

    Months  from  Randomization

    CV  D ea th ,  M I,   St ro ke ,

    Ho sp  fo r  U A,  o r  C or Re va sc

    0 6 12 18 24 30 36

    Hazard  ratio  0.85 (95%  CI,  0.79-­0.92)

    P

  • www.ccs.ca Dyslipidemia  Guidelines

    PCSK9  Inhibition  and  Very  low  LDL-­‐C

    Giugliano  et  al.  Lancet  Aug  28,  2017

    25,982  Fourier  patients  – 4  week  LDL-­C Positive  outcomes  down  to  0.2  mmol/L

  • www.ccs.ca Dyslipidemia  Guidelines

    PCSK9  Inhibition  and  Very  low  LDL-­‐C

    Giugliano  et  al.  Lancet  Aug  28,  2017

    25,982  Fourier  patients  – 4  week  LDL-­C Positive  outcomes  down  to  0.2  mmol/L Primary  EP  – death,  MI,  revasc,   hospitalization  for  UA

  • www.ccs.ca Dyslipidemia  Guidelines

    Ongoing  Outcome  Trials  with  PCSK9  Inhibitors  

    ACS:  acute  coronary  syndrome;  CAD:  coronary  artery  disease;  CHD:  coronary  heart  disease;  CVD:  coronary  vascular  disease;  EZE: ezetimibe;  FH:Familial   Hypercholesterolemia;  HeFH:  Heterozygous  Familial  Hypercholesterolemia;  PAD:  peripheral-­‐artery  disease;  T2DM:  type  2  diabetes  mellitus. clinicaltrials.gov  accessed  August  25,  2015.

    Study   FOURIER ODYSSEY  OUTCOMES SPIRE-­‐1/  SPIRE-­‐2

    Treatment

    Evolocumab:  420  mg  QM  or     140  mg  Q2W  

    Background:  optimal  lipid   lowering  therapy

    Alirocumab:  75  mg  Q2W   (up  titrated  to  150  mg  Q2W  if   LDL  >1.3  mmol/L;;  down  titrated  

    if  LDL  

  • www.ccs.ca Dyslipidemia  Guidelines

    CETP  Inhibition  in  CV  disease

    Landry  et  al.  NEJM;;  Aug  24,  2017 30449  in  TIMI  55/Reveal  Study

  • www.ccs.ca Dyslipidemia  Guidelines

  • www.ccs.ca Dyslipidemia  Guidelines

    Targets  – ACC/AHA  

    Lloyd-­Jones  JACC  2017

  • www.ccs.ca Dyslipidemia  Guidelines

    When  to  Consider  Pharmacological  Treatment  in   Risk  Management  – Statin  Indicated  conditions

  • www.ccs.ca Dyslipidemia  Guidelines

    Targets  – American  Association  of   Clinical  Endocrinologists  

    Jellinger  et  al.  Endocrine  Practice  2017;;23:supplement

  • www.ccs.ca Dyslipidemia  Guidelines

    Quantitative  approach  to  non-­statins

    Robinson  et  al.  JACC  2016;;68:2412

    Defined  risk  based  on   trials Used  %  reduction  in   LDL-­C  for  various   drugs  to  determine   NNT  in  different   scenarios CTT  estimate  of  event   reduction  based  on   22%  per  1  mmol/L

    Very  high  risk  – CVD  plus  DM   or  CKD  or  FH,  or  recent  ACS

    High  risk  – CVD  alone,  or  FH   in  primary  prevention

  • www.ccs.ca Dyslipidemia  Guidelines

    PCSK9  Inhibition  – cost  effectiveness

    Fonarow  et  al,  JAMA  Cardiology,  August  2017

    Annual  event  rate  of  6.4%/yr

  • www.ccs.ca Dyslipidemia  Guidelines

    • Target  levels  of  LDL-­C • Lower  target  of  1.8  for  ASCVD • Elimination  of  target  – use  indications  for  combination   therapy

    • >  50  %  reduction  and  target  of  <  1.8  for  ASCVD

    • Role  of  Combination  therapy • Change  in  status  of  PCSK9  inhibitors

    • Risk  assessment  strategies • More  categories  of  risk   • Diff