Dyslipidemia Management in 2016

Michael Heffernan MD PhD FRCPC FACC

Faculty/Presenter  Disclosure  

•  Faculty:  Dr.  Michael  Heffernan  •  Title  of  Talk:  2016  Dyslipidemia  Update  

•  Relationships  with  commercial  interests:  •  Grants/Research  Support:  Bayer,  Boehringer  Ingelheim,  

Esai,  AstraZeneca  

•  Speakers  Bureau/Honoraria:  AstraZeneca,  Bayer,  Boehringer  Ingelheim,  Bristol  Myers  Squibb,  Pfizer,  Amgen,  Servier,  Sanofi  

•  Consulting  Fees:  Bayer,  AstraZeneca,  Boehringer  Ingelheim,  Amgen,  Sanofi  

•  Other:  None  

Objectives  

  Identify patients not at LDL-C goal despite current treatment and discuss why they would benefit from further LDL-C reduction

  Appraise clinical data and new treatment strategies to lower LDL-C in the high risk patient

  Discuss clinical management of the high risk patient not at goal and implementation of new treatment strategies

At  the  end  of  this  presentation,  the  participant  will  be  able  to:  

The Case: John

  56y  male  

  HTN,  dyslipidemia    Previous  MI  and  angioplasty  at  age  48y  

  Family  history  of  premature  CAD  

  Non-­‐smoker    Exercises  100  min/week  

  ALended  cardiac  rehab  and  adheres  to  dietary  guidelines  

The Case

  Medica'ons  −  ASA  81  mg  once  daily    −  AtorvastaOn  20  mg  −  Bisoprolol  5  mg  once  daily  −  Ramipril  10  mg  once  daily  

  Lipid  Profile  −  TC:  5.9  mmol/L  −  TG:1.4  mmol/L    −  HDL-­‐C:  1.4  mmol/L  −  LDL-­‐C:  3.6  mmol/L  (current)  −  non-­‐HDL-­‐C:  4.3  mmol/L    

−  He  has  tried  rosuvastaOn  but  was  unable  to  tolerate  it  (mylagias)  −  He  was  on  40  mg  of  atorvastaOn  however  this  also  provoked  myalgias  −  He  can  tolerate  20  mg  of  atorvastaOn  

What is John’s Target and Why Do We Want to Get Him There ?

The Cholesterol Hypothesis Originated with Observational Studies

Epidemiologic Data – Serum Cholesterol Levels and CHD

MRFIT trial: age-adjusted CHD death rate and serum cholesterol in 361,662 US men (aged 35–57 years)

Each 1% Increase in Total Cholesterol Level is associated with

a 2% Increase in CHD Risk

Martin MJ, et al. Lancet 1986;2:933–936 8

Clinical Trials Validated The LDL Hypothesis

@>4'(.:(24'$*2(&:%(8:$*2/&'/.:.[$Y@**Z$@4''&M42&O48T$V&8G(:T$PIHI\X]"SH"]ICH"<H\$@&8848$@1,$(:$&'T$^$A%$@4''$@&2-/4'T$PII"\;<YXZS;X<C;!\$A8-(2.48$*^,$W2_94/2($^,$(:$&'T$@&8$^$@&2-/4'T$PIH;\XIY;ZSX]]C<I\$A-&0:(-$?24%$W4L4$A$^2,$`0/($V)T$B259.$?42$:>($)(&2:T$]:>$(-T$1>/'&-('0>/&S$E'.(3/(2$N&58-(2.T$PIIUSX!XT$

30

25

20

10

5

0 1.8 2.5 3.0 3.5 4.0 4.5 5.0 5.4

LDL-C mmol/L

Primary Prevention

CH

D E

vent

Rat

e,%

1.3

Ascot-T

Secondary Prevention

Primary Prevention Ascot-T

Secondary Prevention

DIABETES 1O PREVENTION

JUP-T JUP-P

Ascot-P

AFCAPS-P

AFCAPS-T WPS-T

WPS-P TNT-80

CARDS-T

HPS-T PROS-T

HPS-P PROS-P Care-T

Lipid-T

Care-P

Lipid-P 4S-T

4S-P

15

TNT-10

These trials have demonstrated that LDL-C lowering is associated with greater reduction of CHD events

Amount of LDL-C Reduction is Associated with Proportional Reduction in CV Events

HT! @>4'(.:(24'$*2(&:%(8:$*2/&'/.:.[$@4''&M42&O48T$V&8G(:T$PII!\X""SHP"]CHP]<T$PT! @>4'(.:(24'$*2(&:%(8:$*2/&'/.:.[$@4''&M42&O48T$V&8G(:T$PIHI\X]"SH"]ICH"<H$XT! @&8848$@1,$$761R`aEC7*$783(.O9&:42.T$+$E89'$^$6(-T$PIH!\X]PYP!ZSPX<]CU]T$

10%

0.5 0%

20%

30%

40%

50%

-10%

1.0 1.5 2.0

Reduction in LDL cholesterol (mmol/L)

Prop

ortio

nal r

educ

tion

in e

vent

rate

(SE)

The IMPROVE-IT Study

1.8 mmol/L

1.4 mmol/L

Simvastatin + Ezetimibe

Simvastatin

Simvastatin + Ezetimibe

Simvastatin

Simvastatin + Ezetimibe

Simvastatin

100

90

80

70

60

50

40

Mea

n LD

L-C

(mg/

dL)

Time since randomization (months)

QE R 1 2 8 12 16 24 36 48 60 72 84 96

761R`aEC7*$783(.O9&:42.T$+$E89'$^$6(-T$PIH!\X]PYP!ZSPX<]CU]T

Effect of Lower LDL-C on the Risk of CHD Appears to be Independent of the Mechanism by which LDL-C is Lowered

@>4'(.:(24'$*2(&:%(8:$*2/&'/.:.[$@4''&M42&O48T$V&8G(:T$PII!\X""SHP"]CHP]<\$*>($@4248&2#$B259$124b(G:$R(.(&2G>$W2450T$^A6AT$HU]!\PXHSX"IcX<H\$Q2(8./D($^=,$(:$&'T$@/2G5'&O48T$HU<;\"USXHXcXP;\$Q5G>K&'-$)$(:$&'T$+!"#$%!&!'()T$HUUI\XPXSU;"cU!!\$Q522$6V$(:$&'T$*+#,(-T$HU<U\PS]!]c]"HT$\$@&8848$@1,$$761R`aEC7*$783(.O9&:42.T$+$E89'$^$6(-T$PIH!\X]PYP!ZSPX<]CU]T$

Non-statin lipid-lowering studies suggest coronary event reduction is due to LDL-C reduction, independent of method

CTTC trials (statin)

Niacin

Diet/unsat. Fatty acid

Ileal bypass

Bile acid resin

Ezetimibe

Fibrate

0

10

20

30

40

50

IMPROVE-IT

0.3 0.5 0.8 1.0 1.3 1.5 1.8 2.1 Reduction in LDL-C (mmol/L)

Red

uctio

n in

Car

diov

ascu

lar E

vent

s (%

)

More LDL lowering and risk reduction

-1.2"

-0.6"

0"

0.6"

1.2"

1.8"

1.3" 1.5" 1.8" 2.1" 2.3" 2.6" 2.8" 3.1"

Median Change

In Percent Atheroma

Volume (%)

REVERSAL pravastatin

REVERSAL atorvastatin

CAMELOT placebo

A-Plus placebo

ACTIVATE placebo

Change in Progression of IVUS Percent Atheroma Volume versus LDL-C in IVUS Trials

ASTEROID rosuvastatin"

r2= 0.95 p<0.001

On-Treatment LDL-C (mmol/L) JAMA 2006; 295:1556-1565 Cleve Clin J Med 2006;73:937-944

Summary: The LDL Hypothesis

  Epidemiologic data indicates a direct relationship between total cholesterol levels and CV outcomes

  Clinical trials to date indicate that decrease in total cholesterol or LDL-C with statin therapy or other measures leads to a proportionate decrease in CV outcomes

  The IMPROVE-IT trial has reaffirmed the lipid hypothesis by demonstrating that non-statin therapy can achieve an LDL-C decrease that translates into a similar CV risk reduction as that previously observed with statins

  LDL values well below 2.0 appear to confer additional benefit

Lower is Better – How Do We Get John to Target ?

a)  Double  staOn  dose  

b)  Add-­‐on  ezeOmibe  

c)  Add-­‐on  fibrate  

d)  Add-­‐on  PCSK9  inhibitor  

2012 Canadian Cardiovascular Society Dyslipidemia Guidelines

Anderson et al Can J Cardiol 2013;29151-67:

Risk Level Initiate Therapy if Primary LDL-C Target Alternate Target

LOW FRS < 10%

#!LDL-C > 5.0 mmol/L #!Familial

hypercholesterolemia

!50% reduction in LDL-C

INTERMEDIATE FRS 10 – 19%

#!LDL-C > 3.5 mmol/L #!For LDL-C < 3.5 mmol/L

consider if: Apo B > 1.2 g/L or Non-HDL-C > 4.3 mmol/L

"2 mmol/L or !50% decrease in LDL-C (Strong, Moderate)

#!Apo B "0.8 g/L #!Non-HDL-C "2.6

mmol/L

HIGH* FRS ! 20% Consider treatment in all

"2 mmol/L or !50% decrease in LDL-C (Strong, High)

#!Apo B "0.8 g/L #!Non-HDL-C "2.6

mmol/L

16

Statin Therapy Has Been Effective in Reducing LDL-C, however, Even Maximal Statin Therapy is Insufficient for Some Patients

gA.$0(2$@&8&-/&8$124-5G:$648492&0>.$HT! @2(.:42$Y24.53&.:&O8Z$124-5G:$648492&0>T$A.:2&h(8(G&T$6&#$H,$PIHX$PT! V/0/:42$Y&:423&.:&O8Z$124-5G:$648492&0>T$1ed(2T$N(0T$;,$PIHPT$XT! 12&3&G>4'$Y02&3&.:&O8Z$124-5G:$648492&0>$Q2/.:4'C6#(2.$Ni5/MM$@&8&-&T$^&8T$

HH,$PIHXT$$;T! 6(3&G42$Y'43&.:&O8Z$124-5G:$648492&0>T$6(2GDT$^5'T$P;,$PIHPT$

0% 10% 20% 30% 40% 50% 60%

Atorvastatin 10 mg 20 mg 40 mg

Simvastatin 10 mg 20 mg 40 mg

Pravastatin 10 mg 20 mg 40 mg

Lovastatin 20 mg 40 mg 80 mg

Fluvastatin 20 mg 40 mg

5.! Zocor (simvastatin) Product Monograph. Merck. Jun. 6, 2012. 6.! Lescol (fluvastatin) Product Monograph. Novartis. Sep. 27,

2012. 7.! Adapted from Jones P, et al. for the CURVES Investigators.

Am J Cardiol. 1998;81:582-587.

Rosuvastatin 10 mg 20 mg 5 mg 10 mg 20 mg 40 mg

80 mg

Doubling the statin dose results in only 6% LDL reduction

Add-On Therapy has had Moderate Benefit in Further Lowering LDL-C

j/8$>/9>$2/.D$A@N$0405'&O48$

N5G>#$B,$(:$&'T$1>&2%&G4'$R(0T$PIHH\"XSHXX!C;<\$PT$@&8848$@1,$$761R`aEC7*$783(.O9&:42.T$+$E89'$^$6(-T$PIH!\X]PYP!ZSPX<]CU]\$$;T$R50&2('/&$+,$(:$&'T$@522$`0/8$@&2-/4'T$PIHH\P"S""c]I\$!T$@d/2&D#$6^,$(:$&'T$^$6&8&9$@&2($1>&2%T$PII<\H;Y<$N500'ZSNXCP<\$"T$@2(/-(2$^@,$(:$&'T$+&:T$R(3T$E8-4G2/84'T$PIHP\<S!H]c!P<\$$]T$A76C)7W)$783(.O9&:42.T$+$E89'$^$6(-T$PIHH\X"!SPP!!C"\$<T$)1NPC*>2/3($@4''&M42&O3($W2450T$E52$)(&2:$^T$PIHX\X;YH]ZSHP]UCUH\$$UT$*(8(M&5%$A,$=/.>%&8$EhT$@&2-/43&.G$B/&M(:4'T$PIHP\HHSHP!\$HIT$645:d452/$E,$(:$&'T$a&.G$)(&':>$R/.D$6&8&9T$PIHI\"S!P!CXU\$HHT$@42./8/$A,$(:$&'T$E52$^$@&2-/43&.G$12(3$R(>&M/'T$PIIU\H"YHZSHCUT$

Add-On Therapy$ LDL-C Lowering+ Other Lipid Effects+

Outcome Data (Add-on to statin)+

Niacin4-6$ 20% + " HDL by 30% # TG by 40%$

No benefit as add-on to statin7,8$

Fibrates9,10$ 5 – 20%+" HDL-C (10-50%) # TG (20-50%) No benefit as

add-on to statin$

Bile Acid Sequestrants11$

15 – 20%+ Limited$

Ezetimibe1 15 – 25%

IMPROVE–IT ~6.5% reduction in CV events (CVD/MI/stroke)2†

Current Therapy Options May Not Get Some of Our High Risk Patients to LDL-C Goal

-20

-40

-60

-80

1970’s 1980’s 1990’s 2000’s 2010’s

-20%

-40%

-60%

Nia

cin

BA

S

Stat

ins

1st G

en

Ezet

imib

e

-20% -10% Fi

br-

ates

Stat

ins

2nd G

en -20%

IMPR

OVE

-IT

-20%

0

reduction on top

of statin LDL-

C L

ower

ing

(%)

@'4eM2&:($&8-$8/&G/8$/8$G4248&2#$>(&2:$-/.(&.(T$^A6AT$HU]!\PXHY;ZSX"IcX<H\$*>($V/0/-$R(.(&2G>$@'/8/G.$@4248&2#$12/%&2#$12(3(8O48$*2/&'$2(.5':.T$^A6A$HU<;\P!HYXZSX!HC";\$=2/GD$6),$(:$&'T$+$E89'$^$6(-T$HU<]\$XH]S$HPX]cHP;!\$+&O48&'$78.O:5:($?42$)(&':>$&8-$@'/8/G&'$EFG(''(8G(T$V48-48S$+&O48&'$78.O:5:($?42$)(&':>$&8-$@'/8/G&'$EFG(''(8G(,$PII]\$a&59>&8,$@&2'$^,$(:$&'T$@/2G5'&O48T$PII;\$HHIS$<<"C<UP\$@&8848$@1,$$761R`aEC7*$783(.O9&:42.T$+$E89'$^$6(-T$PIH!\X]PYP!ZSPX<]CU]T$$

Despite Guideline Targets Many High-risk Canadian Patients Treated with Statins Are Not at LDL-C Goal

g)/9>$2/.D$k$,./.#+/0!+/-(/0!)12(+2(3!4(/145(/+%!+/-(/1+%!)12(+2(3!,(/(6/.7+2,8%+/!)12(+2(3!)1+6(-(2!9(%%1-82!./!:/+91#$5+9!;<=0(+/!/12>!2,./(!?@<AB!CDEFE!E-8)0!G!@3HIJ!4+K(#-23!;L;I!51$5!/12>!4+K(#-2B!!j+$k$!,I"U$

HT$W44-%&8$NW,$(:$&'T$48$M(>&'?$4?$:>($BlN7N$@&8&-/&8$783(.O9&:42.T$@&8$^$@&2-/4'T$PIHI\P"YUZS(XXIC(XX!T$$$PT$V(/:(2$VB,$(:$&'T$@&8$^$B/&M(:(.T$PIHX\X]S<PC<UT$

Canadian high-risk patients are NOT at LDL-C target1* ($ 2 mmol/L) !! 88% of patients received a ‘potent’ statin with suboptimal dose !! 14% of patients received additional lipid-lowering agent

45%

g)/9>$2/.D$k$,./.#+/0!+/-(/0!)12(+2(3!4(/145(/+%!+/-(/1+%!)12(+2(3!,(/(6/.7+2,8%+/!)12(+2(3!)1+6(-(2!9(%%1-82!./!:/+91#$5+9!;<=0(+/!/12>!2,./(!?@<AB!CDEFE!E-8)0!G!@3HIJ!4+K(#-23!;L;I!51$5!/12>!4+K(#-2B!!g)/9>$2/.D$k$

Canadian patients with diabetes are NOT at LDL-C target2† ($ 2 mmol/L) !! 82% of patients were on a lipid-lowering agent

43%

New Therapies and New Guidelines

The French Connections

•  Catherine  Boileau  at  the  Necker-­‐Enfants  Malades  Hospital  in  Paris  had  been  following  families  with  FH  • Her  lab  had  idenOfied  a  mutaOon  on  chromosome  1  carried  by  some  of  these  families,  but  had  been  unable  to  idenOfy  the  relevant  gene  

 In  February  2003,  Nabil  Seidah  at  the  Clinical  Research  InsOtute  of  Montreal  discovered  a  novel  human  proprotein  convertase  on  chromosome  1  

• Proprotein  convertase  subOlisin/kexin  type  9  (PCSK9)  

Discovery of PCSK9

•  The  labs  colloborated  and  by  the  end  of  2003  they  published  the  connecOon  between  PCSK9  mutaOons  and  familial  hypercholesterolemia  

•  This  was  the  third  gene  involved  in  autosomal-­‐dominant  familial  hypercholesterolemia  along  with  mutaOons  in  the  LDL  and  ApoB  genes  

• A  gain  of  funcOon  mutaOon  destroys  LDL  receptors  and  therefore  increases  LDL  resulOng  in  familial  hypercholsterolemia  (FH)  and  premature  CAD  

•  PCSK9  became  an  obvious  target  for  drug  development  

PCSK9 Expression

LDL-R Expression

Statin Influence on LDL-C Metabolism and PCSK9

Acetyl-CoA + acetoacetyl-CoA

HMG-CoA reductase Plasma

Nucleus Endoplasmic

Reticulum (ER)

Hepatocyte

SREBP Activation

LDL-R PCSK9 Protein

LDL Protein at Cell Surface

LDL

PCSK9 Secretion PCSK9 Secretion

PCSK9 Expression

LDL-R Expression

Hepatocyte Cholesterol Content

Hepatocyte Cholesterol

HMG-CoA

Intracellular Cholesterol

Biosynthesis

Acetyl-CoA + acetoacetyl-CoA

STATIN HMG-CoAreductase

Intracellular Cholesterol

Biosynthesis

PCSK9

n/&8$lo,$(:$&'T$^$V/0/-$R(.T$PII]\;<SH;<<CH;U<\$)42:48$^B,$(:$&'T$^$V/0/-$R(.T$PIIU\!IY.500'ZSNH]PCNH]]T$$

LDL

LDL-R

Endocytosis

LDL-R Recycling Endosome

LDL Degradation

LDL

LDL-R

Endocytosis

Endosome

PCSK9

PCSK9 Self-procession

Hepatocyte

Plasma

© 2013 Amgen Canada Inc. All rights reserved.

Golgi Apparatus

Endoplasmic Reticulum

(ER) Nucleus LDL, LDL-R and PCSK9 Degradation

LDL Degradation LDL Degradation

LDL, LDL-R and PCSK9 Degradation

PCSK9 Inhibitors: Targeted Therapy

n/&8$lo,$(:$&'T$^$V/0/-$R(.T$PII]\;<SH;<<CH;U<\$)42:48$^B,$(:$&'T$^$V/0/-$R(.T$PIIU\!IY.500'ZSNH]PCNH]]T$$

PCSK9 Self-procession

PCSK9 mAb

LDL-R

Endocytosis

Endosome

LDL Degradation

LDL-R Recycling

Lysosome

LDL

Hepatocyte

Plasma

© 2013 Amgen Canada Inc. All rights reserved.

Golgi Apparatus

Endoplasmic Reticulum

(ER) Nucleus

PCSK9 Inhibitors: Targeted Therapy

PCSK9 Inhibitors Were Developed to Target a Key Process in Lipid Metabolism

  TargeOng  and  inhibiOng  PCSK9  acOvity  leads  to  an  increase  in  LDL  receptor  levels,  which  increases    removal  of  LDL-­‐C  

  PCSK9  inhibitors  (PCSK9i)  −  Evolocumab  −  Alirocumab*  −  Bococizumab*  

* Investigational product, not approved by Health Canada PCSK9 = Proprotein Convertase Subtilisin Kexin Type 9

Patients with Less PCSK9 due to Loss-of-function Mutations have Lower Serum LDL-C and Significantly Lower Incidence of CHD

30

20

10

0 9.7%

PCSK9142x or PCSK9679X

No

12

8

4

0

30

20

10

0

No nonsense mutation

(n = 3,278) 50th Percentile

Plasma LDL cholesterol in black subjects (mmol/L)

Freq

uenc

y (%

)

1.2%

PCSK9142x or PCSK9679X

(n=85)

Cor

onar

y H

eart

Dis

ease

(%)

Mean 3,57 mmol/L

Mean 2,57 mmol/L (-28%)

88% reduction in the risk of CHD events during 15-year follow-up

Yes

1.3

1.3

2.6

2.6

3.9

3.9

5.2

5.2

6.5 7.8

6.5 7.8

Cohen JC et al. N Engl J Med 2006;354:1264-72 29

A Race To Bring PCSK9 Therapy To Patients

PROFICIO Program Evaluates Reduction in LDL, Atherosclerosis, and CV Risk with Evolocumab

DESCARTES (N=901)

OSLER-2 (N>3,800)

OSLER (N=1,324)

Long-term safety and efficacy

Open-label extension

GLAGOV (N=950)

FOURIER (N=27,500)

Plaque imaging study

Secondary prevention

GAUSS2 (N=329)

LAPLACE-2 (N=1,896)

MENDEL-2 (N=614)

GAUSS3 (N=100)

RUTHERFORD-2 (N=307)

TESLA/TAUSSIG (N<250)

LAPLACE (N=629)

MENDEL (N=406)

GAUSS (N=157)

RUTHERFORD (N=167)

TESLA (N<67)

Combo-therapy with statin

Mono-therapy

Statin-intolerant

HeFH with LDLR mutations

HoFH with mutations in both LDLR alleles

Phase 2 Phase 3

ODYSSEY Program Evaluates Reduction in LDL, Atherosclerosis, and CV Risk with Alirocumab

V6*k$'/0/-$%4-/?#/89$:>(2&0#$$g=42$:>($`BlNNEl$@`6Q`$77$4:>(2$V6*$84:$$&''4K(-$&:$(8:2#$@'/8/G&':2/&'.T943$&GG(..(-$A595.:$P!,$PIH!T$

HeFH population HC in high CV risk population Additional populations

Add-on to max tolerated statin (+/- other LMT)

HC in high CV risk population (+/- other LMT)*

ODYSSEY FH I N=471; 18 months

ODYSSEY FH II N=250; 18 months

ODYSSEY HIGH FH N=107; 18 months

ODYSSEY COMBO I N=314; 12 months

ODYSSEY COMBO II N=720; 24 weeks

ODYSSEY CHOICE I N=803; 24 weeks

ODYSSEY LONG TERM N=2,341; 18 months

ODYSSEY OUTCOMES N=18,000; >5 years

ODYSSEY MONO Patient on no background LMT

N=103; 24 weeks

ODYSSEY ALTERNATIVE Patients with defined statin

intolerance N=314; 24 weeks

ODYSSEY OPTIONS I Patients not at goal with

moderate dose atorvastatin N=355; 6 months

ODYSSEY OPTIONS II Patients not at goal with

moderate dose rosuvastatin N=305; 6 months

Primary/secondary Prevention N=77; 12 weeks

PII

PIII

Primary Hypercholesterolemia N=92; 8 weeks

ODYSSEY CHOICE II Patients with

hypercholesterolemia on non-statin LMT or diet

N=200; 6 months

Interesting Concept, But Will It Help John ?

OSLER: Evolocumab Plus Standard of Care Achieved a 61% Reduction in LDL-C over Standard of Care at 12 Weeks

N&M&O8($6N,$(:$&'T$+$E89'$^$6(-T$PIH!\X]PYH"ZSH!IICUT$

61% reduction (95%CI 59-63%), P<0.0001

Absolute reduction: 1.9 mmol/L

(Parent study) (OSLER)

3.1 mmol/L

1.2 mmol/L

3.6

3.1

2.6

2.1

1.6

1.0

.52

0

N=4465 N=1258 N=4259 N=4204 N=1243 N=3727

Evolocumab plus standard of care Standard of care alone

ODYSSEY Long-Term: Alirocumab Achieved a 62% Reduction in LDL-C vs Placebo at 24 weeks

R4M/8.48$^,$(:$&'T$+$E89'$^$6(-T$PIH!\X]PYH"ZSH;<UCUUT$

3.60

3.00

2.40

1.80

1.20

0.60

0.00

Mea

n C

alcu

late

d LD

L-C

(mm

ol/L

)

Week

0 4 8 12 16 24 36 52 64 78

0.8%

3.08 mmol/L 3.17 mmol/L

3.6%

1.25 mmol/L

-61.0%

1.50 mmol/L

-52.4%

Alirocumab + statin therapy at maximum tolerated dose ± other LLT Placebo + statin therapy at maximum tolerated dose ± other LLT

Placebo Alirocumab

780 1530

754 1473

747 1458

746 1436

716 1412

708 1386

694 1359

676 1349

659 1324

652 1269

No. of patients with data available

62% reduction, P<0.001

Absolute reduction: 1.2 mmol/L

OSLER: Reduction in the Rate of CV Events Among Patients Receiving Evolocumab

g12(C.0(G/e(-$$(F0'42&:42#$&8&'#./.$?24%$40(8C'&M('$(F:(8./48$.:5-/(.$`NVER$H$&8-$P$4?$&-b5-/G&:(-$G&2-/43&.G5'&2$(3(8:.T$$$

N&M&O8($6N,$(:$&'T$+$E89'$^$6(-T$PIH!\X]PYH"ZSH!IICUT$

3

2

1

0

0 30 60 90 120 150 180 210 240 270 300 330 365

Cum

ulat

ive

Inci

denc

e (%

)

Days since Randomization

Evolocumab plus standard of care (N=2976) Standard of care alone (N=1489)

Composite Endpoint: Death, MI, UA % hospitalization coronary revasc, stroke, TIA, or CHF % hospitalization

HR 0.47 95% CI 0.28-0.78 P=0.003

53% RRR

2.18%

0.95%

ODYSSEY Long-Term: Reduction in the Rate of CV Events Among Patients Receiving Alirocumab

g$6&b42$@a$(3(8:.$M&.(-$48$02/%&2#$(8-04/8:$?42$:>($`BlNNEl$`p*@`6EN$:2/&'S$@)B$-(&:>,$+48C?&:&'$67,$=&:&'$&8-$848C?&:&'$/.G>(%/G$.:24D(,$p8.:&M'($&89/8&$2(i5/2/89$>4.0/:&'/d&O48T$VV*,$'/0/-C'4K(2/89$:>(2&0#$† q$!P$K((D.$?42$&''$0&O(8:.$G48O85/89$:2(&:%(8:,$/8G'T$"I]$0&O(8:.$K>4$G4%0'(:(-$o]<$3/./:$

R4M/8.48$^,$(:$&'T$+$E89'$^$6(-T$PIH!\X]PYH"ZSH;<UCUUT$

788

1550

776

1534

731

1446

703

1393

682

1352

667

1335

321

642

127

252

84 72 60 48 36 24 12 0 Weeks No. at Risk

Placebo Alirocumab

Cum

ulat

ive

prob

abili

ty o

f eve

nt

0.06

0.05

0.04

0.03

0.02

0.01

0.00

Alirocumab + max-tolerated statin ± other LLT (150 mg q2w) Placebo + max-tolerated statin ± other LLT

54% RRR

Safety Analysis†

Cox model analysis HR 0.46 95% CI: 0.26 to 0.82 P<0.01

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event*

LDL-C

Achieve an LDL-C of 1.4 mmol/L (60% reduction from 3.6 mmol/L)

Improved tolerability in comparison to a statin in his circumstance

A suggestion of a significant decrease in future CV events – proof is pending

What might adding a PCSK9 inhibitor do for John?

ODYSSEY Long-Term*

Ratio of LDL Lowering to CV Event Reduction with PCSK9 Inhibitors Holds True to the “LDL Hypothesis”

g$Q&.(-$48$(F0'42&:42#$(8-04/8:.$?24%$1>&.($X$:2/&'.$

o&:(2.$BBT$).5($1lT$@/2G$R(.T$PIH!\H"SH";XCH";!T$

70%

60%

50%

40%

30%

20%

10%

0%

-10%

0.5 1.0 1.5 2.0

Prop

ortio

nal r

educ

tion

in e

vent

rate

(SE)

Reduction in LDL cholesterol (mmol/L)

OSLER*

IMPROVE-IT

PCSK9i Demonstrate a Further Reduction in LDL-C and an Impact on CV Events

  LDL-­‐C  Reduc'on:  PCSK9i  achieve  a  50-­‐60%  further  reducOon  in  LDL-­‐C  when  added  to  staOn  therapy    

  Safety  of  PCKS9i:  no  safety  signals  to  date  

  Safety  of  very  low  LDL-­‐C:  LiLle  to  no  evidence  to  show  that  very  low  LDL-­‐C  has  cause  for  concern  (geneOc,  staOn  data,  PCSK9i  data)  

  CV  risk:  IniOal  outcome  data  with  PCSK9i  to  date  have  suggested  CV  event  reducOon  (prospecOve  outcome  trials  are  underway).  

PCSK9i Can Achieve a Further 60% Reduction of LDL-C

-20

-40

-60

-80

-100

-120

1970’s 1980’s 1990’s 2000’s 2010’s 2015

-20%

-40%

-60%

Nia

cin

BA

S

Stat

ins

1st

Gen

Ezet

i- m

ibe

-20% -10% Fi

br-

ates

Stat

ins

2nd G

en

-20%

PCSK

9i

BA

CK

GR

OU

ND

LL

T

IMPR

OVE

-IT

-20%

-60%

reduction on top

of statin

LDL-

C L

ower

ing

(%)

PCSK

9i

@'4eM2&:($&8-$8/&G/8$/8$G4248&2#$>(&2:$-/.(&.(T$^A6AT$HU]!\PXHY;ZSX"IcX<H\$*>($V/0/-$R(.(&2G>$@'/8/G.$@4248&2#$12/%&2#$12(3(8O48$*2/&'$2(.5':.T$^A6A$HU<;\P!HYXZSX!HC";\$=2/GD$6),$(:$&'T$+$E89'$^$6(-T$HU<]\$XH]S$HPX]cHP;!\$+&O48&'$78.O:5:($?42$)(&':>$&8-$@'/8/G&'$EFG(''(8G(T$V48-48S$+&O48&'$78.O:5:($?42$)(&':>$&8-$@'/8/G&'$EFG(''(8G(,$PII]\$a&59>&8,$@&2'$^,$(:$&'T$@/2G5'&O48T$PII;\$HHIS$<<"C<UP\$@&8848$@1,$$761R`aEC7*$783(.O9&:42.T$+$E89'$^$6(-T$PIH!\X]PYP!ZSPX<]CU]\$N&M&O8($6N,$(:$&'T$+$E89'$^$6(-T$PIH!\X]PYH"ZSH!IICU\$R4M/8.48$^,$(:$&'T$+$E89'$^$6(-T$PIH!\X]PYH"ZSH;<UCUUT$

Summary

  ObservaOonal,  geneOc,  and  clinical  trial  data  support  the  LDL  hypothesis  −  A  lower  LDL  provides  CV  benefit  

 Many  high  risk  paOents  do  not  achieve  the  target  LDL  

  New  emerging  therapies  may  benefit  high  risk  paOents  that  are  unable  to  achieve  the  LDL  goal  on  a  staOn  plus  ezeOmibe  

  The  2016  Canadian  Dyslipidemia  Guidelines  will  be  released  soon  −  There  will  be  a  target  LDL  −  How  low  will  we  go  ?    

Thank You