Cập nhật điều trị Rối loạn Lipid máu năm 2016

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


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

30

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

CHD Event Rate,%

25

Secondary Prevention

4S-P

20
4S-T

15

1O

DIABETES
PREVENTION

Care-P
Care-T

10

HPS-T
PROS-T
TNT-80
TNT-10

Ascot-T

JUP-T

0
1.3

1.8

Lipid-T

HPS-P

PROS-P
WPS-P

AFCAPS-P

CARDS-T

5

Lipid-P

2.5

Primary Prevention

JUP-P AFCAPS-T

WPS-T
Ascot-P

3.0

3.5
4.0
LDL-C mmol/L

4.5

5.0

5.4

@>4'(.:(24'$*2(&:%(8:$*2/&'/.:.[$Y@**Z$@4''&M42&O48T$V&8G(:T$PIHI\X]"SH"]ICH"

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$


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

Proportional reduction in event rate (SE)

50%

40%

30%

20%

10%

0%
1.0

0.5

1.5

Reduction in LDL cholesterol (mmol/L)
-10%
HT!
PT!
XT!

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

2.0


The IMPROVE-IT Study
100
Simvastatin

Mean LDL-C (mg/dL)

90

Simvastatin + Ezetimibe

80

1.8 mmol/L

70
60

1.4 mmol/L
50
40
QE

R

1

2

8

12

16

24

36

48

60

72

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

84

96

Effect of Lower LDL-C on the Risk of CHD Appears
to be Independent of the Mechanism by which
LDL-C is Lowered
More LDL lowering
and risk reduction

Reduction in Cardiovascular Events (%)

50

40

Ezetimibe
Fibrate
Bile acid resin

30

Niacin
Diet/unsat. Fatty acid
20

Ileal bypass
CTTC trials (statin)

10
IMPROVE-IT
0
0.3

0.5

0.8
1.0
1.3
1.5
Reduction in LDL-C (mmol/L)

1.8

2.1

Non-statin lipid-lowering studies suggest coronary event reduction is due to
LDL-C reduction, independent of method
@>4'(.:(24'$*2(&:%(8:$*2/&'/.:.[$@4''&M42&O48T$V&8G(:T$PII!\X""SHP"]CHP]<\$*>($@4248&2#$B259$124b(G:$R(.(&2G>$W2450T$^A6AT$HU]!\PXHSX"IcXQ2(8./D($^=,$(:$&'T$@/2G5'&O48T$HU<;\"USXHXcXP;\$Q5G>K&'-$)$(:$&'T$+!"#$%!&!'()T$HUUI\XPXSU;"cU!!\$Q522$6V$(:$&'T$*+#,(-T$HU761R`aEC7*$783(.O9&:42.T$+$E89'$^$6(-T$PIH!\X]PYP!ZSPX<]CU]T$


Change in Progression of IVUS Percent
Atheroma Volume versus LDL-C in IVUS Trials
1.8"

CAMELOT
placebo

1.2"
Median
Change 0.6"
In Percent

Atheroma
0"
Volume
(%)

REVERSAL
atorvastatin

-0.6"
-1.2"
1.3"

ACTIVATE
placebo
A-Plus
placebo

r2= 0.95
p<0.001

ASTEROID
rosuvastatin"

1.5"

JAMA 2006; 295:1556-1565
Cleve Clin J Med 2006;73:937-944

1.8"

REVERSAL
pravastatin

2.1"

2.3"

2.6"

On-Treatment LDL-C (mmol/L)

2.8"

3.1"


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

Risk Level
LOW
FRS < 10%

Initiate Therapy if

Primary LDL-C
Target

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

!50% reduction in
LDL-C

Alternate Target

#!LDL-C > 3.5 mmol/L
#!For LDL-C < 3.5 mmol/L
INTERMEDIATE
consider if: Apo B > 1.2
FRS 10 – 19%
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%

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

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

Consider treatment in all

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

16


Statin Therapy Has Been Effective in Reducing
LDL-C, however, Even Maximal Statin Therapy is
Insufficient for Some Patients
0%

10%

20%

30%

40%

50%

Rosuvastatin

10
mg
5 mg

20 mg

10 mg

Atorvastatin

10 mg

20 mg

40 mg 80 mg

Simvastatin

10 mg

Pravastatin

10 mg

Lovastatin

20 mg

Fluvastatin

20 mg

20 mg

20 mg

60%

20 mg 40 mg

40 mg

40 mg

40 mg

80 mg

Doubling the statin
dose results in only
6% LDL reduction

40 mg

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$

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.


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

LDL-C Lowering+

Niacin4-6$

20% +

Other Lipid
Effects+

Outcome Data
(Add-on to statin)+

" HDL by 30%
# TG by 40%$

No benefit as addon to statin7,8$

" HDL-C (10-50%)
# TG (20-50%)

No benefit as
add-on to statin$

Fibrates9,10$

5 – 20%+

Bile Acid
Sequestrants11$

15 – 20%+

Limited$

15 – 25%

IMPROVE–IT
~6.5% reduction in
CV events (CVD/MI/

stroke)2†

Ezetimibe1

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$PIHP\HP]UCUH\$$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$PIIU\H"YHZSHCUT$


-40

-60

-40%

2000’s

-20%

2010’s
IMPROVE-IT

-10%

1990’s

Ezetimibe

-20%

Statins 1st Gen

-20%

Fibrates

BAS

LDL-C Lowering (%)

-20

1980’s

Niacin

0

1970’s

Statins 2nd Gen

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

-20%

reduction
on top
of statin

-60%

-80

@'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$<<"CPIH!\X]PYP!ZSPX<]CU]T$$


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

45% 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

43% Canadian patients with diabetes

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

g)/9>$2/.D$k$

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,./(!?@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

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
 

Statin Influence on LDL-C Metabolism and PCSK9
Acetyl-CoA + acetoacetyl-CoA
HMG-CoA
reductase

STATIN
PCSK9 Secretion

Plasma

HMG-CoA
LDL

Intracellular
Cholesterol
Biosynthesis

LDL Protein
at Cell Surface
LDL-R

PCSK9
Protein

Hepatocyte Cholesterol
Content

Hepatocyte

PCSK9
LDL-R
Expression Expression

SREBP
Activation

Nucleus

Endoplasmic
Reticulum (ER)