Cập nhật điều trị Rối loạn Lipid máu năm 2016

 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

Dyslipidemia

Management in 2016

Michael Heffernan

MD PhD FRCPC FACC

  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

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

Clinical Trials Validated The LDL

WPS-T

WPS-P TNT-80

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

Reduction in LDL cholesterol (mmol/L)

The IMPROVE-IT Study

1.8 mmol/L

1.4 mmol/L

Simvastatin + Ezetimibe

Simvastatin Simvastatin + Ezetimibe

Simvastatin

Simvastatin + Ezetimibe Simvastatin

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

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 "

r 2 = 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

between total cholesterol levels and CV outcomes

cholesterol or LDL-C with statin therapy or other

measures leads to a proportionate decrease in CV

outcomes

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

benefit

Lower is Better – How Do We Get John

to Target ?

a)  b)  c)  d) 

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

"2 mmol/L or !50%

decrease in LDL-C (Strong, Moderate)

# !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

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

" HDL-C (10-50%)

# TG (20-50%) No benefit as add-on to statin$

Bile Acid Sequestrants11$ 15 – 20%+ Limited$

Current Therapy Options May Not Get Some

of Our High Risk Patients to LDL-C Goal

PIH!\X]PYP!ZSPX<]CU]T$$

Despite Guideline Targets Many High-risk

Canadian Patients Treated with Statins Are Not at LDL-C Goal

! ! 88% of patients received a ‘potent’ statin with suboptimal dose

! ! 14% of patients received additional lipid-lowering agent

New Therapies and New Guidelines

The French Connections

• 

• 

 

PCSK9 Expression

LDL-R Expression

Statin Influence on LDL-C Metabolism and PCSK9

LDL-R Expression

Hepatocyte Cholesterol

Content Hepatocyte Cholesterol

HMG-CoA

Intracellular Cholesterol Biosynthesis

Acetyl-CoA + acetoacetyl-CoA

STATIN

HMG-CoA reductase

Intracellular Cholesterol Biosynthesis

PCSK9

Hepatocyte Plasma

© 2013 Amgen Canada Inc All rights reserved

Golgi Apparatus Endoplasmic

Reticulum (ER) Nucleus

LDL, LDL-R and PCSK9 Degradation

LDL Degradation

LDL, LDL-R and PCSK9 Degradation

PCSK9 Inhibitors: Targeted Therapy

PCSK9 Self-procession

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

* 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

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

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

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

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

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)

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

1.50 mmol/L -52.4%

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

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

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

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

Reduction in LDL cholesterol (mmol/L)

OSLER*

IMPROVE-IT

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

 

 

 

 

PCSK9i Can Achieve a Further 60%

?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$

Thank You