ACTUALITES THERAPEUTIQUES EN LIPIDOLOGIE · Data from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists Collaboration

ACTUALITES

THERAPEUTIQUES

EN LIPIDOLOGIE

Dr. P. VAN DE BORNE

Cardiologue

Service de Cardiologie

ULB- Hôpital Erasme

51e CONGRES DE L’A.M.U.B.

Session ACTUALITES DIAGNOSTIQUES ET THERAPEUTIQUES

Modérateurs :

Drs A. FIRKET, M. MAHIEU, T. PEPERSACK

Samedi 9 septembre 2017 14h00-14h45

Conflits d’intérêt en rapport avec la

présentation

• Honoraires de conférence :– Sanofi

• Participation à un « Advisory Board » :– Sanofi, Amgen, MSD

• Etudes cliniques sponsorisées en cours :– Sanofi, Amgen

• Consultance :– <néant>

• Voyages-Congrès :– Sanofi, Amgen, MSD

PLAN :LDL C et pathologie cardiovasculaire

Statines : Effets secondaires ?

PCSK9: mode d’action, variations d’activité,études cliniques

Clinical trial data support achieving lower levels of LDL-C, independent of baseline LDL-C

ACS, acute coronary syndrome; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol.

Rosenson RS. Exp Opin Emerg Drugs 2004;9:269–79; LaRosa JC, et al. N Engl J Med 2005;352:1425–35;

Cannon CP, et al. N Engl J Med 2015;372:2387–97.

4S

pbo

LIPID

pbo

4S

S40

CARE

pboHPS

pboLIPID

P40

CARE

P40HPS

S40

TNT

A10TNT

A80

PROVE-IT TIMI 22

P40PROVE-IT TIMI 22

A80

IMPROVE-IT

S40+EZE

IMPROVE-IT

S40

ACS study

Stable CAD study

men >55 yrs

women > 65 yrs

+ 1 cv risk factor

April 2, 2016

Every 39 mg/dL reduction in LDL-C reduces annual CV risk by up to 28%, regardless of mechanism

Data from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists

Collaboration (CTTC) 2005 meta-analysis. The IMPROVE-IT trial was adequately powered to show the efficacy on incremental

LDL-C lowering on CV outcomes. [To convert, 100 mg/dL=2.59 mmol/L].

CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density

lipoprotein cholesterol.

CTT Collaboration. Lancet 2005:366;1267–78; CTT Collaboration. Lancet 2010;376:1670–81;

Cannon CP, et al. N Engl J Med 2015;372:2387–97.

There is no evidence of any lower LDL-C threshold

CTTC trials (statin)

Niacin

Diet/unsaturated fatty acid

Ileal bypass

Bile acid resin

Ezetimibe

Fibrate

More LDL lowering and risk reduction

Re

du

ctio

n in

CV

eve

nts

(%

)

0

10

20

30

40

50

IMPROVE-IT

10 20 30 40 50 60 70 80

Reduction in LDL-C (mg/dL)?

2 g of extended-release niacin (ie nicotinic acid, vitamin B3 or PP (Pellagra Preventive)) and 40 mg of laropiprant vs. placebo Primary outcome: 1st major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).

LDL = - 10 mg/dl and HDL + 6 mg/dl

Expected to produce a 5 % proportional reduction in the risk of major vascular events

(mainly China)

Consistency of overall

findings with earlier

niacin trials suggests

niacin is the major problem

Great concern: 9% increase in the risk of

death (P = 0.08, number needed

to harm= 200)

HDL cholesterol level:risk marker, not a risk factor

(2) Larger

return

of CE-rich

LDL to the liver

Cholesterol eliminated from the

body

But if not enough LDL-R:

(1) Less CE

in reverse

cholesterol

transport

CE, cholesteryl esterFC, free cholesterol

LPL, LipoproteinlipaseHL,

Hepatic lipase

small-dense LDL-C

SR-B1, scavenger receptor-B1

CETP, cholesteryl ester transfer protein secreted

from the liver

LCAT, lecithin cholesterol acyltransferase


Vascular Health and Risk Management 2012:8 483–493

(2) Less

return

of CE-rich

LDL to the liver

Cholesterol

eliminated

from the

body

(1) More CE

in reverse

cholesterol

transport

CE, cholesteryl esterFC, free cholesterol

LPL, LipoproteinlipaseHL,

Hepatic lipase

small-dense LDL-C


The cetrapibs form a reversible bond between CETP and HDL-C.

Formation of this bond results in the inhibition of CETP-mediated CE and TG transfer

Vascular Health and Risk Management 2012:8 483–493

ACCELERATE: Phase 3, multicenter, double blind, randomized trial, 12 092 patients at high vascular risk:

Patients (77% male; age: 65 years) randomly assigned 1:1 to either 130 mg evacetrapib (n=6038) or placebo (n=6054) for at least 1.5 years. Baseline clinical characteristics matched

Primary end point: Time to first event of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization).

Stopped prematurely for clinical futility (evacetrapib, 12.8% vs placebo, 12.7%; hazard ratio:1.01; P=.85) despite 130% increase in HDL-C (104 mg/dL vs 46 mg/dL) and 37% decrease in LDL-C (55 mg/dL vs 84 mg/dL).

ACCELERATE: Phase 3, multicenter, double blind, randomized trial, 12 092 patients at high vascular risk:

Patients (77% male; age: 65 years) randomly assigned 1:1 to either 130 mg evacetrapib (n=6038) or placebo (n=6054) for at least 1.5 years. Baseline clinical characteristics matched

Primary end point: Time to first event of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization).

Stopped prematurely for clinical futility (evacetrapib, 12.8% vs placebo, 12.7%; hazard ratio:1.01; P=.85) despite 130% increase in HDL-C (104 mg/dL vs 46 mg/dL) and 37% decrease in LDL-C (55 mg/dL vs 84 mg/dL).




Statin-associated autoimmune myopathy is an exceptionally rare

side effect of statin use. Incidence +/- 2 or 3 of every

100,000 patients treated with statins :

• Class II HLA allele DRB1*11:01 • Expression of HMG-CoA reductase markedly

increased when muscle exposed to statins• Regenerating muscle cells express high levels of

HMG-CoA reductase protein

??? Binding of statin to HMG-CoA reductase change the conformation of the protein, lead to the generation of cryptic epitopes to which the immune system is not tolerant ???

e

Docteur de Lorgeril

chercheur au CNRS

Docteur de Lorgeril

chercheur au CNRS

Despite benefits of current LLTs, many secondary prevention patients do not achieve LDL-C goals

CHD, coronary heart disease; EUROASPIRE, European Action on Secondary and Primary Prevention through

Intervention to Reduce Events; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy.

http://www.escardio.org/about/press/press-releases/esc13-amsterdam/Pages/euroaspire-iv-success-challenges-

secondary-prevention-CVD-europe.aspx. [Accessed 11 May 2015].

Data collected from patients <80 years old with

established CHD, 25% women, mean age 64 years,

one-third <60 years

• EUROASPIRE IV

– n=7998, all patients with

established CHD

– 87% on LLTs, almost exclusively

statins

• Almost 80% of patients on LLTs

failed to reach an LDL-C goal of

<1.8 mmol/L (<70 mg/dL)

42%

79% NOT at goal

79% of patients on LLTs did

NOT achieve an LDL-C

goal of <1.8 mmol/L

(<70 mg/dL)

Only 21% of

patients on

LLTs were at

goal

Patients who completed the placebo run-in without

experiencing a skeletal muscle–related AE were

randomizedto alirocumab,

ezetimibe, or atorvastatin

13%

24% 34% 33%

unable to tolerate ≥2 statins, including one at the lowest starting dosedue to muscle symptoms

22%20%16%

During the open-label treatment period (41 wks), when patients knew they were not

receiving statins, rates of skeletal muscle–related

AEs were lower (24%) than during double-blind period (33%)




Clinical Therapeutics

Volume 35, Issue 8, August 2013,

Pages 1082–1098

P= placebo / E= Evolucumab

?

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjsk_f_0v3OAhULLcAKHaJLDyYQjRwIBw&url=http%3A%2F%2Ffrance3-regions.francetvinfo.fr%2Fsociete%2Fparce-que-c-est-comme-ca%3Fr%3Dpoitou-charentes&bvm=bv.131783435,d.ZGg&psig=AFQjCNHFWNQ6ImV4sjE0LhwMNOM-6BtY9g&ust=1473351159852115

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjsk_f_0v3OAhULLcAKHaJLDyYQjRwIBw&url=http%3A%2F%2Ffrance3-regions.francetvinfo.fr%2Fsociete%2Fparce-que-c-est-comme-ca%3Fr%3Dpoitou-charentes&bvm=bv.131783435,d.ZGg&psig=AFQjCNHFWNQ6ImV4sjE0LhwMNOM-6BtY9g&ust=1473351159852115




Effects of 3 sequence variations on Coronary Heart

Disease incidence

in

Atherosclerosis Risk in Communities (ARIC) study:

longitudinal,

biracial cohort study to assess

subclinical and clinical atherosclerosis.

PCSK9 mutations effects on LDL

2 % black subjects have 1 of 2 nonsense mutations

in PCSK9 gene:

426C→G, encoding Y142X

[replacement of the tyrosine at position 142 with a stop

codon]

2037C→A, encoding C679X

[replacement of the cysteine at position 679 with a stop

codon]

3% white subjects (vs. 0.6 % black) PCSK9

sequence variation:

137G→T, encoding R46L

[replacement of the arginine at position 46 with leucine]

nonsense mutations

=9,7%

The only carrier in whom CHD

developed was a black man,

BMI 34 kg/m², BP186/85 mm Hg,

smoker,

family history of CHD,

During the 15-year follow-up period

Familial hypercholesterolemia can be caused by mutations in 4 known genes

ApoB, apolipoprotein B; FH, familial hypercholesterolemia; GoF, gain of function; LDL, low-density lipoprotein;

LDLRAP1, low-density lipoprotein receptor adapter protein 1; PCSK9, proprotein convertase subtilisin/kexin type 9.

De Castro-Oros I, et al. Appl Clin Genet 2010;3:53–64.

ApoBacts as ligand, binding LDL particle to receptor

LDLRAP1(ARH)Mediates internalization via clarithrin coated pitsPCSK9 enzyme

degrades LDL receptors

LDL receptoron hepatocyte,binds to ApoB on LDL particle, inducing endocytosis of LDL

Liver cell

Circulation

LDL particle

17–33% of FH patients

harbour mutations in

unknown genes

Meta-analysis of 312,321 participants: long-term exposure to lower

LDL-C was associated with 54.5% reduction in risk of CHD for each

1 mmol/L (38.7 mg/dL) lower LDL-C1

Clear genetic and epidemiological evidence for

LDL-C as a risk factor

[To convert, 100 mg/dL=2.59 mmol/L].

CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor;

LLT, lipid-lowering therapy; PCSK9, proprotein convertase subtilisin/kexin type 9; SE, standard error.

1. Ference BA, et al. J Am Coll Cardiol 2012;60:2631–9.

2. Ference BA, et al. J Am Coll Cardiol 2015;65:1552–61.

Mendelian randomization

analysis2




Long-term Low-Density Lipoprotein Cholesterol–Lowering Efficacy, Persistence, and Safety of Evolocumab in

Treatment of HypercholesterolemiaResults Up to 4 Years From the Open-Label OSLER-1 Extension Study

4,3 années de traitement

revascularisation

PRIMAIRE : DECES CARDIOVASCULAIRES, INFARCTUS MYOCARDIAQUE,

HOSPITALISATION POUR ANGINE DE POITRINE INSTABLE

OU REVASCULARISATION CORONAIRE

SECONDAIRE : DECES CARDIOVASCULAIRES, INFARCTUS MYOCARDIQUE,

ACCIDENT CEREBROVASCULAIRE

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Baseline Characteristics

Characteristic Value

Age, years, mean (SD) 63 (9)

Male sex (%) 75

Type of cardiovascular disease (%)

Myocardial infarction 81

Stroke (non-hemorrhagic) 19

Symptomatic PAD 13

Cardiovascular risk factor (%)

Hypertension 80

Diabetes mellitus 37

Current cigarette use 28

Pooled data; no differences between treatment arms

Median time from most

recent event ~3 yrs

Rate of secondary

preventive therapies

high:

92% taking

antiplatelet therapy,

76% taking beta-

blockers,

and 78% taking an

ACE/ARB/aldosterone

antagonist,

.



Lipid Lowering Therapy

& Lipid Levels at Baseline

Characteristic Value

Statin use (%)*

High-intensity 69

Moderate-intensity 30

Ezetimibe use (%) 5

Median lipid measures (IQR) – mg/dL

LDL-C 92 (80-109)

Total cholesterol 168 (151-189)

HDL-C 44 (37-53)

Triglycerides 133 (100-182)

Pooled data; no differences between treatment arms

*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.

1% were on low intensity or intensity data were missing.

Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines.

10% of patients

had alterations in their

background lipid-lowering

therapy



0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96 108 120

LD

L C

ho

leste

rol

(mg

/dl)

Weeks

LDL Cholesterol

Cohort of 11,077 patients who

• had all measurements through 120 weeks

• did not discontinue study drug

• did not D concomitant background lipid-lowering Rx

Evolocumab

Placebo

Similar data out to 4 years

in OSLER-1

(JAMA Cardiology online)


Brigham and Women’s Hospital and Harvard Medical SchoolConfidential

LDL Cholesterol

At 48 weeks, LDL cholesterol level was reduced to:

Evolocumab group:

<70 mg per deciliter (1.8 mmol per liter) in 87% of the patients,



Placebo group:


<40 mg per deciliter (1.0 mmol per liter) in 0.5% of the patients,

<25 mg per deciliter (0.65 mmol per liter) in 0.1% of the patients, P<0.001 for all comparisons of evolocumab vs. placebo).



0%

2%

4%

6%

8%

10%

12%

14%

16%

Primary Endpoint

Evolocumab

Placebo

Months from Randomization

CV

Death

, M

I, S

tro

ke,

Ho

sp

fo

r U

A,

or

Co

rR

evasc

0 6 12 18 24 30 36

Hazard ratio 0.85

(95% CI, 0.79-0.92)

P<0.0001 12.6%

14.6%

Primary end point occurred

in 1344 patients (9.8%)

in the evolocumab group and

in 1563 patients (11.3%)

in the placebo group

Magnitude of risk reduction tended to increase

over time, from 12% (95% CI, 3 to 20)

in the first year to 19% (95% CI, 11 to 27)

beyond the first year.



0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

Key Secondary Endpoint

Months from Randomization

CV

Death

, M

I, o

r S

tro

ke

0 6 12 18 24 30 36

Hazard ratio 0.80

(95% CI, 0.73-0.88)

P<0.00001

Evolocumab

Placebo7.9%

9.9%

Key secondary end point in

816 patients (5.9%) in

evolocumab group and in

1013 patients (7.4%) in

the placebo group.

Risk reduction increased from

16% (95% CI, 4 to 26) in the first year

to 25% (95% CI, 15 to 34) beyond the first year.



Types of CV Outcomes

Endpoint

Evolocumab

(N=13,784)

Placebo

(N=13,780) HR (95% CI)

3-yr Kaplan-Meier rate

CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)

Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)

Death due to acute MI 0.26 0.32 0.84 (0.49-1.42)

Death due to stroke 0.29 0.30 0.94 (0.58-1.54)

Other CV death 1.9 1.8 1.10 (0.90-1.35)

MI 4.4 6.3 0.73 (0.65-0.82)

Stroke 2.2 2.6 0.79 (0.66-0.95)

Evolocumab had no observed effect on cardiovascular mortality,

and hence P values for other outcomes should be considered exploratory.

-2%

-0,5%

No effect

Overall, 74 patients would need to be treated over a

period of 2 years to prevent a cardiovascular death,

myocardial infarction, or stroke.



More Intensive LDL-C Lowering

& CV Death

# of CV Deaths

Trial Year More

Intensive

Rx Arm

Less

Intensive

Rx Arm

HR (95% CI)

PROVE-IT TIMI 22 2004 27 36 0.74 (0.45-1.22)

A2Z 2004 86 111 0.76 (0.57-1.01)

TNT 2005 101 127 0.80 (0.61-1.03)

IDEAL 2005 223 218 1.03 (0.85-1.24)

SEARCH 2010 565 572 0.99 (0.88-1.11)

IMPROVE-IT 2015 538 537 1.00 (0.89-1.13)

Summary 1540 1601 0.96 (0.90-1.03)

More intensive

therapy better

Less intensive

therapy better

0.2 0.5 1 2 5NEJM 2004;350:1495-504

JAMA 2004;292:1307-16

NEJM 2005;352:1425-35

JAMA 2005;294:2437-45

Lancet 2010;376:1658-69

NEJM 2015;372:2387-97

No clear benefit on CV mortality



Types of CV Outcomes

Endpoint

Evolocumab

(N=13,784)

Placebo

(N=13,780) HR (95% CI)

3-yr Kaplan-Meier rate

CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92)

CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)

Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)

MI 4.4 6.3 0.73 (0.65-0.82)

Stroke 2.2 2.6 0.79 (0.66-0.95)

Hosp for unstable angina 2.2 2.3 0.99 (0.82-1.18)

Coronary revasc 7.0 9.2 0.78 (0.71-0.86)

Urgent 3.7 5.4 0.73 (0.64-0.83)

Elective 3.9 4.6 0.83 (0.73-0.95)

Death from any cause 4.8 4.3 1.04 (0.91-1.19)



Comparison to Cholesterol

Treatment Trialists Collaboration

Major Coronary Events

Stroke

Coronary revascularization

Urgent

Elective

Major Vascular Events

0.78 (0.70-0.86)

0.80 (0.71-0.90)

0.77 (0.66-0.91)

0.77 (0.63-0.94)

0.75 (0.67-0.84)

0.73 (0.62-0.86)

0.84 (0.73-0.98)

0.77 (0.73-0.82)

0.83 (0.76-0.90)

Lipid-lowering therapy better Lipid-lowering therapy worse

Hazard Ratio (95% CI) per 1 mmol/L reduction in LDL-C

2.01.0

CTTC Meta-analysis Year 2

FOURIER Year 2

CTTC data from Lancet 2010;376:1670-81

0.5



Lower LDL-C Is Better

P<0.0001

Patients divided by quartile of baseline LDL-C and by treatment arm

Q4

Q3

Q2

Q1

Q4Q3

Q2

Q1

Placebo

Evolocumab

The magnitude of benefit of evolocumab in largely consistent with the

benefit with statins on a

per–millimole-per-liter basis

of LDL cholesterol lowering



Safety Evolocumab

(N=13,769)

Placebo

(N=13,756)

Adverse events (%)

Any 77.4 77.4

Serious 24.8 24.7

Allergic reaction 3.1 2.9

Injection-site reaction 2.1 1.6

Treatment-related and led to d/c of study drug 1.6 1.5

Muscle-related 5.0 4.8

Cataract 1.7 1.8

Diabetes (new-onset) 8.1 7.7

Neurocognitive 1.6 1.5

Laboratory results (%)

Binding Ab 0.3 n/a

Neutralizing Ab none n/a

New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC



Conclusions

In patients with known cardiovascular disease:

1. PCSK9 inhibition with evolocumab

significantly & safely major cardiovascular

events when added to statin therapy

2. Benefit was achieved with lowering LDL

cholesterol well below current targets

Overall, 74 patients would need to be treated over a

period of 2 years to prevent a cardiovascular death,

myocardial infarction, or stroke.

52

PCSK9 Therapeutic Hypothesis: Phase 1 RNAi therapeutic targeting PCSK9 protein synthesis

PCSK9 mRNA

PCSK9

synthesis

LDLR

synthesis

PCSK9

LDL

Lysosomal

degradation

Endosome

Nucleus

ALN-PCS

Anti-

PCSK9

Mabs Transiently

block

PCSK9

binding

to

LDL

receptor

(LDLR)

PCSK9 Synthesis

Inhibitors

Durably block

PCSK9 synthesis

and all intracellular

and extracellular

PCSK9 functions

LDLR

Khvorova A. N Engl J Med 2017;376:4-7.

53

54

In the multiple-dose phase, the most common adverse events (occurring in ≥10% of the participants in the inclisiran

group) were headache (in 6 of 33 participants [18%]), back pain and diarrhea (in 5 [15%] each), and

nasopharyngitis (in 4 [12%])




Documents

ACTUALITES THERAPEUTIQUES EN LIPIDOLOGIE · Data from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists Collaboration