Healthy Heart (Vol-6, Issue-69) August, 2015 - Dr. Urmil Shah-4 · 2019. 5. 12. · Dr. Urmil Shah...

Volume-6 | Issue-69 | August 5, 2015

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Healthy HeartHonorary Editor : Dr. Urmil Shah

From the Desk of Hon. Editor:

Dear Friends,

Elevated LDL cholesterol remains an

important driver of atherosclerotic

vascular disease, a primary cause of

premature cardiovascular mortality and

morbidity. Many randomised, controlled

trials have proven the utility of statins in

reducing LDL cholesterol and

cardiovascular disease during the last 25

years, but we need to go beyond the

limitations of statins. The next

generation of treatments to control

elevated LDL cholesterol must address

the substantial residual cardiovascular

risk remaining after even intensive

statin-based therapy, the

unpredictability of the response to a

statin in an individual patient, and the

frequent occurrence of statin

intolerance. An exciting new treatment

for marked reduction of LDL cholesterol

levels is now on the horizon: the PCSK9

inhibitors, a new class of biologics. This

article seeks to summarize the rationale,

current evidence base supporting the

use and current status of PCSK9

inhibition for the improvement of long-

term cardiovascular outcomes.

- Dr. Urmil Shah

PCSK9 INHIBITION : New Therapies in Cardiovascular Risk Reduction

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LDL cholesterol remains the key target of

lipidmodifying therapy

European and US guidelines continue to

identify LDL-C as the main target for lipid-

modifying therapy, with the aim of

improving long-term cardiovascular

prognosis.

The concept of the lifetime burden of

elevated LDL cholesterol accounts for the

early development of cardiovascular

disease. The severity and duration of

hypercholesterolaemia act together with

additional cardiovascular risk factors such

as other lipid abnormalities, smoking and

diabetes, with a substantial risk of CHD

occurring once the patient

has reached a cumulative

exposure to 160 mmol of LDL

cholesterol.

Treatment with a statin delays

the age at which CHD

presents, by reducing the

circulating level of LDL

cholesterol and thus reducing

exposure to LDL cholesterol

over time. It is clear from

Figure-1 that it is better to

intervene earlier, rather than

later, to address elevated LDL cholesterol,

especially in a patient at severely elevated

cardiovascular risk due to familial

hypercholesterolaemia.

Familial hypercholesterolaemia is the

most common genetic condition known

to medical science, with a population

prevalence that may be as high as about

1:200 - 99 % of which are not diagnosed.

P a t i e n t s w i t h f a m i l i a l

hypercholesterolaemia have severely

elevated LDL cholesterol levels from early

i n l i fe . T h e y t y p i c a l l y d e ve l o p

atherosclerotic vascular disease in

childhood followed by clinical CHD by

their twenties (homozygous familial

Female sex increases the cumulative threshold of LDL cholesterol for CHD, while cardiovascular risk factors (smoking etc.) decrease it so that CHD appears at an earlier age.

Figure-1 : Clinical importance of the concept of a lifetime burden of elevated LDL cholesterol

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Healthy Heart

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hypercholesterolaemia) or before middle

a g e ( h e t e r o z y g o u s f a m i l i a l

hypercholesterolaemia). Achieving

treatment goals with statins in patients

with familial hypercholesterolaemia is

challenging, even when they are

diagnosed and treated. All patients with

familial hypercholesterolaemia should

receive a statin, but 79% of patients with

h e t e r o z y g o u s f a m i l i a l

h y p e r c h o l e s t e r o l a e m i a i n T h e

Netherlands did not achieve their goal for

LDL cholesterol (<2.5 mmol/L [100

mg/dL]), despite 96% receiving a statin.

Limitation of Statin Therapy

Many patients with elevated LDL

cholesterol do not achieve LDL

c h o l e ste ro l go a l s w i t h c u r re nt

treatments. A survey of 9,950 high-risk

patients with CHD showed that more

than half did not achieve LDL cholesterol

<1.8 mmol/L (70 mg/dL) either with a

s tat i n a l o n e , o r w i t h a s tat i n

combined with other lipid modifying

agents (Figure 2).

Poor adherence to statin therapy is

common (the majority of patients stop

taking their statin within a year) and this

is an important cause of the variable

therapeutic response which is predictor

of subsequent cardiac event.

The incidence of adverse events

attributable to statins in randomised

clinical trials is low. However, side-effects

in muscle occurred in up to 29% of statin-

treated patients in observational studies,

presenting a potential barrier to

treatment.

Though the introduction of statins has

revolutionised the management of

patients at increased cardiovascular risk

due to elevated LDL cholesterol. As

described above, these agents provide

marked (if variable) reductions in LDL

cholesterol and clinically significant

reductions in cardiovascular event rates

in patients at high cardiovascular risk.

Nevertheless, most patients do not

achieve their goal LDL cholesterol on

these agents, particularly people with

the severe hypercholesterolaemia

a s s o c i a t e d w i t h f a m i l i a l

hypercholesterolaemia. Also, statins

reduce the risk of a cardiovascular event

by only up to about 50% at most, leaving a

substantial burden of cardiovascular

morbidity and mortality even after

treatment. There remains a need for a

consistently effective, well-tolerated

treatment that will provide reductions in

LDL cholesterol beyond those available

with a statin, with reductions in other

atherogenic lipoproteins, including VLDL

cholesterol, lipoprotein remnants and

lipoprotein(a) that will address the

residual risk after treatment with a statin.

Lipid Metabolism and Mechanism of

Lipid Lowering Agent

Figure-3 provides a simplified overview

of the main sources of plasma LDL

cholesterol. 75 % of circulating LDL

cholesterol is synthesised in the liver, by

HMG-CoA reductase and the principal

means of removal of LDL cholesterol from

the circulation is via a family of hepatic

LDL receptors. Current therapies are

targeted at reducing the rate of

cholesterol biosynthesis (the main effect

Figure-2 : Low rates of LDL cholesterol goal achievement in patients with coronary artery disease on lipid-modifying therapy

Figure-3 : Overview of cholesterol metabolism and transport

PCSK9: proprotein convertase subtilisin/kexin type 9.

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Healthy HeartVolume-6 | Issue-69 | August 5, 2015

of statins) or reducing the rate of

absorption of cholesterol into the

circulation (ezetimibe, bi le acid

sequestrants or plant sterols/stanols)

derived from food and/or from bile.

The hepatic LDL receptor is the most

important mechanism of removal of LDL

cholesterol from the circulation.

Reducing the activity or expression of

PCSK9 increases the number of LDL

receptors, which reduces circulating LDL

cholesterol. People with mutations of the

PCSK9 gene that decrease its activity

have lifelong low LDL cholesterol and a

lower risk of cardiovascular events than

t h e g e n e r a l p o p u l a t i o n .

Mutations of the PCSK9 gene that

increase its activity can give rise to the

fa m i l i a l hy p e rc h o l e s t e ro l a e m i a

phenotype.

PCSK9 inhibitor

A number of PCSK9 inhibitors are

currently in clinical development. All

these agents are monoclonal antibodies

which must be given by injection; they

have a long duration of action requiring

infrequent administration compared

with current therapies.

Evolocumab (Amgen)

This agent has been evaluated using 2-

weekly (140 mg dose) or monthly (420

mg dose) administration schedules in

P h a s e I I I t r i a l s ( t h e P RO F I C I O

programme).

Alirocumab (Sanofi/Regeneron)

Phase III studies have generally involved

administration of 75–150 mg of this

agent at 2-weekly intervals (the ODYSSEY

programme).

Bococizumab (Pfizer) is in Phase III

clinical evaluation (the SPIRE trial

programme).

A one-year evaluation of evolocumab

demonstrates the marked reductions in

LDL-C that result from PCSK9 inhibition,

irrespective of the nature of background

lipid-modifying therapy (Figure 4). Mean

reductions from baseline in LDL-C

approaching 50%, or greater, were seen

in patients on background diet therapy,

low- or high-intensity statin treatment, or

high-intensity statin plus ezetimibe. A

reduction in LDL cholesterol of

comparable magnitude was seen in a

Phase III study in which alirocumab was

compared with ezetimibe in patients

with hypercholesterolaemia (Figure 5).

Lipoprotein(a) [Lp(a)] is an atherogenic

lipoprotein that is closely associated with

increased risk of cardiovascular disease

independently of levels of LDL

cholesterol or non–HDL cholesterol.

Lp(a) should be controlled to below the

80th percentile of the population, which

is about 50 mg/dL. The MENDEL-2 study

also showed that PCSK9 inhibition was

effective in reducing LPa significantly

(Figure-6).

Figure-5 : Effects of 24 weeks of treatment with alirocumab vs.ezetimibe on LDL cholesterol in patients with hypercholesterolaemia

Me

an

LD

L-C

(m

mo

l/L)

4

3

2

1

0

160

140

120

100

80

60

40

20

None

Δ -56% Δ -62% Δ -57%

Me

an

LD

L-C

(mg

/dL)

Placeb o E volocumab

Baseline

52 weeks

Figure-4 : Substantial reductions in LDL-C with evolocumabirrespective of background intensity of lipid-modifying therapy

Background therapy (all patients received diet therapy)

Mean placebo-subtracted treatment difference at 52 weeks

Δ: mean treatment difference vs. placebo. Atorva: atorvastatin.

Atorva 10 mg Atorva 80 mg Atorva 80 mg+ ezetimibe

10 mg

10

0

-10

-20

-30

-40

-50

-60

-70

10

0

-10

-20

-30

-40

-50

-60

-70

10

0

-10

-20

-30

-40

-50

-60

-70

ApoB

HDL-C

p=0.007 p=0.001

p=0.001 p=0.001

Lp(a)

Figure-6 : Effects of PCSK9 inhibition on LDL-C and other components of the lipid profile

10

0

-10

-20

-30

-40

-50

-60

-70

LDL-C

2 Doses given were 75 mg s.c. Q2W for alirocumab and 10 mg QD for ezetimibe.


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An exploratory analysis (pooled analysis

of the randomised OSLER-1 and OSLER-2

trials) showed significant beneficiary

effect of Evolocumab for reduction of

cardiovascular outcomes (Figure-7).

Preliminary data from the ODYSSEY long

term outcome study suggest a reduced

frequency of adverse cardiovascular

outcomes associated with a PCSK9

inhibitor - alirocumab in patients with

hypercholesterolaemia.

PCSK9 inhibitors have been generally well

tolerated in clinical trials (Figure-8). The

main side-effects associated with these

agents are injection site reactions, which

is unsurprising for an injectable

treatment. The tolerability and safety

profiles of these agents so far support

long-term administration for lifelong

c o n d i t i o n s s u c h a s h y p e r -

cholesterolaemia.

Treatment with a statin, however

intensive, leaves unaddressed a high

level of residual cardiovascular risk.

While improvements in the management

of cardiovascular risk have reduced the

burden of cardiovascular disease to some

extent, future progress will depend on

the implementation of new treatment

strategies that are able to make inroads

into this residual risk. PCSK9 inhibitor

reduces LDL by improving the hepatic

clearance of LDL (via LDL receptor) is new

promising way of reducing LDL. Looking

at large long term trials and beneficial

effect on cardiovascular end point.

USFDA approved alirocumab as lipid

lowering therapy recently for following

indication :

• Pe o p l e w i t h fa m i l i a l hy p e r -

cholesterolaemia who are likely to

have lifelong exposure to very high

levels of LDL cholesterol and other

atherogenic lipoproteins, such as

Lp(a) , causes early onset of

cardiovascular disease and low

likelihood of achieving optimal

control of LDL cholesterol on current

therapies.

• People with statin intolerance

especially with higher dose with

problem of low adherence to LDL

cholesterol-lowering therapy among

this population

• People at high residual cardiovascular

risk who are not at their LDL

cholesterol goal for secondary

prevention inspite of statin.

Figure-7 : Effect of evolocumab on cardiovascular outcomes in apooled analysis of the OSLER-1 and OSLER-2 trials

Figure-8 : Tolerability profile of a PCSK9 inhibitor over one year of treatment from the preliminary analysis of the ODYSSEY LONG TERM outcomes trial


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