Is lower better? LDL targets and beyond.

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22 Φεβ 2014 (πριν από 3 χρόνια και 3 μήνες)

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Is lower better? LDL targets and beyond.

Implications of the relationship between
risk factor (LDL
-
C) level and event rate

Risk factor level

Risk factor level

LOG of

event

rate

Event

rate

1: Is there a continuous relationship?

2: Is there a lower limit?

3: What is the nature of the relationship?

Log


linear:

No lower limit

Law of diminishing returns

LDL
-
lowering lowers the risk of

MAJOR CARDIOVASCULAR
EVENTS

and more lowering provides more benefit

0

1

2

3

4

5

0

5

10

15

20

LDL cholesterol, mmol/L

Five year risk of a major

vascular event, %

Control

Combined evidence:

33% relative risk reduction

per 1.5 mmol/L

(since 0.79 x 0.84 = 0.67
)

21% relative risk

reduction in CVD per mmol/L

Statin

16% relative risk

reduction in CVD per 0.5 mmol/L

More statin


Lancet 2010

Implications of the relationship between risk
factor treatment and event rate.

Is there a “J” curve?

Treated risk factor level:

Event

rate

Antihypertensive & hypoglycaemic therapy in ACCORD Trial adverse

What is the Harm : Benefit ratio for LDL reduction?.

Ox
chol

and LXR

TG
-
rich
lipoproteins

LPL

PLA2

FAS

CD36

oxLDL

β

oxidation

FFAs

FFAs

oxysterol
s

SR

ACAT

FAS

Cholesterol

Cholesterol

Cholesteryl
esters

PG, LTs

Lipid
Uptake &
Synthesis

Lipid
Catabolism,
Efflux &
Storage

CD36
LXR
α

Cpt1
Ech1
PexIIa
LPL

ABCA1
ABCG1
apoE
LPL
SREBP1c

FAS

TATA

PPAR/RXR

RXR/LXR

TATA

apoE

apoA1

ABCA1

FFAs

CPT1

ECH1

PexIIa

Mitochondria

ACAT

Many animal
species, neonates,
and patients with
genetic diseases
tolerate very low
LDL
-
C

Is low LDL a causative risk factor for
non
-
CVD morbidity and mortality?


Cancer and
chronic disease
reduce LDL
-
C
rather than vice
-
versa





Need to adjust for
undiagnosed
cases





Mendelian

randomisation” re
LDL
-
C and
cancer : not
associated







Hazard/odds ratio for

Cancer (95
%
CI)

PCSK9
R46L

Non
-
carriers

Heterozygotes

Homozygotes

ABCG8
D19H

Non
-
carriers

Heterozygotes

Homozygotes

APOE
ε
2/
ε
3/
ε
4



44


43


33


42


32


22

0
50
100
150
0.5
0.75
1.0
1.25
1.5
0.5
0.75
1.0
1.25
1.5
Theoretically

predicted

risk


Observed

risk

P=0.54

P=0.78

P=0.96

Does LDL lowering lead to a net increase
in risk (
ie

via non
-
CVD events)?


Significant decrease in CV.



Even in “low risk”



AR <5% NNT 167


AR 5
-
10% NNT 67





No increase in non
-
CVD


NNH diabetes 250


NNH H’ stroke 1000


NNH
myopathy

10000


NNH
rhabdo

50000


How were lower LDL
-
C Targets decided?


“Reversal Trial” benefit at <1.6
mmol
/l


“TIMI 22” & “TNT” benefit at <2
mmol
/l




ATP interim target in high risk <1.8
mmol
/l


PBS review recommendation <2.0mmol/l




“IDEAL”



Simvastatin

20 mg
vs

Atorvastatin

80 mg


LDL =



2.5

vs


2
mmol
/l


11% benefit (ns) over 4.8 y



The special case of Familial
Hypercholesterolaemia


Often sole risk factor


Untreated LDL
-
C often >> 5
mmol
/l


Aim to reduce untreated LDL
-
C by > 50%



Lipase


CETP

TG affects cholesterol content, and hence size,
composition and density of lipoproteins

Small

LDL

TG

CE

Cholesterol ester

Triglyceride

Otvos JD, et al.
AJC

2002;90(8A):22i
-
29i

When TG is elevated

LDL
-
C may under
-
estimate

LDL particle number and

CVD risk.

CVD risk is proportional to the number of
atherogenic

lipoproteins rather than their
cholesterol content (or composition).

Low
High
0
1
2
3
4
5
6
7
Large
Small
1

1

2.1

6.2

LDL particle size

LDL particle
number
(Apo B)

Risk of IHD

Lamarche B, et al.
Circulation
1997; 95:69
-
75

Quebec Cardiovascular Study

Apo B: 1 per particle


Is LDL


C the best target?

US
Health Professionals Study


Biomarker


CHD RR, 95% CI


P
-
Trend


LDL
-
C


2.07 (1.24


3.45)


< 0.001

Non
-
HDL
-
C


2.75 (1.62


4.67)

< 0.001

Apo B


2.98 (1.76


5.06)

< 0.001



Quintile 5 vs. Quintile 1


P
-
Trend is a test for a rise or fall in RR from Q1 to Q5

Pischon

et al.
Circulation

2005;112:3375
-
3383
.

NMR Measures LDL Particle Number

Not LDL Cholesterol

LDL
NMR
Signals

Measured
LDL
-
C

2.5
mmol
/l

Measured
LDL
-
C

2.5
mmol
/l

LDL
particles
900
nmol
/L

LDL
particles

1600
nmol
/L

LDL

VLDL

Study

CHD Status

Atherosclerotic Endpoint

Associations Stronger for
LDL
-
P than LDL
-
C *

Women’s Health Study

Circulation

2002; 106:1930
-
1937

Circulation

2009;119:931
-
939

Primary
Prevention

Incident MI, CHD death,
CVA

YES

VA
-
HDL Intervention Trial

Circul
ation 2006;113:1556
-
63

Secondary
Prevention

Non
-
fatal MI or CHD Death

YES

MESA Trial

Atherosclerosis
2007;192:211

217.

Primary
Prevention

Carotid IMT

YES

Framingham Heart Study

J

Clin Lipidology

2007
;1(6):583
-
592

Primary
Prevention

Incident
CVD Events

YE
S

Cardiovascular Health
Study

ATVB
2002; 22:1175
-
1180

Primary
Prevention

Incident MI or Angina

YES

PLAC
-
I

AJC
2002;90:89
-
94

Secondary
Prevention

Angiographic

MLD

YES

Health Women Study

AJC

2002;90(suppl): 71i
-
77i

Primary
Prevention

EBCT Coronary Calcium

Score

YES



*
Significant and independent after multivariate modeling (lipids and established risk factors)

Outcome Associations of NMR LDL Particle
Number (LDL
-
P) versus LDL Cholesterol (LDL
-
C)

Effect of LDL Lowering Therapies
on
LDL
-
C, Non
-
HDL
-
C, Apo B, and LDL
-
P

Sniderman

AD.
J
Clin

Lipidology

2008;2:36
-
42

Treatments That Alter Cholesterol Content of
LDL Change LDL
-
C and LDL
-
P Differentially

LDL
-
C may overestimate reduction in
LDL particle number:



Statins



Statin

+
Ezetimibe

or Bile


Acid
Sequestrants



Estrogen Replacement


Therapy



Anti
-
retrovirals

(some)



Low fat, High
carb

diet

Therapy LDL
-
C More

Than LDL
-
P

LDL
-
C may underestimate reduction
in LDL particle number
:



Fibrates



Niacin



Pioglitazone




Omega 3 FAs



Exercise



Mediterranean and


low
carb

diet

Therapy LDL
-
P More

Than LDL
-
C

Little Change in Cholesterol per Particle with
:



Bile Acid
Sequestrant

or
Ezetimibe

Monotherapy

Similar Change in LDL
-
C and LDL
-
P

Cromwell WC. In:
Clinical Challenges in Lipid
Disorders
.Toth

PP,
Sica

DA, editors. Oxford: Clinical Publishing; 2008.p. 249
-
259.

Current treatment LDL
-
C lowering
treatment options


Maximum tolerated
statin

dose


Maximum
statin

+
Ezetimibe



Maximum
statin

+
Ezetimibe

+ Niacin &/or BAS resin


Maximum
statin

+
Ezetimibe

+ Niacin + BAS resin



Depending on NHDL
-
C,
apo

B etc, consider
fibrates

& n
-
3


If desperate, consider
plasmapheresis



New treatment options currently under investigation


Future LDL
-
C treatment options


Antibodies or antisense
oligonucleotides

against PCSK9



Highly potent CETP Inhibitors can reduce LDL
-
C and
Lp
(a)


Anacetrapib

and
Evacetrapib



LXR inhibitors cause fatty liver: Target related
mechanisims


IDOL (Inducible degrader of LDL Receptor)?


Trans intestinal cholesterol transport







Inhibitors of
atherogenic

lipoproteins also cause fatty liver


Judicious use of Apo B antisense
oligonucleotide

(
Mipomersin
)


Judicious use of
Microsomal

Transfer Protein (MTP) inhibitors



Less likely:
Eprotirome
, Inhibitors of
Squalene

Synthase

or ACAT

Blockade of PCSK9/LDLR
Interaction May Lower LDL Levels


1. Chan JC, et al.
Proc Natl Acad Sci U S A.

2009;106:9820
-
9825.

low intracellular sterol level



SREBP

cholesterol

biosynthesis

LDLR

HMGCoAR

Statins

cholesterol uptake

+

+

-

Cellular
sterol regulation:

LXR reduces LDL
-
R uptake via IDOL

(Inducible degrader of LDL
-
receptor)

Zelcer
et al.

Science 2009;325:100
-
104

high intracellular sterol level



LXRs

ABCA1

ABCG1

cholesterol efflux

(oxysterol, GW, T)


LDLR

IDOL

+

-

ubiquitin

LXR promotes LDL excretion by direct

Trans Intestinal Cholesterol Excretion

Options for further LDL
-
C reduction:
Mipomersin

and MTP inhibitors

Cytosol

Endoplasmic Reticulum

Hepatocyte or
Enterocyte

apoB

+ MTP/Lipid

Nascent apoB interacts with
lipid free MTP and is
ubiquinated

Ribosome

mRNA

Degradation

Mature VLDL or
Chylomicron

apoB associates with MTP
-
Lipid complexes and forms a
VLDL precursor which after
lipidation with TG becomes a
mature VLDL in the Golgi

MTP = Microsomal
TG Transfer Protein

Golgi

Triglycerides

VLDL Precursor

Endosomal free &
esterified
cholesterol

LDL
-
C reduction: A treatment of last resort?


Prevention of unexplained or resistant CVD risk:





Attributable to unknown or novel risk factors:
Lp
(a), Ch 9p22 etc



Progression despite optimal treatment of other classic
modifiable risk factors (such as BP, Glucose etc) to the lower
end of physiological range



Due to “hard to treat” risk factors such as isolated low HDL
-
C




LDL
-
C lowering therapy to achieve levels well below the
usual physiological range appears to be safe and
effective






Link to cases:

Mrs E. T.


Mrs E.T is a slightly overweight (BMI 26) woman with type 2 diabetes, which
was diagnosed 11 years ago. She is
normotensive

on
Atacand

16 mg, ACR
is within normal limits but
eGFR

is 55mls/min. HbA1C is 6.9%. ECG
suggested silent AMI, so
Atorvastatin

was increased to 40
mg.nocte
. Follow
-
up lipids include: TC=3.9, TG=2.5, HDL=1.1, LDL=1.7
mmol
/l.


Questions concerning Mrs E.T.


LDL
-
C and HDL
-
C are within target levels. Are you satisfied
with lipid control?

Yes/No



Which of the following would assist your assessment?

A)
TC/HDL ratio

B) TG/HDL ratio

C) Apo A1

D) Apo B

E) Apo A1:ApoB ratio



A renal dose (48mg) of
fenofibrate

is commenced. Would you
be discouraged if LDL
-
C increased?

Yes/No



Mrs E.T. Is concerned about the increase in
statin

does and the
prospects of low cholesterol because of media reports that
breast cancer rates were increased in the CARE trial. You can
reassure her that this finding has been refuted. True / False


LDL
-
C and HDL
-
C are within target levels. Are you satisfied
with lipid control?


Yes/No







Which of the following would assist your assessment?


A) TC/HDL ratio

B) TG/HDL ratio

C) Apo A1


D) Apo B

E) Apo A1:ApoB ratio






Mrs E.T. Is concerned about the increase in
statin

does and the
prospects of low cholesterol because of media reports that
breast cancer rates were increased in the CARE trial. You can
reassure her that this finding has been refuted. True / False


Mrs E.T is a slightly overweight (BMI 26) woman with type 2
diabetes, which was diagnosed 11 years ago. She is
normotensive

on
Atacand

16 mg, ACR is within normal limits but
eGFR

is 55mls/min. HbA1C is 6.9%. ECG suggested silent AMI,
so
Atorvastatin

was increased to 40
mg.nocte
. Follow
-
up lipids
include: TC=3.9, TG=2.5, HDL=1.1, LDL=1.7
mmol
/l.


LDL
-
C and HDL
-
C are within target levels. Are
you satisfied with lipid control?


Yes




No


LDL
-
C and HDL
-
C are within target levels. Are
you satisfied with lipid control?

The case for “no”

CETP = cholesterol ester transfer protein

Liver

VLDL

TG

TG

CE

CE

CETP

LDL

CETP

HDL

SD

HDL

Hepatic
Lipase

Kidney

Rapid

Degradation

Apo A
-
I

HDL

SD
LDL

SD
LDL


TG


VLDL
-
C

1

2

3


Athero

Dyslip


1.
↑TG/VLDL
-
C

2.
SD LDL

3.
↓HDL
-
C

↑Central

Adiposity

Insulin

Resistance

FFA/TG

Hepatic
Lipase


Which of the following would assist
your assessment?


A) TC/HDL ratio





B) TG/HDL ratio





C) Apo A1





D) Apo B





E) Apo A1:ApoB ratio



Which of the following would assist your
assessment?

The case for “D”

A renal dose (48mg) of
fenofibrate

is
commenced. Would you be discouraged if
LDL
-
C and
creatinine

increased?



Yes



No


A renal dose (48mg) of
fenofibrate

is
commenced. Would you be discouraged if
LDL
-
C and
creatinine

increased?

The case for “No”

5
-
year
CVD
Event
Rate (%)


creatinine


<78 78
-
94 >94

0

2

4

6

8

10

12

14

16

Placebo

Placebo

Fenofibrate


<78 78
-
94 >94


You can reassure her that this finding
(increased breast cancer) has been
refuted....


True




False


You can reassure her that this finding
(increased breast cancer) has been refuted....

The case for “true”

Ahern TP, Pedersen L, Tarp M

et al
.

Statin

Prescriptions and Breast
Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort
Study
.

Journal of the National Cancer Institute

(2011) 103 : 1461
-
1468.


RESULTS:

Most prescriptions for
lipophilic

statins

in the study population were for
simvastatin
. Exclusive
simvastatin

users experienced approximately 10
fewer breast cancer recurrences per 100 women after 10 years of follow
-
up (adjusted 10
-
year risk difference =
-
0.10, 95% confidence interval =
-
0.11 to
-
0.08), compared with women who were not prescribed a
statin
.
Exclusive hydrophilic
statin

users had approximately the same risk of
breast cancer recurrence as women not prescribed a
statin

over follow
-
up
(adjusted 10
-
year risk difference = 0.05, 95% confidence interval =
-
0.01
to 0.11).

More questions
concerninig

Mrs E. T.


Despite this, Mrs E.T. subsequently suffers an acute coronary syndrome and
aspirin has been commenced. Would you





A) Intensify
antihypertensives

although BP is 118/75



B) Intensify oral
hypoglycaemics

although
HbAIC

is < 7%


C) Intensify
fibrate

although TG and HDL are now at target (<2mmol/l
and > 1
mmol
/l respectively)







D) Intensify LDL
-
lowering although LDL
-
C is < 1.8
mmol
/l


E) Rely on the addition of aspirin to avoid further events?



You add
ezetimibe

and LDL
-
C falls to < 1.0
mmol
/l. Is this safe? Yes / No



Mrs E.T. Starts a trial of addition of a CETP inhibitor. You are not blinded to
her lipid results, which include: TC = 3.2, TG=1.7, HDL=2.4
mmol
/l, so you
calculate LDL
-
C as zero. Should you believe this result?

Yes / No




Despite this, Mrs E.T. subsequently suffers an
acute coronary syndrome and aspirin has
been commenced. Would you....

A)
Intensify
antihypertensives

although BP is
118/75





B)
B) Intensify oral
hypoglycaemics

although
HbAIC

is < 7%




C)
C) Intensify
fibrate

although TG and HDL
are now at target (<2mmol/l and > 1
mmol
/l
respectively)








D)
D) Intensify LDL
-
lowering although LDL
-
C
is < 1.8
mmol
/l




E)
E) Rely on the addition of aspirin to avoid
further events?


You add
ezetimibe

and LDL
-
C falls to < 1.0
mmol
/l. Is this safe?


Yes




No

You add
ezetimibe

and LDL
-
C falls to < 1.0
mmol
/l. Is this safe?

The case for “Yes”

Ann Surg.

2010 Jun;251:1034
-
40.

Overall mortality, incremental life expectancy, and cause of death at
25 years in the program on the surgical control of the
hyperlipidemias
.

Buchwald H
,

Rudser

KD
,

Williams SE
,

Michalek

VN
,

Vagasky

J
,

Connett

JE
.


There were 838 patients randomized in POSCH (421 surgery, 417
control). At 25 years follow
-
up, the difference was statistically
significant, with survival probabilities of 0.57 (surgery) and 0.51
(controls). Cause of death data indicated a significant increase in
cardiovascular deaths in the control group; cancer deaths were also
greater in the control group but this was not significant. The estimated
incremental increase in life expectancy over more than 25 years of
follow
-
up was 1.0 year overall and 1.7 years in the cohort with an
ejection fraction > or = 50%.

Mrs E.T. starts a trial of addition of a CETP
inhibitor. You are not blinded to her lipid
results, which include: TC = 3.2, TG=1.7,
HDL=2.4
mmol
/l, so you calculate LDL
-
C as
zero. Should you believe this result?


Yes




No




Mrs E.T. starts a trial of addition of a CETP
inhibitor. You are not blinded to her lipid
results, which include: TC = 3.2, TG=1.7,
HDL=2.4
mmol
/l, so you calculate LDL
-
C as
zero. Should you believe this result?

An explanation of “No”

VLDL

CETP

TG

CE

HDL

LDL

CETP

TG

CE

LIPASE

sdLDL

FATTY ACIDS

GLYCEROL

Inhibition of CETP will invalidate the assumptions about VLDL

composition that form the
founndation

of the
Friedewald

equation


LDL
-
C = Total
-
C


HDL
-
C


(TG/2.2)
mmol
/l

Ms J.A.


Mrs J.A. Is a 27 year old woman who has recessively inherited
Microsomal

Transfer Protein (MTP) deficiency that prevents her from
lipidating

apo

B
-
containing lipoproteins. Her lipid profile features:


TC=2.7, TG=0.4, HDL=2.3, LDL = 0.2
mmol
/l

Questions concerning Ms J.A.


Which organ systems are likely to be adversely affected in this condition
(more than 1 answer is possible)

A) Cardiovascular



B) Neurological


C) Renal

D) Gastrointestinal



E) Respiratory


Diet should include:

A) More fat

B) Less fat

C) Extra Fat Soluble
Vitamins

D) A + C

E) B + C


Ms J.A plans to start a family: Is her reproductive capacity diminished by the
very low levels of LDL
-
C?

Yes /No


Treatment up until now has avoided any consequences. Is Ms J.A.’s life
expectancy

A) Decreased

B) Unaltered

C) Increased

Which organ systems are likely to be
adversely affected in this condition (more
than 1 answer is possible)


A) Cardiovascular




B) Neurological



C) Renal




D) Gastrointestinal




E) Respiratory


Which organ systems are likely to be
adversely affected in this condition?

The case for “B” and “D”

Malabsorption

syndrome

Erythrocyte sedimentation rate low

Anemia

Acanthocytosis

Hepatic
steatosis

Nystagmus

Short stature

Retinitis
pigmentosa

Demyelination

Diarrhoea

Kyphosis

Cerebellar

syndrome


Diet should include:


A) More fat




B) Less fat




C) Extra Fat Soluble Vitamins




D) A + C




E) B + C



Diet should include:

The case for “E”

INABILITY TO TRANSPORT
FAT


Malabsorption

syndrome

Hepatic
steatosis

Diarrhoea


DEFICIENCY OF FAT SOLUBLE
VITAMINS


Nystagmus

Retinitis
pigmentosa

Demyelination

Cerebellar

syndrome


Kyphosis
Short

stature



Ms J.A plans to start a family: Is her
reproductive capacity diminished by
the very low levels of LDL
-
C?


Yes




No

Questions concerning Ms J.A. Ms J.A plans to
start a family: Is her reproductive capacity
diminished by the very low levels of LDL
-
C?

The case for “No”

Treatment up until now has avoided any
consequences. Is Ms J.A.’s life expectancy



A) Decreased




B) Unaltered




C) Increased

Treatment up until now has avoided any
consequences. Is Ms J.A.’s life expectancy

The case for “increased”

Familial
HypobetalipoproteinemiaAbsence

of Atherosclerosis in a
Postmortem

Study

Jeffrey A. Kahn, MD; Charles J.
Glueck
, MD

JAMA.

1978;240:47
-
48.


Men and women from
hypobetalipoproteinemic

kindreds

had reported
life expectancies that were seven and six years longer, respectively, than
for US white populations (
P
<.002).
2

Combined myocardial infarction
morbidity and mortality was 2.5% in
hypobetalipoproteinemic

kindreds
,
fivefold less than in
normolipemic

controls (11%;

P
<.01).
2

In
hypobetalipoproteinemia
, low C
-
LDL, the
atherogenic

lipoprotein,
2
-
4

or a
low ratio of C
-
LDL to C
-
HDL, the
antiatherogenic

lipoprotein,
2,4

may
facilitate longevity and decrease morbidity and mortality from
myocardial infarction.
2