Is lower better? LDL targets and beyond.
Implications of the relationship between
risk factor (LDL-C) level and event rate
LOG of
event
rate
Event
rate
Risk factor level
Risk factor level
1: Is there a continuous relationship?
Log – linear:
2: Is there a lower limit?
No lower limit
3: What is the nature of the relationship? Law of diminishing returns
LDL-lowering lowers the risk of
MAJOR CARDIOVASCULAR EVENTS
and more lowering provides more benefit
20
Control
21% relative risk
reduction in CVD per mmol/L
Five year risk of a major
vascular event, %
Statin
15
More statin
16% relative risk
reduction in CVD per 0.5 mmol/L
10
Combined evidence:
33% relative risk reduction
per 1.5 mmol/L
(since 0.79 x 0.84 = 0.67)
5
0
0
1
2
3
4
LDL cholesterol, mmol/L
5
Lancet 2010
Implications of the relationship between risk
factor treatment and event rate.
Is there a “J” curve?
Event
rate
Treated risk factor level:
Antihypertensive & hypoglycaemic therapy in ACCORD Trial adverse
What is the Harm : Benefit ratio for LDL reduction?.
Ox chol and LXR
CD36
TG-rich
lipoproteins
SR
Cholesterol
FFAs
PG, LTs
oxysterols
LPL
PLA2
FAS
TATA
Many animal
species, neonates,
and patients with
genetic diseases
tolerate very low
LDL-C
TATA
RXR/LXR
ABCA1
ABCG1
apoE
LPL
SREBP1c
CD36
LXRα
Cpt1
Ech1
PexIIa
LPL
Cholesteryl
esters
FAS
CPT1
Lipid
Uptake &
Synthesis
ACAT
PPAR/RXR
FFAs
oxLDL
ECH1PexIIa
FAS
FFAs
ACAT
Mitochondria
β oxidation
Cholesterol
ABCA1
apoE
apoA1
Lipid
Catabolism,
Efflux &
Storage
Is low LDL a causative risk factor for
non-CVD morbidity and mortality?
• Cancer and
chronic disease
reduce LDL-C
rather than viceversa
• Need to adjust for
undiagnosed
cases
•
“Mendelian
randomisation” re
LDL-C and
cancer : not
associated
Theoretically predicted
risk
PCSK9 R46L
Non-carriers
Heterozygotes
Homozygotes
Observed risk
P=0.54
ABCG8 D19H
Non-carriers
Heterozygotes
Homozygotes
P=0.78
APOE ε2/ε3/ε4
44
43
33
42
32
22
P=0.96
0
50 100 0.5
150
0.75
1.0
1.25
1.5 0.5
0.75
Hazard/odds ratio for
Cancer (95% CI)
1.0
1.25
1.5
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%
TG affects cholesterol content, and hence size,
composition and density of lipoproteins
Small
LDL
Cholesterol ester
Triglyceride
TG
Lipase
CETP
CE
When TG is elevated
LDL-C may under-estimate
LDL particle number and
CVD risk.
Otvos JD, et al. AJC 2002;90(8A):22i-29i
CVD risk is proportional to the number of
atherogenic lipoproteins rather than their
cholesterol content (or composition).
Quebec Cardiovascular Study
Apo B: 1 per particle
7
6.2
6
Risk of IHD
5
4
3
LDL particle
number
(Apo B)
2.1
2
1
0
1
1
High
Low
LDL particle size
Large
Small
Lamarche B, et al. Circulation 1997; 95:69-75
Is LDL – C the best target?
US Health Professionals Study
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
Biomarker
•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
VLDL
Measured
LDL-C
2.5 mmol/l
LDL
LDL
particles
900 nmol/L
LDL
NMR
Signals
Measured
LDL-C
2.5 mmol/l
LDL
particles
1600
nmol/L
Outcome Associations of NMR LDL Particle
Number (LDL-P) versus LDL Cholesterol (LDL-C)
Study
Women’s Health Study
Circulation 2002; 106:1930-1937
Circulation 2009;119:931-939
VA-HDL Intervention Trial
Circulation 2006;113:1556-63
MESA Trial
Atherosclerosis 2007;192:211–217.
Framingham Heart Study
J Clin Lipidology 2007;1(6):583-592
Cardiovascular Health
Study
ATVB 2002; 22:1175-1180
PLAC-I
AJC 2002;90:89-94
Health Women Study
AJC 2002;90(suppl): 71i-77i
CHD Status
Atherosclerotic Endpoint
Associations Stronger for
LDL-P than LDL-C *
Primary
Prevention
Incident MI, CHD death,
CVA
YES
Secondary
Prevention
Non-fatal MI or CHD Death
YES
Primary
Prevention
Carotid IMT
YES
Primary
Prevention
Incident CVD Events
YES
Primary
Prevention
Incident MI or Angina
YES
Secondary
Prevention
Angiographic
MLD
YES
Primary
Prevention
EBCT Coronary Calcium
Score
YES
* Significant and independent after multivariate modeling (lipids and established risk factors)
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:
LDL-C may underestimate reduction
in LDL particle number:
• Statins
• Fibrates
• Statin + Ezetimibe or Bile
Acid Sequestrants
• Niacin
• Estrogen Replacement
Therapy
• Omega 3 FAs
• Anti-retrovirals (some)
• Low fat, High carb diet
Therapy LDL-C More
Than LDL-P
• Pioglitazone
• 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.
Cellular sterol regulation:
LXR reduces LDL-R uptake via IDOL
(Inducible degrader of LDL-receptor)
cholesterol uptake
LDLR
LDLR
+
cholesterol
biosynthesis
+
cholesterol efflux
IDOL
ubiquitin
+
ABCA1
HMGCoAR
SREBP
Statins
ABCG1
LXRs
(oxysterol, GW, T)
low intracellular sterol level
high intracellular sterol level
Zelcer et al. Science 2009;325:100-104
LXR promotes LDL excretion by direct
Trans Intestinal Cholesterol Excretion
Options for further LDL-C reduction:
Mipomersin and MTP inhibitors
Hepatocyte or
Enterocyte
Endoplasmic Reticulum
Degradation
mRNA
Ribosome
MTP = Microsomal
TG Transfer Protein
+ MTP/Lipid
Cytosol
Nascent apoB interacts with
lipid free MTP and is
ubiquinated
apoB associates with MTPLipid complexes and forms a
VLDL precursor which after
lipidation with TG becomes a
mature VLDL in the Golgi
apoB
VLDL Precursor
Golgi
Endosomal free &
esterified
cholesterol
Mature VLDL or
Chylomicron
Triglycerides
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. Followup 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
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
• 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
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”
“Athero Dyslip”
1. ↑TG/VLDL-C
2. SD LDL
3. ↓HDL-C
TG
Liver
FFA/TG
1
VLDL-C
VLDL
↑Central
Adiposity
CE
CETP
Hepatic
HDL Lipase
TG
3
CE CETP
Insulin
Resistance
TG
Hepatic
Lipase
LDL
2
SDLDL
Kidney
Rapid
Degradation
Apo A-I
SD
HDL
HDL
SDLDL
CETP = cholesterol ester transfer protein
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”
16
14
12
5-year
CVD
Event
Rate (%)
10
8
6
4
2
0
Placebo
creatinine
Placebo
<78
78-94
Fenofibrate
>94
<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 followup (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”
TG
VLDL
TG
CETP HDL CETP
CE
CE
LDL
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 Bcontaining 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
Vitamins
D) A + C
E) B + C
C) Extra Fat Soluble
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
DEFICIENCY OF FAT SOLUBLE
VITAMINS
Malabsorption syndrome
Hepatic steatosis
Diarrhoea
Nystagmus
Retinitis pigmentosa
Demyelination
Cerebellar syndrome
KyphosisShort 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