The effects of serum cholesterol, LDL, and HDL levels on ...
targets and LDL Non HDL C, - Lipid · PDF fileLDL Cholesterol LDL-C 130 mg/dL LDL-C 130 mg/dL...
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New targets and treatments: Understanding LDL‐P, Non‐HDL‐C, and ApoB
Samia Mora, MD, MHS
Associate Physician, BWH Heart and Vascular Center; Assistant Professor of Medicine, Harvard Medical School www.brighamandwomens.org/heart
Disclosures
•Consultant:
Cerenis, Lilly, Pfizer
•Institutional research grants:Atherotech DiagnosticsQuest Diagnostics (in kind)
– What are the clinically important lipids or lipoproteins for CVD risk?
– LDL-C, non-HDL-C, Total/HDL-C– LDL-P, apoB
– Are small LDL more atherogenic than large LDL particles?
– Residual risk on statin therapy
Topics to be covered
LDL cholesterol
Non-HDL chol
Total / HDL chol
Woman A
130 mg/dL
162 mg/dL
3.1
Woman B
130 mg/dL
181 mg/dL
5.3
Which woman is
at higher risk?
Mora, Circ 2009;119:2396
Woman A
130 mg/dL
162 mg/dL
3.1
22.1 nm (large)
1011 nmol/L
712 nmol/L
299 nmol/L
106 mg/dL
Woman B
130 mg/dL
181 mg/dL
5.3
20.4 nm (small)
1723 nmol/L
360 nmol/L
1286 nmol/L
127 mg/dL
Fewer Particles More Particles
Which woman is
at higher risk?
Mora, Circ 2009;119:2396
LDL cholesterol
Non-HDL chol
Total / HDL chol
LDL size (NMR)
LDL particle number (LDL-P, NMR)
Large LDL-P
Small LDL-P
ApoB
LDLCholesterol
LDL-C 130 mg/dL LDL-C 130 mg/dL
Larger
LDL Size
Smaller
LDL Size
LDL cholesterol
Non-HDL chol
Total / HDL chol
LDL size (NMR)
LDL particle number (LDL-P, NMR)
Large LDL-P
Small LDL-P
ApoB
Woman A
130 mg/dL
162 mg/dL
3.1
22.1 nm (large)
1011 nmol/L
712 nmol/L
299 nmol/L
106 mg/dL
Woman B
130 mg/dL
181 mg/dL
5.3
20.4 nm (small)
1723 nmol/L
360 nmol/L
1286 nmol/L
127 mg/dL
Fewer Particles More Particles
Which woman is
at higher risk?
Mora, Circ 2009;119:2396
– What are the clinically important lipids or lipoproteins for CVD risk?
– LDL-C, non-HDL-C, Total/HDL-C– LDL-P, apoB
– Are small LDL more atherogenic than large LDL particles?
– Residual risk on statin therapy
Topics to be covered
1
1.4
1.8
2.2
2.6
3
LDL-C Non-HDL-C Total / HDL-C
Q1 Q2 Q3 Q4 Q5
Rel
ativ
e R
isk
ofC
ardi
ovas
cula
r Eve
nts
Women’s Health Study (N=27,673)
Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes
Total/HDL-C or Non-HDL-C better than LDL-C for incident CVD
Mora et al, Circulation 2009;119:931
* All P <0.0001
*
*
*
1
1.4
1.8
2.2
2.6
3
LDL-C Non-HDL-C Total / HDL-C ApoB LDL-P (NMR)
Q1 Q2 Q3 Q4 Q5
Rel
ativ
e R
isk
ofC
ardi
ovas
cula
r Eve
nts
Mora et al, Circulation 2009;119:931
* All P <0.0001
Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes
ApoB and LDL-PNMR similar to Total/HDL-C or Non-HDL-C
Women’s Health Study (N=27,673)
*
*
**
*
Women’s Health Study
Little improvement in CVD risk classification with adding apoB or LDL-PNMR to total/HDL-C
Mora et al, Circulation 2009;119:931
C-Index NRI (p-value)† % reclassified
Total / HDL-C* 0.784 Ref. Ref.
plus LDL-P 0.785 0 (0.52) 1.1
plus ApoB 0.786 1.9 (0.02) 2.6
* Total/HDL-C plus standard CVD risk factors
† NRI: net reclassification index, which compares the proportion moving up or downclinical categories in cases or controls, comparing models that added LDL-P or apoB to a model with total/HDL-C ratio and standard CVD risk factors
0.5 1.0 1.2 1.4 1.8
Total Chol
Non-HDL-C
Total / HDL-C
ApoB
1.22 (1.17-1.27)
1.27 (1.22-1.33)
1.32 (1.24-1.39)
1.24 (1.19-1.29)
Hazard Ratio (95%CI)
Emerging Risk Factors Collaboration
26 Prospective Studies (N=139,581)
Hazard Ratio (95%CI) per 1-SD higher usual values
Adjusted for age, sex, smoking, BP, and diabetes
ERFC, JAMA 2012;307:2499-2506
Emerging Risk Factors Collaboration
No improvement in CVD risk classification with adding apoB to total/HDL-C
C-Index NRI (p-value)† % reclassified
Total / HDL-C* 0.724 Ref. Ref.
plus ApoB 0.725 - 0.2 (0.34) --
plus ApoB/A-I 0.725 0.1 (0.40) 1.1
* Total/HDL-C plus standard CVD risk factors
† NRI: net reclassification index, which compares the proportion moving up or downclinical categories in cases or controls, comparing models that added apoB to a model with total/HDL-C ratio and standard CVD risk factors
ERFC, JAMA 2012;307:2499-2506
Potential clinical utility of advanced lipid testing in certain subgroups
• Diagnosing certain dyslipidemias (eg. familial dysbetalipoproteinemia or Type III)
• Individuals whose LDL-C level is discordant (inconsistent) with LDL particle measures (eg. ApoB, LDL-P)– LDL-C low but ApoB or LDL-P high– LDL-C high but ApoB or LDL-P low
LDL-C and NHDL-C
Concordant
88
12
Discordant
Concordant
19
81
Discordant
Concordant
24
76
Discordant
Concordant
%
%
%
%
%
%
LDL-C and LDL-PNMR
LDL-C and ApoB
r = 0.91
Mora S et al, Circulation 2014; 129:553-61
LDL-P < Median (Concordant)
Discordant LDL-C and LDL particle measures?
010
0020
0030
0040
00LD
L-P
, nm
ol/L
0 100 200 300 400LDL-C, mg/dL
010
020
030
040
0N
HD
L-C
, mg/
dL
0 100 200 300 400LDL-C, mg/dL
010
020
030
040
0A
poB
, mg/
dL
0 100 200 300 400LDL-C, mg/dL
Discordant
Discordant Concordant
Concordant
Discordant
Discordant Concordant
Concordant
Discordant
Discordant Concordant
Concordant
r = 0.91
r = 0.78
r = 0.69
Women’s Health Study(N=27,533)
LDL-C vs NHDL-C
Concordant
Concordant
LDL-C vs LDL-P
LDL-C vs ApoB
r = 0.91
0.00
0.02
0.04
0.06
0.08
0.10
Cum
ulat
ive
Prob
abili
ty o
fIn
cide
nt C
HD
2 4 6 8 10 12 14 16 18Follow-Up (Years)
Low LDL-C, High Non-HDL-CLow LDL-C, Low Non-HDL-C
0.00
0.02
0.04
0.06
0.08
0.10
Cum
ulat
ive
Prob
abili
ty o
fIn
cide
nt C
HD
2 4 6 8 10 12 14 16 18Follow-Up (Years)
Low LDL-C, High ApoBLow LDL-C, Low ApoB
0.00
0.02
0.04
0.06
0.08
0.10
Cum
ulat
ive
Prob
abili
ty o
fIn
cide
nt C
HD
2 4 6 8 10 12 14 16 18Follow-Up (Years)
Low LDL-C, High LDL-PLow LDL-C, Low LDL-P
LDL-P ≥ Median (Discordant)
LDL-P < Median (Concordant)
ApoB ≥ Median (Discordant)
ApoB < Median (Concordant)
NHDL-C ≥ Median (Discordant)
NHDL-C < Median (Concordant)
Mora et alCirc 2014; 129:553-61
NHDL-C ≥ Median (Concordant)
NHDL-C < Median (Discordant)
ApoB ≥ Median (Concordant)
ApoB < Median(Discordant)
LDL-P ≥ Median (Concordant)
LDL-P < Median (Discordant)
LDL-C < Median LDL-C ≥ Median
– What are the clinically important lipids or lipoproteins for CVD risk?
– LDL-C, non-HDL-C, Total/HDL-C– LDL-P, apoB
– Are small LDL more atherogenic than large LDL particles?
– Residual risk on statin therapy
Topics to be covered
Large LDL (Pattern A) Small LDL (Pattern B)
Carries more cholesterol per
particle
Elevated in FH
Elevated with high sat fat
Low in countries with low fat
diet (Costa Rica)
High in Native Americans,
Scotland (high CAD)
Oxidized more rapidly
Elevated in metabolic
syndrome/insulin resistance
Associated with low HDL-C,
high TG
Altered endothelial function
Altered fibrinolysis
Sacks and Campos, J Clin Endocrinol Metab 2003;88:4525-4532.
Both have reduced affinity to LDL receptorIn vivo, similar transit time across arterialintimaBoth bind arterial proteoglycans thusactivating plaque progression
Both large and small LDL share atherogenic properties:
Sacks and Campos, J Clin Endocrinol Metab 2003;88:4525-4532.
Controversy over the importance of LDL size as independent risk factor
Adjustment for other risk factors (TG, HDL) attenuated the association of LDL size to non-significant in most studies
LDL size and CVD: prior studies
Stampfer et al JAMA 1996;276:882-888.
Physicians Health Study nested case-control
Quebec Cardiovascular Study
"Among lipid, lipoprotein, and apolipoprotein variables, apo B came out as the best and only significant predictor of CHD risk in multivariate stepwise logistic analyses (P=.002).”
“[LDL size] as a continuous variable did not contribute to the risk of CHD after the contribution of apo B levels to CHD risk had been considered."
Lamarche et al Circulation 1997; 95:69-75
Most previous studies examined LDL size phenotype by GGE
Limitation of gradient gel electrophoresis(GGE): Decrease in average LDL size does not necessarily translate into greater number of small LDL particles, since it could also be due to fewer large LDL particles
Measurement of LDL size
Mora, Circ 2009;119:2396
LDL size (average)
Large LDL
Small LDL
Large LDL
Small LDL
Less LDL particles
More LDL particles
Mora, Circ 2009;119:2396
A confounder is associated with the risk factor and is causally related to the outcome
Risk factor Outcome
Confounder
Alcohol CHD
Smoking
Is the relation of LDL size with CHD confounded by LDL particle number ?
A confounder is associated with the risk factor and is causally related to the outcome
Risk factor Outcome
Confounder
LDL Size CHD
LDL-P
?
Is the relation of LDL size with CHD confounded by LDL particle number ?
Mora, Circ 2009;119:2396
Adjusting for small LDL-P unmasks the true relation of large LDL-P with IMT
MESA Study (N=5538)
920
950
980
1010
1040
Q1 Q2 Q3 Q4 Q5Large LDL-P Quintiles
Ptrend = 0.94 Ptrend <0.001
Adjusted for age and sex Adjusted for age,sex, and small LDL-P
IMT
(mic
rons
)
Mora et al, Atherosclerosis 2007;192:211-17
Relation of LDL size with IMT
IMT (SE) in m per
1-SD P value
LDL Size (unadjusted for LDL-P) -20.9 (4.5) <0.001
LDL Size (adjusted for LDL-P*) +14.5 (7.2) 0.05
Models adjusted for age, sex, race, smoking, and hypertension.
*correlation of LDL size with LDL-P = -0.64
Mora et al, Atherosclerosis 2007;192:211-17
0
0.5
1
1.5
2
2.5
Small LDL-P Large LDL-P
Q1 Q2 Q3 Q4 Q5
Rel
ativ
e R
isk
ofC
ardi
ovas
cula
r Eve
nts
Mora et al, Circulation 2009;119:931
* P <0.0001
Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes
Women’s Health Study: Small vs large LDL-PNMR
N=27,673
*
0
0.5
1
1.5
2
2.5
Small LDL-P Large LDL-P Large LDL-Padjusted forsmall LDL-P
LDL-P(Total)
Q1 Q2 Q3 Q4 Q5
Rel
ativ
e R
isk
ofC
ardi
ovas
cula
r Eve
nts
Mora et al, Circulation 2009;119:931
* P <0.0001
Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes
Both small and large LDL associated with increased CVD
N=27673
*
*
*
For type 2 diabetes, LDL particle size was strong and independent predictor
Q1 Q2 Q3 Q4 Q5 Ptrend
LDL size 4.16 3.04 2.21 1.63 1.00 <0.001
Small Large
* Relative risk adjusted for age, race, smk, menopause, HRT, BP, BMI, exercise, education, FHx, CRP, HbA1c
Mora et al, Diabetes 2010 ; 59:1153-1160
0
0.5
1
1.5
2
2.5
3
3.5
4
LDL-C Small LDL-P IDL-P LDL-P (Total) Large LDL-P
Q1 Q2 Q3 Q4 Q5
Rel
ativ
e R
isk
ofD
iabe
tes
* P <0.0001
Large LDL associated with lower risk of diabetes
Women’s Health Study (N=26,836)
*
*
**
Mora et al, Diabetes 2010 ; 59:1153-1160
Relative risk adjusted for age, race, smk, menopause, HRT, BP, BMI, exercise, education, FHx, CRP, HbA1c
Mora et al, ATVB meeting, Toronto, 2014, manuscript in preparation
JUPITERIon Mobility LDL Subclasses and CVD Risk in
placebo groupBaseline LDL-C 109 mg/dL
– What are the clinically important lipids or lipoproteins for CVD risk?
– LDL-C, non-HDL-C, Total/HDL-C– LDL-P, apoB
– Are small LDL more atherogenic than large LDL particles?
– Residual risk on statin therapy
Topics to be covered
Final model * % or SD HR (95% CI) PBMI (per 1-SD), kg/m2 4.5 1.09 (1.02, 1.17) 0.01Myocardial infarction 58 1.60 (1.36, 1.87) <0.001Angina 82 1.36 (1.10, 1.68) 0.004Cerebrovascular disease 5 1.73 (1.36, 2.19) <0.001Peripheral vascular disease 12 1.32 (1.09, 1.61) 0.005Congestive heart failure 8 1.54 (1.24, 1.90) <0.001CABG 47 1.26 (1.08, 1.47) 0.004Calcium channel blocker 27 1.31 (1.12, 1.54) <0.001Aspirin 87 0.67 (0.56, 0.81) <0.001Baseline (per 1-SD, on-statin), mg/dL
Apolipoprotein BApolipoprotein A-IBUN
19254.9
1.19 (1.11, 1.28)0.91 (0.84, 0.99)1.10 (1.03, 1.17)
<0.0010.020.003
* Final model included randomized treatment, age, sex, HTN, smk, DM plus these variables Mora S et al. Circulation, 2012:125:1979-87.
Treating to New Targets (TNT)Multivariable Predictors of Residual Risk
Lipid or Apoipoprotein SD, mg/dL HR (95% CI) * P
LDL-C 27.4 1.31 (1.09-1.56) 0.004
Non-HDL-C 30.8 1.25 (1.04-1.50) 0.02
Apo B 22.1 1.27 (1.06-1.53) 0.009
Triglycerides 62.7 0.93 (0.74-1.17) 0.56
HDL-C 16.3 0.89 (0.70-1.12) 0.29
Apo A-I 32.4 0.81 (0.65-1.01) 0.06
JUPITER:On-Treatment Lipids and Residual Risk
On-Treatment LDL-C 55 mg/dL
* Standardized hazard ratios adjusted for age, sex, smoking, BP, glucose, BMI, family history
Mora S et al., JACC 2012; 59:1521-8
Boekholdt et al JACC 2014;64:485
Achieved LDL-C
mg/dL
Large inter-individual variability in response to high-intensity statin
Meta-analysis of TNT, IDEAL, SPARCL, JUPITERN=18,661
Achieved Non-HDL-C Achieved ApoB
mg/dLmg/dL
N
Lipid or Apoipoprotein
AdjustedHR (95% CI) * P
LDL-C 1.13 (1.10-1.17) <0.001
Non-HDL-C 1.16 (1.12-1.19) <0.001
Apo B 1.14 (1.11-1.18) <0.001
Boekholdt SM et al., JAMA 2012; 307:1302-9
Meta-analysis of 8 statin trials(N=38,153; No. events=5,387)
On-Treatment Lipids and Residual Risk
Boekholdt SM et al., Circulation 2013; 128:1504-12
Differential genetic effects on statin-induced changes in LDL-C, apoB, LDL-P, LDL size
JUPITER, N=7046 Caucasians
Chu A et al, in preparation
LDL-C NHDL-C ApoB LDL-P LDL size
SNP cluster ∆ LDL size
SNP cluster ∆ LDL-P
SNP cluster ∆ ApoB
SNP cluster ∆ All
LDLCholesterol
LDL-C 130 mg/dL LDL-C 130 mg/dL
Larger
LDL Size
Smaller
LDL Size
LDL cholesterol
Non-HDL chol
Total / HDL chol
LDL size
LDL particle number (LDL-P)
Large LDL-P
Small LDL-P
ApoB
Woman A
130 mg/dL
162 mg/dL
3.1
22.1 nm (large)
1011 nmol/L
712 nmol/L
299 nmol/L
106 mg/dL
Woman B
130 mg/dL
181 mg/dL
5.3
20.4 nm (small)
1723 nmol/L
360 nmol/L
1286 nmol/L
127 mg/dL
Fewer Particles More Particles
Which woman is
at higher risk?
Mora, Circ 2009;119:2396
– What are the clinically important lipids or lipoproteins for CVD risk?
– LDL-C, non-HDL-C, Total/HDL-C– LDL-P, apoB
– Are small LDL more atherogenic than large LDL particles?
– Residual risk on statin therapy
Topics covered