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 Diagnostics Quest Diagnostics (in kind)
Topics to be covered 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
Which woman is at higher risk? 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 Mora, Circ 2009;119:2396
Which woman is at higher risk? Fewer Particles More Particles 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 Mora, Circ 2009;119:2396
Which woman is at higher risk? Larger LDL Size Smaller LDL Size LDL-C 130 mg/dl LDL-C 130 mg/dl Fewer Particles LDL Cholesterol More Particles 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 Mora, Circ 2009;119:2396
Topics to be covered 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
Total/HDL-C or Non-HDL-C better than LDL-C for incident CVD 3 2.6 Women s Health Study (N=27,673) * All P <0.0001 * Relative Risk of Cardiovascular Events 2.2 1.8 1.4 * * 1 LDL-C Non-HDL-C Total / HDL-C Q1 Q2 Q3 Q4 Q5 Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes Mora et al, Circulation 2009;119:931
ApoB and LDL-P NMR similar to Total/HDL-C or Non- HDL-C Relative Risk of Cardiovascular Events 3 2.6 2.2 1.8 1.4 * All P <0.0001 * Women s Health Study (N=27,673) * * * * 1 LDL-C Non-HDL-C Total / HDL-C ApoB LDL-P (NMR) Mora et al, Circulation 2009;119:931 Q1 Q2 Q3 Q4 Q5 Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes
Women s Health Study Little improvement in CVD risk classification with adding apob or LDL-P NMR to total/hdl-c 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 down clinical 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 Mora et al, Circulation 2009;119:931
Emerging Risk Factors Collaboration 26 Prospective Studies (N=139,581) Hazard Ratio (95%CI) 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) 0.5 1.0 1.2 1.4 1.8 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 down clinical 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
Discordant LDL-C and LDL particle measures? Concordant Women s Health Study (N=27,533) LDL-C and NHDL-C 88 % 12 % Discordant Concordant NHDL-C, mg/dl 0 100 200 300 400 Discordant Concordant Concordant Discordant r = 0.91 r = 0.91 Mora S et al, Circulation 2014; 129:553-61 LDL-C and ApoB 81 76 % % 19 24 % % Discordant Concordant LDL-C and LDL-P NMR Discordant Concordant ApoB, mg/dl 0 100 200 300 400 LDL-P, nmol/l 0 1000 2000 3000 4000 0 100 200 300 400 LDL-C, mg/dl Discordant Concordant Concordant Discordant 0 100 200 300 400 LDL-C, mg/dl Discordant Concordant Concordant Discordant r = 0.78 r = 0.69 LDL-P < Median (Concordant) 0 100 200 300 400 LDL-C, mg/dl
LDL-C vs NHDL-C Cumulative Probability of Incident CHD 0.00 0.02 0.04 0.06 0.08 0.10 LDL-C < Median Concordant r = 0.91 NHDL-C Median (Discordant) NHDL-C < Median (Concordant) 2 4 6 8 10 12 14 16 18 Follow-Up (Years) Concordant LDL-C Median NHDL-C Median (Concordant) NHDL-C < Median (Discordant) LDL-C vs ApoB Cumulative Probability of Incident CHD 0.00 0.02 0.04 0.06 0.08 0.10 Low LDL-C, High Non-HDL-C Low LDL-C, Low Non-HDL-C ApoB Median (Discordant) ApoB < Median (Concordant) 2 4 6 8 10 12 14 16 18 Follow-Up (Years) ApoB Median (Concordant) ApoB < Median (Discordant) LDL-C vs LDL-P Cumulative Probability of Incident CHD 0.00 0.02 0.04 0.06 0.08 0.10 Low LDL-C, High ApoB Low LDL-C, Low ApoB LDL-P Median (Discordant) LDL-P < Median (Concordant) 2 4 6 8 10 12 14 16 18 Follow-Up (Years) LDL-P Median (Concordant) LDL-P < Median (Discordant) Mora et al Circ 2014; 129:553-61 Low LDL-C, High LDL-P Low LDL-C, Low LDL-P
Topics to be covered 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
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 large and small LDL share atherogenic properties: Both have reduced affinity to LDL receptor In vivo, similar transit time across arterial intima Both bind arterial proteoglycans thus activating plaque progression Sacks and Campos, J Clin Endocrinol Metab 2003;88:4525-4532.
LDL size and CVD: prior studies Controversy over the importance of LDL size as independent risk factor Physicians Health Study nested case-control Adjustment for other risk factors (TG, HDL) attenuated the association of LDL size to non-significant in most studies Stampfer et al JAMA 1996;276:882-888.
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
Measurement of LDL size 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 Mora, Circ 2009;119:2396
More LDL particles Less LDL particles Large LDL Small LDL Large LDL Small LDL LDL size (average) Mora, Circ 2009;119:2396
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 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? Mora, Circ 2009;119:2396 LDL-P
Adjusting for small LDL-P unmasks the true relation of large LDL-P with IMT MESA Study (N=5538) Large LDL-P Quintiles Q1 Q2 Q3 Q4 Q5 1040 P trend = 0.94 P trend <0.001 IMT (microns) 1010 980 950 920 Adjusted for age and sex Adjusted for age, sex, and small LDL-P 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
Women s Health Study: Small vs large LDL-P NMR 2.5 N=27,673 2 * P <0.0001 Relative Risk of Cardiovascular Events 1.5 1 0.5 0 * Small LDL-P Large LDL-P Mora et al, Circulation 2009;119:931 Q1 Q2 Q3 Q4 Q5 Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes
Both small and large LDL associated with increased CVD 2.5 N=27673 2 * P <0.0001 * Relative Risk of Cardiovascular Events 1.5 1 0.5 0 * Small LDL-P Large LDL-P Large LDL-P adjusted for small LDL-P * LDL-P (Total) Mora et al, Circulation 2009;119:931 Q1 Q2 Q3 Q4 Q5 Relative risk adjusted for age, smk, menopause, hormone use, BP, BMI, diabetes
For type 2 diabetes, LDL particle size was strong and independent predictor Small Large Q1 Q2 Q3 Q4 Q5 P trend LDL size 4.16 3.04 2.21 1.63 1.00 <0.001 * Relative risk adjusted for age, race, smk, menopause, HRT, BP, BMI, exercise, education, FHx, CRP, HbA1c Mora et al, Diabetes 2010 ; 59:1153-1160
Large LDL associated with lower risk of diabetes Women s Health Study (N=26,836) Relative Risk of Diabetes 4 3.5 3 2.5 2 1.5 1 * * * P <0.0001 * * 0.5 0 LDL-C Small LDL-P IDL-P LDL-P (Total) Large LDL-P Mora et al, Diabetes 2010 ; 59:1153-1160 Q1 Q2 Q3 Q4 Q5 Relative risk adjusted for age, race, smk, menopause, HRT, BP, BMI, exercise, education, FHx, CRP, HbA1c
JUPITER Ion Mobility LDL Subclasses and CVD Risk in placebo group Baseline LDL-C 109 mg/dl Mora et al, ATVB meeting, Toronto, 2014, manuscript in preparation
Topics to be covered 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
Treating to New Targets (TNT) Multivariable Predictors of Residual Risk Final model * % or SD HR (95% CI) P BMI (per 1-SD), kg/m 2 4.5 1.09 (1.02, 1.17) 0.01 Myocardial infarction 58 1.60 (1.36, 1.87) <0.001 Angina 82 1.36 (1.10, 1.68) 0.004 Cerebrovascular disease 5 1.73 (1.36, 2.19) <0.001 Peripheral vascular disease 12 1.32 (1.09, 1.61) 0.005 Congestive heart failure 8 1.54 (1.24, 1.90) <0.001 CABG 47 1.26 (1.08, 1.47) 0.004 Calcium channel blocker 27 1.31 (1.12, 1.54) <0.001 Aspirin 87 0.67 (0.56, 0.81) <0.001 Baseline (per 1-SD, on-statin), mg/dl Apolipoprotein B Apolipoprotein A-I BUN 19 25 4.9 1.19 (1.11, 1.28) 0.91 (0.84, 0.99) 1.10 (1.03, 1.17) <0.001 0.02 0.003 * Final model included randomized treatment, age, sex, HTN, smk, DM plus these variables Mora S et al. Circulation, 2012:125:1979-87.
JUPITER: On-Treatment Lipids and Residual Risk Lipid or Apoipoprotein On-Treatment LDL-C 55 mg/dl 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 * Standardized hazard ratios adjusted for age, sex, smoking, BP, glucose, BMI, family history Mora S et al., JACC 2012; 59:1521-8
Large inter-individual variability in response to high-intensity statin Meta-analysis of TNT, IDEAL, SPARCL, JUPITER N=18,661 Achieved LDL-C Achieved Non-HDL-C Achieved ApoB N mg/dl mg/dl mg/dl Boekholdt et al JACC 2014;64:485
Meta-analysis of 8 statin trials (N=38,153; No. events=5,387) On-Treatment Lipids and Residual Risk Lipid or Apoipoprotein Adjusted HR (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 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 LDL-C NHDL-C ApoB LDL-P LDL size SNP cluster LDL size SNP cluster LDL-P SNP cluster ApoB Chu A et al, in preparation SNP cluster All
Which woman is at higher risk? Larger LDL Size Smaller LDL Size LDL-C 130 mg/dl LDL-C 130 mg/dl Fewer Particles LDL Cholesterol More Particles 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 Mora, Circ 2009;119:2396
Topics covered 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