LDL Should Remain the Primary Treatment Target but
LDL Should Remain the Primary Treatment Target but LDL Cholesterol is Not the Best Clinical Measure of LDL Jim Otvos, Ph. D Chief Scientific Officer Lipo. Science, Inc. Adjunct Professor Department of Biochemistry North Carolina State University
Some Facts About LDL • LDL cholesterol (LDLc) is not LDL. • LDLc is the cholesterol in LDL (c. LDL, CLDL). • LDLc is a surrogate measure of LDL. • Non-HDLc is also a surrogate measure of LDL. • There’s nothing wrong with a surrogate, if it’s a good surrogate.
Some Facts About LDL • Population studies support the “adequacy” of LDLc and non-HDLc. • But populations consist of individuals who are not the same. • LDLc and non-HDLc are good LDL surrogates for most individuals, but poor surrogates for many others. • Treating to LDL targets (LDLp, apo. B) instead of LDLc targets would benefit many patients and simplify clinical decision-making.
LDL Cholesterol Is Not LDL!!! Apo B POLAR SURFACE COAT Phospholipid Free cholesterol This is LDL NONPOLAR LIPID CORE Cholesterol Ester Triglyceride This is LDL Cholesterol A convenient analytic surrogate of LDL since 1972
Why LDLc and LDL are Used Interchangeably 1) Clinical trial results are consistent: High LDLc is bad. Lowering LDLc is good. “If it ain’t broke, why fix it? ” 2) LDLc makes sense pathophysiologically.
The Cholesterol in LDL is Pathologic. How Can LDLc Be Considered a Surrogate? Lumen C C C TC CC CC C TC CC TCT CC CC C LDLc Intima CCC C C C C C CC C C Atheroma
The Cholesterol in LDL is Pathologic Only After Passing Through LDL Particle “Filters” Lumen C C C TC CC CC C TC Intima TC CTC CC TCT CC CC C LDLp TC C C C TC CCT CC CC C prooxidants ox C C C TC ox antioxidants (HDL) proteoglycan binding CCT CC CC C macrophage uptake CCC C C CC C C Atheroma
LDL Cholesterol Is Not LDL!!! Apo B This is LDL (LDLp, ~apo. B) POLAR SURFACE COAT Phospholipid Free cholesterol NONPOLAR LIPID CORE Cholesterol Ester Triglyceride This is LDL Cholesterol (LDLc, c. LDL)
NMR Lipoprotein Particle Analysis VLDL HDL Nuclear magnetic resonance (NMR) quantifies lipoprotein subclass particles, not the cholesterol inside. Each subclass emits a distinguishable NMR signal. The measured amplitudes of these signals give the subclass particle concentrations. NMR lipoprotein analysis is rapid, automated and reproducible, since no physical separation of the particles is necessary. Clin Lab Med 2006; 26: 847 -70
Future NMR Clinical Analyzer
NMR Lipo. Profile Analysis Large VLDL Medium VLDL Small VLDL IDL Large Small LDL Large Med Small HDL HDL LDL Particle Number (LDLp) in units of nmol/L (1 nmol/L = ~6 x 1014 particles/L) Clin Lab Med 2006; 26: 847 -70
LDLc and LDLp in the Multi-Ethnic Study of Atherosclerosis (MESA) • MESA is a large (n=6814) multi-center NHLBI observational study of the pathogenesis and progression of subclinical atherosclerosis. • Baseline blood samples were used to determine relations of lipids measured by traditional enzymatic assays and lipoprotein particles measured by NMR Lipo. Profile analysis. • Cross-sectional relations were examined of lipids and lipoprotein particles with carotid intima -media thickness (IMT), an established surrogate endpoint of atherosclerotic cardiovascular disease. Mora et al. Atherosclerosis. 2007; 192: 211 -17.
LDLc and LDLp in MESA (n=6, 490) LDLp (nmol/L) r = 0. 71 LDLc (mg/d. L)
LDL Cholesterol Content Variability Has Two Sources: LDL Size and Core Lipid Composition Less cholesterol per particle LDLc at equal LDLp =1500 nmol/L ~150 mg/d. L ~125 mg/d. L ~100 mg/d. L Cholesterol molecules per LDL particle (LDLc, mmol/L LDLp, nmol/L) ~2600 ~2150 ~1700
Concordance/Discordance Between LDLc and LDLp in MESA Discordant LDLp >LDLc (17%) Concordant (65%) Discordant LDLp < LDLc (18%) n Cholesterol Molecules per LDL Particle LDLc (mg/d. L) LDLp (nmol/L) >40 240 1590 98 1597 20 to 40 682 1872 107 1478 0 to 20 1802 2128 114 1391 0 to -20 1696 2623 1244 -20 to -40 700 3022 134 1156 > -40 242 3589 144 1047 Percentile Difference (LDLp – LDLc)
Concordance/Discordance Between LDLc and LDLp in MESA These “independent” CVD risk markers are all associated with LDLc underestimating LDL Percentile TG HDLc Waist Glucose Met. Syn Difference (mg/d. L) (cm) (mg/d. L) Traits (LDLp – LDLc) Discordant LDLp > LDLc (17%) Concordant (65%) Discordant LDLp < LDLc (18%) >40 210 41 101 112 2. 8 20 to 40 170 42 100 108 2. 5 0 to 20 134 47 99 105 1. 9 0 to -20 102 55 96 100 1. 4 -20 to -40 91 60 95 98 1. 3 > -40 82 66 91 97 1. 1
LDL-C and LDL-P in Framingham Men With Different Numbers of Metabolic Syndrome Components N=286 N=407 N=355 N=233 N=113 N=30 4 5 LDL-C (mg/d. L) LDL-P (nmol/L) LDL-P 0 1 Met. Syn (-) 2 3 Met. Syn (+) Kathiresan et al. Circulation 2006; 113: 20 -29
LDL Management Questions How do LDLc and LDLp compare in their associations with CVD risk? What is the clinical significance of any differences in risk prediction?
Relations of LDLc, Non-HDLc, and LDLp with Carotid Atherosclerosis in MESA and CVD Events in Framingham MESA (n=5, 362) Carotid IMT Framingham (n=3, 066) Future CVD Events IMT (SE) p HR (95% CI) p LDLc 35. 8 (4. 1) <0. 0001 1. 11 (1. 01 -1. 22) 0. 03 Non-HDLc 38. 5 (4. 1) <0. 0001 1. 21 (1. 10 -1. 33) <0. 0001 LDLp 39. 9 (4. 1) <0. 0001 1. 28 (1. 17 -1. 39) <0. 0001 Estimates are from multivariable regression analyses, per 1 SD increment of the lipoprotein variable Mora et al. Atherosclerosis, 2007 Cromwell et al. J Clin Lipidol, 2007 in press
Relations of LDLc and LDLp with Carotid IMT in Concordant and Discordant MESA Subgroups Overall n=5, 362 Concordant 1 n=3, 498 (65. 3%) Discordant 2 n=1, 864 (34. 7%) IMT (SE) p LDLc 35. 8 (4. 1) <0. 0001 42. 0 (4. 6) <0. 0001 13. 4 (8. 9) 0. 13 LDLp 39. 9 (4. 1) <0. 0001 40. 3 (4. 6) <0. 0001 37. 6 (9. 0) <0. 0001 LDLc and LDLp values differ by < ± 20 percentile units 2 LDLc and LDLp values differ by ± 20 percentile units 1
Relations of Non-HDLc and LDLp with Carotid IMT in Concordant and Discordant MESA Subgroups Overall n=5, 362 Concordant 1 n=4, 092 (76. 3%) Discordant 2 n=1, 270 (23. 7%) IMT (SE) p Non-HDLc 38. 5 (4. 1) <0. 0001 41. 2 (4. 4) <0. 0001 21. 4 (11. 3) 0. 06 LDLp 39. 9 (4. 1) <0. 0001 39. 9 (4. 4) <0. 0001 42. 0 (11. 5) <0. 0003 Non-HDLc and LDLp values differ by < ± 20 percentile units 2 Non-HDLc and LDLp values differ by ± 20 percentile units 1
Carotid Atherosclerosis in MESA (adjusted for age, sex, race, smoking, diabetes, TG, and HDLc) Carotid IMT (microns) Quartile 1: LDLc <100 mg/d. L (n=1, 425) n=32 Ptrend = 0. 006 n=352 n=153 n=888 Q 1 Q 2 Q 3 Q 4 LDL Particle Number Mora et al, AHA/ADA Metabolic Syndrome meeting, May 2006
Carotid Atherosclerosis in MESA (adjusted for age, sex, race, smoking, diabetes, TG, and HDLc) Quartile 2: LDLc = 100 -118 mg/d. L (n=1, 362) Carotid IMT (microns) Ptrend <0. 001 n=143 n=371 n=499 n=349 Q 1 Q 2 Q 3 Q 4 LDL Particle Number Mora et al, AHA/ADA Metabolic Syndrome meeting, May 2006
Relations of LDLc and LDLp with Event-Free Survival in Concordant and Discordant Framingham Subgroups Cromwell et al. J Clin Lipidol, in press
Treatments that Alter the Cholesterol Content of LDL Change LDLc and LDLp Differentially Cholesterol per particle decreases with: Cholesterol per particle increases with: • statins • fibrates • statin + ezetimibe • niacin • estrogen replacement therapy • glitazones • anti-retrovirals (some) • low fat, high carb diet LDLc More • omega 3 FAs • exercise • low carb diet LDLp More
Conclusions • LDLc is not LDL!!!!! • The cholesterol content of LDL is far more variable than generally appreciated. • Cholesterol-depleted LDL is prevalent not only in individuals with elevated TG/low HDL etc. , but also in those with low LDL. • LDLp is a more sensitive indicator of low risk than LDLc or non-HDLc, and therefore a more discriminating LDL treatment target.
Conclusions • Many therapies not considered to be LDL lowering therapies increase the cholesterol content of LDL, thereby lowering LDLp more than LDLc and helping patients achieve LDLp treatment goals. • The (CVD risk management) world is more understandable and less complex when viewed through an LDL particle lens rather than a cholesterol lens. • LDLc is not LDL!!!!!
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