Beyond LDL Cholesterol NMR Lipid Fractionation and Treating
Beyond LDL Cholesterol: NMR Lipid Fractionation and Treating Residual Risk G. T. Gau, M. D. Mayo Clinic Rochester, MN
Disclosures Relevant Financial Relationship(s) None Off-Label Usage None
PROVE-IT Changes from (Post-ACS) Baseline in Median LDLc LDL-C (mg/d. L) 120 Median LDL-C (Q 1, Q 3) 100 95 (79, 113) 80 21% Pravastatin 40 mg 62 (50, 79) 60 49% Atorvastatin 80 mg 40 P<0. 001 20 <24 h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event • ACS response lowers LDL-C from true baseline
All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40 mg (26. 3%) 25 20 % with Event 15 Atorvastatin 80 mg (22. 4%) 10 16% relative risk reduction (p = 0. 005) 5 But absolute residual risk is 22% 0 0 3 6 9 12 15 18 Months of Follow-up 21 24 27 30
Sources of Residual Risk • • • Not providing appropriate medical therapy? Inadequate control of non-lipid risk factors? Not addressing emerging risk factors? CRP, Lp(a) • LDL target – inadequate lipid control Non-HDL Apo B Small, dense LDL
What is New in Cholesterol Management ATP-III • LDLc - primary treatment goal - non-HDLc = total cho - HDLc (accounts for triglycerides) - Apo-B - measurement of total number of atherogenic particles (better marker for vascular disease and treatment effect) - Apo-B/Apo-A 1 - better than cholesterol/HDLc
What is New in Cholesterol Management How to understand this: B VLDL large B LDLc B intermediate B Liver Measure Apo-B = catches all (VLDLc + LDLc) Non-HDLc - not as accurate (surrogate) small dense B
LPL B VLDLc B B LDLc C-II Intermediate LDLc Oxidation B Smaller dense LDLc E LDL-receptor Liver SR-BI A-I Y APO A-I ABCAI Artery Y Y CE LRP Cholesterol ester transfer protein inhibitor Lipid Pool Mature HDLC Y A-I CE Bile Cholesterol in tissue ABCAI LPL A-I CE Gut B Chylomicrons and remnants E C-II CP 1211619 -1
What is New in Cholesterol Management small dense LDLc slow YY fast Y macrophage
Small, Dense LDL • Modified apo-B has lower affinity for hepatic LDL-receptor Longer residence time in circulation • More easily oxidized • Easier entry into arterial intima • More readily retained in intima • Atherogenicity twice as great as large LDL particle
Small, Dense Low-Density Lipoprotein Particles as a Predictor of the Risk of Ischemic Heart Disease in Men Prospective Results From the Quebec Cardiovascular Study Circulation 1997; 95: 69 -75 Risk of IHD 6. 2 1. 0 LDL particle size L nu DL mb pa er rtic (ap le o. B ) 2. 1
LDL Particle Number Distribution in MESA LDL-C = 100 -118 mg/d. L 5 th 1% (n=10) 20 th 24% (n=215) 50 th 54% (n=484) 80 th 19% (n=168) percentile 3% (n=26) 22% Percent of Subjects Met. Syn (-) (n=903) 700 0% (n=0) 1000 4% (n=20) 1300 33% (n=153) 1600 (nmol/L) 46% (n=210) 17% (n=76) 63% Percent of Subjects Met. Syn (+) (n=459) 700 1000 1300 AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3 -5, 2006 1600 (nmol/L)
LDL Particle Number Distribution in T 2 DM Patients with Low LDL-C (n=2, 355) 5 th 1% (n=19) 20 th 24% (n=364) 50 th 43% (n=631) 80 th 21% (n=307) percentile 11% (n=163) LDL-C 71 -99 mg/d. L Percent of Subjects (n=1, 484) 700 16% (n=147) 1000 43% (n=377) 1300 30% (n=260) 1600 (nmol/L) 9% (n=76) 2% (n=15) 41% Percent of Subjects LDL-C <70 mg/d. L (n=871) 700 1000 Presented at AHA Scientific Sessions 2005. 1300 1600 (nmol/L)
LDL-C and LDL-P in Framingham Men Having Different Numbers of Met. Syn Components N=286 N=407 N=355 N=233 N=113 N=30 LDL-C (mg/d. L) LDL-P (nmol/L) LDL-P 0 1 Met. Syn (-) 2 3 4 5 Met. Syn (+) ~2. 3 x risk Circulation. 2006; 113: 20 -29
What is New in Cholesterol Management LDLc - number does not show us small (vs) large particles - LDLc = 70 If all large - good If mainly small - bad Apo-B - more representative of particle number but still does not tell - large vs small
What is New in Cholesterol Management Nuclear magnetic resonance spectroscopy (NMR) - gives all particles (LDLc and HDLc) total number of large number of small - allows risk prediction with greater accuracy - small LDLc particles are critical – predicts events
Treatment Goals for LDL Cholesterol, Non-HDL Cholesterol, Total Apolipoprotein B, and LDL Particle Concentration Therapeutic Goal Primary Target: LDL-C (mg/d. L) Secondary Target: Non-HDL-C* (mg/d. L) Secondary Target: Total Apo B (mg/d. L) Secondary Target: LDL-P (nmol/L) CHD and CHD risk equivalents: including diabetes <100 <130 <90 <1000 Multiple (2+) risk factors <130 <160 <110 <1300 Zero to 1 risk factor <160 <190 <130 <1600 Risk Status * Non-HDL cholesterol becomes a secondary target of therapy when serum triglycerides range from 200 to 500 mg/d. L. Rosenson RS. Cardiol Rev. September 2003; Grundy SM. Circulation. 2002; 106: 2526 -2569.
NMR Particle Goals Total LDLc particle # Small LDLc particle # Large LDLc particle # Optimal < 1000 < 500 > 500 Total HDLc particle # Large HDLc particle # Small HDLc particle # > 40 > 9 > 31 High Risk Pt 600 -800 < 350 > 40 > 9 > 31
What is New in Cholesterol Management 67 -year-old male 2 prior angioplasties BP 130/80 on treatment Ex-smoker Body fat - 24% Blood sugar 108 mg/d. L Cholesterol 140 mg/d. L Triglycerides 150 mg/d. L HDLc 40 mg/d. L LDLc 70 mg/d. L Aspirin 325 mg/day Metoprolol 50 mg bid Statin 20 mg/day ACE 20 mg/day
What is New in Cholesterol Management 67 -year-old male 2 prior angioplasties BP 130/80 on treatment Ex-smoker Body fat - 24% Blood sugar 108 mg/d. L Cholesterol 140 mg/d. L Triglycerides 150 mg/d. L HDLc 40 mg/d. L LDLc 70 mg/d. L Aspirin 325 mg/day Metoprolol 50 mg bid Statin 20 mg/day ACE 20 mg/day NMR - total particles = 1600 small particles = 1300
What is New in Cholesterol Management Small particle reduction • statins 30 -40% • niacin 30 -40% • fibrates 30% • CETP blocker 100% • weight loss • sugar control • exercise
Case Study • • • 62 year old woman presenting with chest pain s/p ischemic stroke Family history of premature CHD Mother MI age 52 • Treated hypertension Hydrochlorothiazide 12. 5 mg Current BP = 145/73 • No smoking or diabetes (FBG = 89 mg/d. L)
Treated Hyperlipidemia • • Total cholesterol = 158 mg/d. L Triglycerides = 127 mg/d. L HDL cholesterol = 50 mg/d. L LDL cholesterol = 83 mg/d. L Current Rx = atorvastatin 10 mg/day Lp(a) < 7 mg/d. L CRP = 0. 9 mg/d. L Homocysteine = 7 µmol/L
Next Step 1. 2. 3. 4. Increase Atorvastatin? Add Ezetimibe? Add niacin? Continue same meds?
NMR Results • • Total LDL particles = 1300 nmol/L Small LDL particles = 1140 nmol/L Total HDL particles = 39 µmol/L Large HDL particles = 6. 6 µmol/L • Additional Rx Niacin 1000 mg daily Amlodipine 2. 5 mg/day
Follow-Up 5 Months • • Total cholesterol 158 150 mg/d. L HDL cholesterol 50 66 mg/d. L LDL cholesterol 83 64 mg/d. L Triglycerides 127 102 mg/d. L Total LDL particles 1300 752 nmol/L Small LDL particles 1140 425 nmol/L Total HDL particles 39 43 µmol/L Large HDL particles 6. 6 11. 1 µmol/L
Comments • Despite intervention and aggressive medical therapy, patients continue to have CHD events • This “residual risk” may still be present in some patients despite LDL cholesterol levels at target • NMR spectroscopy represents one potential strategy for identifying residual risk and guide therapy
Case 1 67 y/o male Wt = 67 kg Ht = 168 cm BMI = 23. 6 Regular exercise program No history of prior MI or angina No diabetes Never smoker * Premature family history CAD (father 54 yrs) * Coronary calcium score (784) ( 8. 5%/yr over last 4 yrs) * Moderate hypertension – controlled * Hyperlipidemia
67 y/o male Baseline lipids on Pravachol 40 mg: Cholesterol 252 mg/d. L Triglycerides 162 mg/d. L HDL cholesterol 53 mg/d. L LDL cholesterol 167 mg/d. L Glucose 99 mg/d. L AST 26 mg/d. L
Total LDLc particle number = 791 LPL B VLDLc B B LDLc C-II Intermediate LDLc Oxidation 274 B E 518 LDL-receptor Liver Artery SR-BI A-I 7 Y APO A-I ABCAI Smaller dense LDLc Lipid Pool Y Y CE LRP Y A-I 36 Bile Cholesterol in tissue CE ABCAI LPL A-I Gut Zocor 40 Wel. Chol 625 (3 BID) Fish oil – 2 qd 29 B CE Chylomicrons and remnants E C-II Chol Trig HDL LDL AST = 252 = 162 = 53 = 167 = 26 8/06 159 125 50 84 33 CP 1211619 -4
Total LDLc particle number = 791 (755) LPL B VLDLc B B LDLc C-II 274 (192) Intermediate LDLc Oxidation B 518 (563) E LDL-receptor Liver Artery SR-BI A-I Y APO A-I ABCAI Y Lipid Pool Y 7 (5. 5) LRP CE Y A-I 36 (31) Bile Cholesterol in tissue CE ABCAI LPL A-I CE Gut Zocor 40 Wel. Chol 625 (3 BID) Fish oil – 2 qd Niacin 500 qd Smaller dense LDLc 29 (25. 5) B Chylomicrons and remnants E C-II Chol = Trig = HDL = LDL = AST = 252 162 53 167 26 8/06 11/06 159 131 125 83 50 51 84 63 33 32 CP 1211619 -4
Total LDLc particle number = 791 (755) 561 LPL B VLDLc B LDLc C-II 274 (192) 295 B Intermediate LDLc Oxidation B E 518 (563) 267 LDL-receptor Liver Artery SR-BI A-I Y APO A-I ABCAI Smaller dense LDLc Y Lipid Pool Y CE 7 (5. 5) 9 LRP Y A-I 36 (31) 34 Bile CE ABCAI LPL A-I Gut Zocor 40 Wel. Chol 625 (3 BID) Fish oil – 2 qd E (did not tolerate niacin – myositis) Exercise + diet - 5 kg (3 mo) CE B Cholesterol in tissue 29 (25. 5) 25 Chylomicrons and remnants C-II Chol = Trig = HDL = LDL = Gluc = AST = 8/06 11/06 2/07 252 159 131 130 162 125 83 85 53 50 51 54 167 84 63 59 93 26 33 32 CP 1211619 -4 41
Points 1) lipid profile does not predict small particle number 2) total LDLc particle number -statins ++++ -bowel acting Zetia ++ Wel. Chol ++ resins ++ -niacin + -fibric acids + 3) small dense LDLc particle – No -statins +++ -bowel acting ++ -niacin dose +++ -fibric acids ++ 4) shifting small dense to large LDLc -niacin +++ -fenofibrate ++ *wt loss ++ (very sensitive) *exercise ++ (sensitive) *glucose control ++ (sensitive)
Enhanced Clinical Utility Provided by NMR Lipo. Profile • Refines LDL management (more vs less aggressive treatment than indicated by LDLc) • More tangible responsiveness to lifestyle interventions • New indications for combination therapies
Total cholesterol • Questions • Comments LDL particle concentration LDL cholesterol
Logical Treatment of LDLc 2000 COURAGE Trial PROVE IT REVERSAL NCEP Horse LDLc (mg/d. L) 30 Heart disease does not exist ATP 3 CVD events 2004 Costal people (Japan China) 50 Average American 2001 Elephant New born baby NCEP Circ 60 70 100 130 177 Framingham data, Castelli CP 1255635 -1
LDL Particles Cause Atherosclerosis Low Density Lipoprotein particles (LDL) are the causal agents in atherosclerosis. 1 The more lipoprotein particles a person has, the higher the risk for plaque buildup that causes heart attacks, regardless of how much cholesterol those particles carry. 1 Fredrickson et al. NEJM 1967; 276: 148
20+ years of studies: Patients with smaller LDL size have greater CHD risk at any given level of LDL-C Lower risk Higher risk 130 mg/d. L Large LDL (Pattern A) Small LDL (Pattern B) LDL Cholesterol Balance But they also have more particles = more Apo B
LDL Particle Number Distribution in MESA LDL-C <100 mg/d. L (n=1, 425) 5 th 20 th 10% (n=141) 42% (n=603) 50 th 80 th percentile 36% (n=509) 10% (n=150) 2% (n=22) Percent of Subjects LDL Size (nm) 700 21. 3 (0. 7) 1000 20. 5 (0. 6) 1300 20. 1 (0. 5) HDL-C (mg/d. L) 58 (18) 47 (15) 41 (11) Triglycerides (mg/d. L) 98 (60) 136 (71) 199 (75) AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3 -5, 2006 1600 (nmol/L)
- Slides: 42