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Beyond LDL Cholesterol: NMR Lipid Fractionation and Treating Residual Risk

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/dL).

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Beyond LDL Cholesterol: NMR Lipid Fractionation and Treating Residual Risk

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  1. Beyond LDL Cholesterol: NMR Lipid Fractionation and Treating Residual Risk G. T. Gau, M.D. Mayo Clinic Rochester, MN

  2. Disclosures Relevant Financial Relationship(s) None Off-Label Usage None

  3. PROVE-ITChanges from (Post-ACS) Baseline in Median LDLc LDL-C (mg/dL) Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) 120 100 Pravastatin 40mg 21% 80 60 Atorvastatin 80mg 49%  40 P<0.001 20 <24h Rand. 30 Days 4 Mos. Final 8 Mos. 16 Mos. • 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

  4. 0 30 3 6 9 12 15 18 21 24 27 All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 16% relative risk reduction (p = 0.005) 10 5 But absolute residual risk is 22% 0 Months of Follow-up

  5. 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 • HDL • Apo B • Small, dense LDL

  6. 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-A1 - better than cholesterol/HDLc

  7. What is New in Cholesterol Management How to understand this: Measure Apo-B = catches all (VLDLc + LDLc) Non-HDLc - not as accurate (surrogate) large intermediate B B B VLDL LDLc B small dense B Liver

  8. LPL Intermediate LDLc B B B LDLc C-II VLDLc Oxidation Smaller dense LDLc B E LDL-receptor Liver Artery SR-BI A-I Y Cholesterol ester transfer protein inhibitor APO A-I Lipid Pool Y ABCAI CE Y LRP Mature HDLC Y A-I Cholesterol in tissue CE Bile ABCAI LPL A-I CE Gut B Chylomicrons and remnants E C-II CP1211619-1

  9. What is New in Cholesterol Management small dense LDLc slow Y Y fast Y macrophage

  10. 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

  11. 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 6.2 Risk of IHD 2.1 1.0 1.0 LDL particle number (apoB) LDL particle size

  12. 22% 63% LDL Particle Number Distribution in MESA LDL-C = 100-118 mg/dL 5th 20th 50th 80th percentile 1% (n=10) 24% (n=215) 54% (n=484) 19% (n=168) 3% (n=26) MetSyn (-) (n=903) Percent of Subjects 700 1000 1300 1600 (nmol/L) 0% (n=0) 4% (n=20) 33% (n=153) 46% (n=210) 17% (n=76) MetSyn (+) (n=459) Percent of Subjects 700 1000 1300 1600 (nmol/L) AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006

  13. LDL Particle Number Distribution in T2DM Patients with Low LDL-C (n=2,355) 5th 20th 50th 80th percentile 1% (n=19) 24% (n=364) 43% (n=631) 21% (n=307) 11% (n=163) LDL-C 71-99 mg/dL (n=1,484) Percent of Subjects 700 1000 1300 1600 (nmol/L) 16% (n=147) 43% (n=377) 30% (n=260) 9% (n=76) 2% (n=15) LDL-C <70 mg/dL (n=871) 41% Percent of Subjects 700 1000 1300 1600 (nmol/L) Presented at AHA Scientific Sessions 2005.

  14. LDL-C LDL-P LDL-C and LDL-P in Framingham Men Having Different Numbers of MetSyn Components N=286 N=407 N=355 N=233 N=113 N=30 LDL-C (mg/dL) LDL-P (nmol/L) 0 1 2 3 4 5 MetSyn (+) MetSyn (-) ~2.3x risk Circulation. 2006;113:20-29

  15. What is New in Cholesterol Management LDLc - number does not show us small (vs) large particles - LDLc = 70 Apo-B - more representative of particle number but still does not tell - large vs small If all large - good If mainly small - bad

  16. What is New in Cholesterol Management Nuclear magnetic resonance spectroscopy (NMR) - gives all particles (LDLc and HDLc) total number number of large number of small - allows risk prediction with greater accuracy - small LDLc particles are critical – predicts events

  17. Secondary Target: LDL-P (nmol/L) Primary Target: LDL-C (mg/dL) Secondary Target: Non-HDL-C* (mg/dL) Secondary Target: Total Apo B (mg/dL) Risk Status 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 Treatment Goals for LDL Cholesterol, Non-HDL Cholesterol, Total Apolipoprotein B, and LDL Particle Concentration Therapeutic Goal * Non-HDL cholesterol becomes a secondary target of therapy when serum triglycerides range from 200 to 500 mg/dL. Rosenson RS. Cardiol Rev. September 2003; Grundy SM. Circulation. 2002;106:2526-2569.

  18. NMR Particle Goals OptimalHigh Risk Pt Total LDLc particle # < 1000 600-800 Small LDLc particle # < 500 < 350 Large LDLc particle # > 500 > 350 Total HDLc particle # > 40 > 40 Large HDLc particle # > 9 > 9 Small HDLc particle # > 31 > 31

  19. What is New in Cholesterol Management Aspirin 325 mg/day Metoprolol 50 mg bid Statin 20 mg/day ACE 20 mg/day 67-year-old male 2 prior angioplasties BP 130/80 on treatment Ex-smoker Body fat - 24% Blood sugar 108 mg/dL Cholesterol 140 mg/dL Triglycerides 150 mg/dL HDLc 40 mg/dL LDLc 70 mg/dL

  20. What is New in Cholesterol Management Aspirin 325 mg/day Metoprolol 50 mg bid Statin 20 mg/day ACE 20 mg/day 67-year-old male 2 prior angioplasties BP 130/80 on treatment Ex-smoker Body fat - 24% Blood sugar 108 mg/dL Cholesterol 140 mg/dL Triglycerides 150 mg/dL HDLc 40 mg/dL LDLc 70 mg/dL NMR - total particles = 1600 small particles = 1300

  21. 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 

  22. 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/dL)

  23. Treated Hyperlipidemia • Total cholesterol = 158 mg/dL • Triglycerides = 127 mg/dL • HDL cholesterol = 50 mg/dL • LDL cholesterol = 83 mg/dL • Current Rx = atorvastatin 10 mg/day • Lp(a) < 7 mg/dL • CRP = 0.9 mg/dL • Homocysteine = 7 µmol/L

  24. Next Step • Increase Atorvastatin? • Add Ezetimibe? • Add niacin? • Continue same meds?

  25. NMR Results • Total LDL particles = 1300 nmol/L • Small LDL particles = 1140 nmol/L • Total HDL particles = 39 µmol/L • Large HDL particles = 6.6µmol/L • Additional Rx • Niacin 1000 mg daily • Amlodipine 2.5 mg/day

  26. Follow-Up 5 Months • Total cholesterol 158  150 mg/dL • HDL cholesterol 50  66 mg/dL • LDL cholesterol 83  64 mg/dL • Triglycerides 127  102 mg/dL • Total LDL particles 1300  752 nmol/L • Small LDL particles 1140  425 nmol/L • Total HDL particles 39  43µmol/L • Large HDL particles 6.6 11.1µmol/L

  27. 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

  28. 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

  29. 67 y/o male Baseline lipids on Pravachol 40 mg: Cholesterol 252 mg/dL Triglycerides 162 mg/dL HDL cholesterol 53 mg/dL LDL cholesterol 167 mg/dL Glucose 99 mg/dL AST 26 mg/dL

  30. Total LDLc particle number = 791 LPL Intermediate LDLc B B B LDLc C-II VLDLc Oxidation Smaller dense LDLc B E LDL-receptor Liver Artery SR-BI A-I Y APO A-I Lipid Pool Y ABCAI CE Y LRP Y A-I Cholesterol in tissue CE Bile ABCAI LPL A-I CE Gut B Chylomicrons and remnants E C-II 274 518 7 36 8/06 29 Chol = 252159 Trig = 162 125 HDL = 5350 LDL = 16784 AST = 2633 Zocor 40 WelChol 625 (3 BID) Fish oil – 2 qd CP1211619-4

  31. Total LDLc particle number = 791 (755) LPL Intermediate LDLc B B B LDLc C-II VLDLc Oxidation Smaller dense LDLc B E LDL-receptor Liver Artery SR-BI A-I Y APO A-I Lipid Pool Y ABCAI CE Y LRP Y A-I Cholesterol in tissue CE Bile ABCAI LPL A-I CE Gut B Chylomicrons and remnants E C-II 274(192) 518 (563) 7 (5.5) 36 (31) 11/06 8/06 29 (25.5) Zocor 40 WelChol 625 (3 BID) Fish oil – 2 qd Niacin 500 qd Chol = 252 159 131 Trig = 162 125 83 HDL = 53 50 51 LDL = 167 8463 AST = 26 3332 CP1211619-4

  32. Total LDLc particle number = 791 (755) 561 LPL Intermediate LDLc B B B LDLc C-II VLDLc Oxidation Smaller dense LDLc B E LDL-receptor Liver Artery SR-BI A-I Y APO A-I Lipid Pool Y ABCAI CE Y LRP Y A-I Cholesterol in tissue CE Bile ABCAI LPL A-I CE Gut B Chylomicrons and remnants E C-II 274 (192)295 518 (563)267 7 (5.5)9 36 (31)34 11/06 2/07 8/06 Chol = 252 159 131 130 Trig = 162 125 8385 HDL = 53 50 5154 LDL = 167 84 63 59 Gluc = 93 AST = 26 33 32 41 29 (25.5)25 Zocor 40 WelChol 625 (3 BID) Fish oil – 2 qd (did not tolerate niacin – myositis)  Exercise + diet -  5 kg (3 mo) CP1211619-4

  33. 3) small dense LDLc particle – No • -statins +++ • -bowel acting ++ • -niacin  dose +++ • -fibric acids ++ • shifting small dense to large LDLc • -niacin +++ • -fenofibrate ++ • *wt loss ++ • (very sensitive) • *exercise ++ • (sensitive) • *glucose control ++ • (sensitive) • 1) lipid profile does not • predict small particle number • 2)  total LDLc particle number • -statins ++++ • -bowel acting • Zetia ++ • WelChol ++ • resins ++ • -niacin + • -fibric acids + Points

  34. Enhanced Clinical Utility Provided by NMR LipoProfile • Refines LDL management (more vs less aggressive treatment than indicated by LDLc) • More tangible responsiveness to lifestyle interventions • New indications for combination therapies

  35. Total cholesterol • Questions • Comments LDL cholesterol LDL particle concentration

  36. 2000 COURAGE Trial PROVE IT REVERSAL Average American NCEP 2001 ATP3 Elephant Horse Costal people (Japan China) NCEP 2004 Circ New born baby 30 50 60 70 100 130 177 Heart disease does not exist Logical Treatment of LDLc CVD events LDLc (mg/dL) Framingham data, Castelli CP1255635-1

  37. 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

  38. 130 mg/dL 130 mg/dL LDL Cholesterol Balance 20+ years of studies: Patients with smaller LDL size have greater CHD risk at any given level of LDL-C Lower risk Higher risk Large LDL (Pattern A) Small LDL (Pattern B) But they also have more particles = more Apo B

  39. LDL Particle Number Distribution in MESA LDL-C <100 mg/dL (n=1,425) 5th 20th 50th 80th percentile 10% (n=141) 42% (n=603) 36% (n=509) 10% (n=150) 2% (n=22) Percent of Subjects 700 1000 1300 1600 (nmol/L) LDL Size (nm) 21.3 (0.7) 20.5 (0.6) 20.1 (0.5) HDL-C (mg/dL) 58 (18) 47 (15) 41 (11) Triglycerides (mg/dL) 98 (60) 136 (71) 199 (75) AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006

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