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Beyond LDL Cholesterol: NMR Lipid Fractionation and Treating Residual Risk

Beyond LDL Cholesterol: NMR Lipid Fractionation and Treating Residual Risk. Thomas G. Allison, PhD, MPH Mayo Clinic Rochester, MN. DISCLOSURE. Relevant Financial Relationship(s) None Off Label Usage None. Learning Objectives. As a result of attending this presentation,

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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 Thomas G. Allison, PhD, MPH Mayo Clinic Rochester, MN

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

  3. Learning Objectives As a result of attending this presentation, participants will be able to: • Address “residual risk” in the secondary prevention of CHD • Appropriately order NMR spectroscopy lipid results for intensive lipid management • Interpret NMR results to identify higher and lower risk patients with the same LDL

  4. PROVE IT - TIMI 22: Study Design 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy Double-blind “Standard Therapy” Pravastatin 40 mg “Intensive Therapy” Atorvastatin 80 mg 2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke

  5. Changes from (Post-ACS) Baseline in Median LDL-C 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

  6. PROVE IT:Concomitant Therapies PCI for initial ACS pre-random. 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14%

  7. 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

  8. Sources of Residual Risk • Not providing appropriate medical therapy? • Inadequate control of non-lipid risk factors? • Not addressing emerging risk factors? • CRP, Lp(a) • Inadequate control of lipids using LDL target only? • Non-HDL • HDL • Apo B • Small, dense LDL

  9. 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

  10. 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

  11. LDL Particle Number Has Been Repeatedly Shown to be Superior to LDL Cholesterol * Significant and independent in multivariate models adjusted for lipids

  12. LDL Particle Number Has Been Repeatedly Shown to be Superior to LDL Cholesterol * Significant and independent in multivariate models adjusted for lipids

  13. Predicting cardiovascular risk in Women’s Health Study by NMR-determined LDL particle concentration versus size Blake GJ et al: Circ 2002;106:1930-1937

  14. 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

  15. 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

  16. 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

  17. 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

  18. lipoproteins EDTA sugars

  19. Case Study • 62 year old woman presenting with chest pain • S/p prior 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 • Weight = 78.6 kg; BMI = 27.8 kg/m2

  20. Treated Hyperlipidemia • Total cholesterol = 158 mg/dL • HDL cholesterol = 50 mg/dL • LDL cholesterol = 83 mg/dL • Triglycerides = 127 mg/dL • Current Rx = Atorvastatin 10 mg/day • Lp(a) < 7 mg/dL • FBG = 89 g/dL • CRP = 0.9 mg/dL • Homocysteine = 7 µmol/L

  21. Next Step • Do nothing else for lipids? • Increase Atorvastatin? • Add Ezetimibe? • Add niacin?

  22. 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 500 mg b.i.d. • Amlodipine 2.5 mg/day

  23. 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 • Weight 78.6  77.6 kg

  24. Conclusions • 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 guiding therapy

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

  26. Case Study #2 • 63 year old man completing cardiac rehab • S/p recent CABG (LIMA  LAD) • Prior PCI LAD and Cx • Treated hypertension • Atenolol 50 mg daily; current BP = 118/61 mmHg • Treated hyperlipidemia • Simvastatin 40 mg • Remote past smoking • Weight = 91.8 kg; BMI = 31.8 kg/m2

  27. Treated Hyperlipidemia • Total cholesterol = 152 mg/dL • HDL cholesterol = 48 mg/dL • LDL cholesterol = 73 mg/dL • Triglycerides = 154 mg/dL • Current Rx = Simvastatin 40 mg/day • Lp(a) < 7 mg/dL • FBG = 103 mg/dL

  28. Next Step • Do nothing else for lipids? • Increase Simvastatin? • Add Ezetimibe? • Add niacin?

  29. NMR Results • Total LDL particles = 1200 nmol/L • Small LDL particles = 1008 nmol/L • Total HDL particles = 35 µmol/L • Large HDL particles = 6.5µmol/L • Additional Rx • Ezetimibe 10 mg/day

  30. Follow-Up 10 Weeks • Total cholesterol = 152  138 mg/dL • HDL cholesterol = 48  45 mg/dL • LDL cholesterol = 73  65 mg/dL • Triglycerides = 154  140 mg/dL • Total LDL particles = 1200  1093 nmol/L • Small LDL particles = 1008  943 nmol/L • Total HDL particles = 36  35µmol/L • Large HDL particles = 6.6 6.5µmol/L • Weight 91.8  90.5 kg

  31. Conclusion • Probably the wrong drug was added • A few more large LDL were cleared • Small, dense LDL minimally changed • No improvement in HDL • Now add niacin 500 mg b.i.d.

  32. Spectrum 1 Spectrum 2

  33. PROVE IT Subgroups: Reduction in All-Cause Mortality or Major CV Events 2 Year Event Rates Atorva 80 Prava 40 23.0% 26.2% 20.3% 27.0% 28.8% 34.6% 21.0% 24.6% 28.1% 29.5% 20.1% 25.0% 27.5% 28.9% 20.6% 25.5% 21.7% 26.7% 23.1% 26.0% 20.1% 28.2% 23.5% 25.6% % of Pts 78 22 18 82 30 70 25 75 44 56 27 73 Male Female Diabetes No Diabetes Age > 65 Age < 65 Prior Statin No Prior Statin HDL-C > 40 HDL-C < 40 LDL-C > 125 pi = 0.02 LDL-C < 125 All pinteraction = NS except as noted 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80 mg Better Pravastatin 40 mg Better

  34. COURAGE Long-Term Improvement in Non-Lipid Treatment Targets (Group Median ± SE)

  35. COURAGE Long-Term Improvement in Lipid Treatment Targets(Group Median ± SE)

  36. COURAGEPrimary and Secondary Outcomes Outcome Hazard Ratio (95% Cl) p-value Number of Events

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