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Patient Management with LDL Particle Number and Traditional Lipid Values

Patient Management with LDL Particle Number and Traditional Lipid Values. Insert Name. Questions of the Day. Are unrecognized (and under-treated) LDL particle elevations common and significant contributors to the residual risk of many patients with “acceptable” levels of LDL-C?

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Patient Management with LDL Particle Number and Traditional Lipid Values

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  1. Patient Management with LDL Particle Number and Traditional Lipid Values Insert Name

  2. Questions of the Day Are unrecognized (and under-treated) LDL particle elevations common and significant contributors to the residual risk of many patients with “acceptable” levels of LDL-C? When cholesterol (LDL-C, non HDL-C) and particle number (LDL-P) measures of LDL quantity are discordant (esp. diabetes, metabolic syndrome), which is most predictive of observed cardiovascular risk? Is LDL-P is a more sensitive indicator of low risk than LDL-C or non HDL-C? Are achievement of LDL-P treatment goals superior to LDL-C or non HDL-C values to indicate a the patient has achieved adequate LDL reduction? Does LDL size (“quality”) contribute independently to risk once LDL particle number is taken into account? What therapies lower LDL-P?

  3. POLAR SURFACE COAT Phospholipid Free cholesterol Lipoprotein Particles Apolipoprotein Apolipoprotein NON-POLAR LIPID CORE Cholesterol Ester Triglyceride Apolipoprotein LipoScience 2007

  4. Up to 70% More Particles Cholesterol Balance Among Individuals At The Same LDL-C Level, The Number of LDL Particles Vary At the same LDL cholesterol, with small versus large size LDL Particles 100 mg/dL 100 mg/dL Large LDL Small LDL Otvos JD, et al. Am J Cardiol2002;90(suppl):22i-29i Cromwell WC, et al. J Clin Lipidology. 2007;1(6):583-592.

  5. Up to 40% More Particles 100 mg/dL 100 mg/dL Among Individuals At The Same LDL-C Level, The Number of LDL Particles Vary At the same LDL cholesterol, with the same size LDL Particles (at any triglyceride level) Normal Cholesterol Carried Per Particle Less Cholesterol Carried Per Particle Cholesterol Balance Otvos JD, et al. Am J Cardiol2002;90(suppl):22i-29i Cromwell WC, et al. J Clin Lipidology. 2007;1(6):583-592.

  6. NMR Lipoprotein Analysis Lipoprotein subclasses of different size broadcast lipid NMR signals that are naturally distinguishable. The measured amplitudes of these signals provide subclass quantification. Otvos JD. Handbook of Lipoprotein Testing. AACC Press 2000

  7. NMR Measures LDL Particle NumberNot LDL Cholesterol Measured LDL-C 90 mg/dL Measured LDL-C 90 mg/dL LDL NMR Signals LDL particles 900 nmol/L LDL particles 1600 nmol/L

  8. LDL Particles LDL Particles LDL Cholesterol (mg/dL) LDL Particles (nmol/L) LDL Cholesterol LDL Cholesterol HDL Cholesterol (mg/dL) Triglycerides (mg/dL) Relations of LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides Framingham Offspring Study Cromwell WC and Otvos JD. CurrAthero Reports 2004;6:381-387

  9. Clinical Cutpoints for LDL Percentile: 20th 50th 80th Optimal High LDL Cholesterol Percent of Subjects Framingham Offspring 1 70 100 130 160 190 220 250 mg/dL LDL Particle Number Percent of Subjects MESA 2 700 1000 1300 1600 1900 2200 2500 nmol/L 1 Otvos JD, Jayarajah E, Cromwell, WC. AJC 2002;90(8A):22i-29i. 2 Mora S, et al. AHA/ADA Met Syn/Met Risks, San Francisco, May 3-5, 2006.

  10. LDL Particle Number Distribution in MetS “Optimal” LDL-C < 100 mg/dL (<20th Percentile) Discordant Concordant 20th 50th 80th percentile 23% (n=21) 43% (n=39) 28% (n=26) 6% (n=6) Percent of Subjects 1000 1300 1600 LDL Particles (nmol/L) Otvos JD, Cromwell WC, et al. AHA Scientific Sessions 2003

  11. LDL Particle Number is Highly Heterogeneous Among Patients with Type 2 Diabetes Mellitus at LDL Cholesterol Target Goal <100 mg/dL W.C. Cromwell and J.D. Otvos American Journal of Cardiology 2006;98:1599-1602

  12. 5th 20th 50th 80th percentile 1% (n=19) 24% (n=364) 43% (n=631) 21% (n=307) 11% (n=163) Percent of Subjects 700 1000 1300 1600 (nmol/L) 16% (n=147) 43% (n=377) 30% (n=260) 9% (n=76) 2% (n=15) Percent of Subjects 700 1000 1300 1600 (nmol/L) LDL Particle Number Distribution in T2DM Subjects 25% 75% LDL-C 70-99 mg/dL (n=1,484) 40% LDL-C < 70 mg/dL (n=871) CromwellWC,OtvosJD.AJC.2006;98:1599-1602.

  13. Relationship of Alternate Measures of LDL Quantity • Low Density Lipoprotein (LDL) can be quantified by cholesterol (LDL-C) or particle number (LDL particle number) tests. • Cholesterol content per particle is highly variable • Measuring cholesterol content does not equal particle number • Alternate measures of LDL quantity (LDL-C versus LDL particle number) are highly correlated, but also highly discordant • The greatest discordance between cholesterol and particle measures of LDL quantity is noted in patients with: • Metabolic Syndrome • Insulin Resistance • Type 2 Diabetes Mellitus • High Triglycerides or Low HDL-C

  14. Relationship of LDL Particle Number with CHD

  15. Even in high TG patients, more than 90% of total plasma apoB is associated with LDL particles, except in type III hyperlipidemia [1,2] LDL particle number (ApoB) is a superior predictor of CHD risk versus LDL-Cin: Prospective epidemiologic trials [3-12] In assessing residual risk on statin or fibrate therapy in intervention trials [13-17]. LDL particle number (ApoB) is a superior predictor of CHD risk versus non HDL-C: Prospective epidemiologic trials [8,11,18] In assessing residual risk on statin or fibrate therapy in intervention trials [13-15,]. Atherosclerosis.1991;89:109-16. ClinChemActa.1978;82:151-60. Circulation.1996;94:273-8. Circulation.1999;99:2517-22. Lancet.2001;358:2026-33. ArteriosclerThrombVascBiol.2002;22:1918-23. AJC.2005;997-1001. Diabetologica.2006;49:937-944. ArteriosclerThrombVascBiol.2007;27:661-670. JAMA.2005;294:326-33. JLipidRes.2007;48:2499-2505. JAMA.2007;298:776-785. Circulation.2000;101:477-84. Circulation.2002;105:1162-9. ArteriosclerThrombVascBiol.2000;20:2408-2413. JACC.1998;32:1648-1656. Circulation.2003;107:1733-1737. Lancet.2003;361:777-780. Associations of LDL Particle Number (ApoB) versus LDL Cholesterol (LDL-C)

  16. Weight of Evidence Supporting LDL-P by NMR * Significant and independent after multivariate modeling (lipids and established risk factors)

  17. CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study (n=3,066) Cromwell WC et al. J ClinLipidology 2007;1(6):583-592.

  18. Incidence CHD Events at Alternative Measures of Lipoprotein ConcentrationsQuartile 1 Framingham Offspring Study* (n=3,066) * Adjusted for age and gender Cromwell WC, et al. J ClinLipidology. 2007;1(6):583-592.

  19. Recommendations from ADA/ACC Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk • “Measurement of LDL cholesterol (the cholesterol within LDL particles) has been the standard approach to approximate LDL levels.” • “However, the cholesterol content of LDL particles varies from person to person and is influenced by metabolic abnormalities such as insulin resistance and hyperglycemia.” • “Hence, measurement of LDL cholesterol may not accurately reflect the true burden of atherogenic LDL particles, especially in those with the typical lipoprotein abnormalities of cardio-metabolic risk.” Brunzell, et al. Diabetes Care. 2008. 31(4): 811-822.

  20. Recommendations from ADA/ACC Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk • “A more accurate way to capture the risk posed by LDL may be to measure the number of LDL particles directly using nuclear magnetic resonance (NMR).” • “Measurements of apoB or LDL particle number by NMR may more closely quantitate the atherogenic lipoprotein load. Some studies suggest that both are better indices of CVD risk than LDL cholesterol or non-HDL cholesterol and more reliable indexes of on-treatment residual CVD risk.” • “ApoB or LDL particle number also appear to be more discriminating measures of the adequacy of LDL lowering therapy than are LDL cholesterol or non-HDL cholesterol.” Brunzell, et al. Diabetes Care. 2008. 31(4): 811-822.

  21. Effect of LDL Lowering Therapies on LDL-C, Non-HDL-C, Apo B, and LDL-P Sniderman AD. J ClinLipidology 2008;2:36-42

  22. 2009 Position Statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices • “Any measure of LDL-C, including the b-quantification reference method, suffers from the fact that measurement of the cholesterol component of LDL does not consistently reflect the concentration of LDL particles in serum/plasma.” • “Despite a high correlation, these markers are only modestly concordant, indicating that one cannot simply substitute for another in classifying patients into risk categories.” • “Importantly, on-treatment non HDL-C concentrations may not reflect residual risk associated with increased LDL particle number.” • “We believe that the medical decision cutpoints should be set so that the apoB and LDL-P cutpoints are equivalent to those for LDL-C in terms of population percentiles.” Contois, et al. Clinical Chemistry 2009;55:407-419.

  23. Population Equivalent Cutpoints for Alternate LDL Measures (LDL-C, Measured Apo B and NMR LDL-P) 1 Contois, et al. Clinical Chemistry 2009;55:407-419 2 Cromwell WC. Clinical Challenges in Lipid Disorders. Oxford:Clinical Publishing, 2008:249-259.

  24. Relationship of LDL Particle Size with CHD

  25. Relationship of LDL Particle Size with CHD • The relationship of small LDL size with CHD risk is intertwined with a complex physiologic syndrome that includes high TG, low HDL-C and increased LDL particle number [1-3] • While LDL size is a strong risk marker, no significant association with CVD is present after adjustment for LDL particle number [1-8] (Quebec, MESA, Framingham, EPIC-Norfolk, VA-HIT, Women’s Health Study). • CurrAtherosclerRep.2004;6(5):381-7. 2.JAmCollCardiol.2008,51:1512-24. 3.ClinChem.2009,55:407-19. 4.Circulation.1997;95:69-75. 5.Atherosclerosis.2007,192:211-7. 6.Circulation.2009;119:931-939. 7.Circulation.2006;113:1556-63. 8.Circulation.2002;106:1930-1937.

  26. Approach to Use of Lipids and LDL Particle Number in Clinical Practice Step 1: Assess clinical CHD risk (Very-High, High, Moderately-High, Moderate, Low Risk) Step 2: Establish goals of therapy appropriate for degree of clinical risk present (Lipids and LDL Particle Number) Step 3: Laboratory evaluation Step 4: Consider therapeutic lifestyle changes and medications as indicated to achieve targets: Primary target: LDL Secondary targets: HDL and TG Step 5: Assess response to therapy and modify intervention as indicated to achieve LDL-P target Cromwell WC, et al. Lipid and Lipoprotein Disorders: Current Clinical SolutionsBaltimore: International Guidelines Center; 2009.

  27. Assess Clinical Risk Cromwell WC, et al. Lipid and Lipoprotein Disorders: Current Clinical SolutionsBaltimore: International Guidelines Center; 2009.

  28. Establish Goals of Therapy 1. Contois JH, et al. Clin Chem. 2009;55:407-419 2. Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p. 249-59. 3. Cromwell WC, Barringer TA. CurrCardiol Reports 2009;11(6):468-475 * More aggressive LDL lowering may be necessary based on clinical judgement.

  29. Laboratory Evaluation • Fasting Lipid Profile, LDL Particle Number • Additional testing as indicated to evaluate secondary causes of dyslipoproteinemia • TSH • Fasting glucose • HbA1C • Bun • Creatinine • Urinalysis • Liver Function Tests • May consider additional laboratory studies to further assess risk or direct therapy • hs-CRP • Lp-PLA2 • Lp(a) • Additional lipoprotein analysis (size, subclasses) Cromwell WC, et al. Lipid and Lipoprotein Disorders: Current Clinical SolutionsBaltimore: International Guidelines Center; 2009.

  30. Pharmacologic Options for Reaching Lipid and LDL Particle Number Goals Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6):468-475.

  31. Assess Response to Therapy If not at Lipid and LDL Particle Number goal – modify therapy and repeat laboratory tests in 3 months Following therapeutic changes, repeat laboratory testing every 3 months until goal values for lipid and LDL Particle Number are achieved Once at goal – continue therapy and repeat laboratory tests in 1 year Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6):468-475.

  32. Case ES • Patient is a 55 year-old male who entered for evaluation of low HDL-C. • Patient became aware of low HDL-C 10 years prior to office visit during routine laboratory screening showed HDL-C 30 mg/dL. No specific therapy has been recommended for this condition to date. He has been intermittently physically active which he tolerates without symptoms. Patient follows no specific diet at presentation. • He has no known history of CHD. No specific workup has been performed to date. • Past Medical History: Non contributory • Current Medications: None

  33. Case ES • Family History: Unremarkable • Review of Systems: Unremarkable, • Weight unchanged x 6 months • PE: BP 115/72 Pulse 68 Wt 178 Ht 5’10” Waist 37” BMI 25.5 • Unremarkable

  34. Baseline Total-C 148 mg/dL TG 105 mg/dL HDL-C 35 mg/dL LDL-C 92 mg/dL Glucose 85 mg/dL No Specific Diet Intermittent Aerobic Exercise Case ES Is increased lipoprotein related CHD risk present? What is the source of lipoprotein related risk? Has the patient been managed to appropriate target(s)?

  35. Case ES • Step 1: Assess Clinical Risk • 2 major risk factor (male > age 45, HDL-C < 40 mg/dL) • 10-year Framingham Risk Score = 6% (moderate risk) • What additional evaluation should be considered? • A. Carotid IMT testing? • B. Coronary Calcium Score? • C. hs-CRP test? • D. Other testing?

  36. Case ES • Step 1: Assess Clinical Risk • 2 major risk factor (male > age 45, HDL-C < 40 mg/dL) • 10-year Framingham Risk Score = 6% (moderate risk) • Additional Results: • hs-CRP = 4.7 • 10-year Reynolds Risk Score = 6% (moderate risk) • Carotid IMT = 0.605 mm (55th percentile) • 1.877 mm Plaque present in Right Carotid Bulb • Coronary Calcium Score = 210 (88th percentile) • 10-year MESA Risk Score = 20% (CHD Risk Equivalent) • Overall CHD Risk = High Risk

  37. Case ES • Step 2: Establish Goals of Therapy • Overall CHD Risk = High RisK • Goals of Therapy: • LDL-C: < 70 mg/dL • non HDL-C: < 100 mg/dL • LDL-P: < 1000 nmol/L • HDL-C: > 40 mg/dL • Triglycerides: < 150 mg/dL

  38. Case ES • Step 3: Assess Laboratory Results • Overall CHD Risk = High Risk • Goals of Therapy: Results • LDL-C: < 70 mg/dL 92 mg/dL • non HDL-C: < 100 mg/dL 113 mg/dL • LDL-P: < 1000 nmol/L 1952 nmol/L (1675 small) • HDL-C: > 40 mg/dL 35 mg/dL • Triglycerides: < 150 mg/dL 105 mg/dL

  39. Case ES • Step 4: Clinical Management • Therapeutic Lifestyle Changes • Mediterranean - American Diet • Exercise 30 minutes, 5 days per week • Pharmacologic Therapy • Simvastatin40mg daily

  40. Case ES • Step 5: Assess Response to TherapyModify Treatment As Indicated • Therapeutic Lifestyle Changes • Mediterranean - American Diet • Exercise 30 minutes, 5 days per week • Pharmacologic Therapy • Simvastatin40mg daily • Goals of Therapy: 3 Months Later (wt. same) • (Compliant with meds only) • LDL-C: < 70 mg/dL 79 mg/dL • non HDL-C: < 100 mg/dL 97 mg/dL • LDL-P: < 1000 nmol/L 1501 nmol/L (1175 small) • HDL-C: > 40 mg/dL 36 mg/dL • Triglycerides: < 150 mg/dL 90 mg/dL

  41. Case ES • Modify Treatment As Indicated • Therapeutic Lifestyle Changes • Mediterranean - American Diet • Exercise 30-45 minutes, 5 days per week • Pharmacologic Therapy • Simvastatin40mg daily • What other therapies might you consider? • Goals of Therapy: 3 Months Later (10# wt. loss) • (Compliant with TLC & meds) • LDL-C: < 70 mg/dL 72 mg/dL • non HDL-C: < 100 mg/dL 86 mg/dL • LDL-P: < 1000 nmol/L 948 nmol/L (675 small) • HDL-C: > 40 mg/dL 42 mg/dL • Triglycerides: < 150 mg/dL 70 mg/dL

  42. Conclusions Unrecognized (and under-treated) LDL particle elevations are common and a significant contributor to the residual risk of many patients with “acceptable” levels of LDL-C. When LDL-C and LDL-P levels are discordant (esp. diabetes, metabolic syndrome), risk tracks with LDL-P, not LDL-C. Achievement of LDL-P treatment goals is superior to LDL-C or non HDL-C values to indicate a the patient has achieved adequate LDL reduction. LDL size (“quality”) does not contribute independently to risk once LDL particle number is taken into account. LDL-P is a more sensitive indicator of low risk than LDL-C or non-HDL-C, and therefore a more discriminating LDL treatment target. LDL-P may be lowered not only by statins, but by lifestyle change and combination drug therapy.

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