Advanced Lipid testing for the Assessment of Cardiac

Advanced Lipid testing for the Assessment of Cardiac Risk Tara Dall, MD Advanced Lipidology Delafield, Wisconsin Diplomate, American Board of Clinical Lipidology

Is Lowering LDL-C Enough? FDespite on-therapy LDL-C <80 mg/d. L, a significant number of patients still have events 1, 2 FMajor statin trials consistently show an approximate 25%– 40% risk reduction for cardiovascular events, regardless of baseline LDL-C levels 3, 4 FDespite LDL-C lowering, residual risk remains high for at least 2 years following the index event, with about two thirds of CHD events not avoided 1 FThere is a great need for further reducing cardiovascular risk, as 65%-70% of major cardiac events still occur 5 CHD = coronary heart disease. 1. Cannon CP, et al. N Engl J Med. 2004; 350: 1495 -1504; 2. de Lemos JA, et al. JAMA. 2004; 292: 1307 -1316; 3. La. Rosa J, et al. JAMA. 1999; 282: 2340 -2346; 4. HPS Collaborative Group. Lancet. 2002; 360: 7 -22; 5. Assmann G, Gotto AM Jr. Circulation. 2004; 109(suppl III): 8 -14.

Atherogenic Cholesterol and Lipoproteins Non. HDL-C = [Total-C] minus [HDL-C] F Can be accurately measured in nonfasting state F Apo B concentration represents total number of lipoprotein particles in LDL + IDL + VLDL F This may be called “non-HDL” cholesterol or “atherogenic cholesterol” F All apo B-containing lipoproteins may truly possess similar atherogenic potential? F Grundy, et al, Circulation. 1997; 95: 1 -4

Measures of Atherogenic Lipoproteins Non HDL = Apo B = LDL particle Concentration (NMR) >90 % Apo B is on LDL

Small LDL Particles Contain Less Cholesterol Than Large LDL Particles Up to 70% More Particles 100 mg/d. L Large LDL Small LDL Cholesterol Balance

Even LDL Particles of the Same Size can Differ in Cholesterol Content Up to 40% More Particles 100 mg/d. L Normal Cholesterol Per Particle Less Cholesterol Per Particle Cholesterol Balance

LDL-P (NMR) vs LDL-C Prospective CVD Outcome Studies * Independent predictors in multivariate models adjusted for lipids MESA & Framingham

High Triglycerides Are Associated With LDL Subclass Pattern B Cumulative Percent 100 Pattern A 80 60 Pattern B 40 20 0 40 80 120 160 200 TGs (mg/d. L) LDL=low-density lipoprotein; TG=triglyceride. Austin MA, King MC, Vranizan KM, Krauss RM. Circulation. 1990; 82: 495 -506. 240 280

CHD Event Associations of NMR LDL Particle Number (LDL-P) versus LDL Cholesterol (LDL-C)

Advanced Lipoprotein testing F Berkeley Heartlab, Quest • Particle size, Apo B F Liposcience NMR • Subparticle size, LDL particle concentration F Atherotech VAP • Subparticle cholesterol content

Conclusions 1. 2. 3. 4. Non HDL-C , Apo B, LDL particle conc improve risk assessment compared to LDLC Non HDL-C and Apo B may be better than LDL-C for assessing optimal lipid therapy particulary in patients with high TG Non HDL-C should be included in the written lab reports by all labs Achieving Non HDL-C targets in clinical practice will require more intensive therapy than currently practiced

Treatment Goals for LDLC, Non–HDL-C, and Apo B Therapeutic goal, mg/d. L Risk category LDL-C Non–HDL-C Apo B CHD or CHD risk equivalent <100 <130 <90 2+ risk factors <130 <160 <110 0– 1 risk factors <160 <190 <130 Grundy SM. Circulation 2002; 106: 2526– 2529.

Linear Regression of Non-HDL-C vs Apo B Slope Intercept R Non-HDL-C (mg/d. L) for Apo B = 90 Low TG 1. 02 +38. 8 0. 87 130. 7 High TG 1. 02 +44. 1 0. 84 135. 8 All patients 1. 06 +34. 4 0. 89 129. 8 1. 27 1. 25 1. 26 − 10. 0 − 8. 3 − 8. 9 0. 96 104. 1 104. 4 Baseline On statin Low TG High TG All patients On statin: Achieving target apo B <90 mg/d. L requires lower non-HDL-C Ballantyne CM et al. J Am Coll Cardiol 2008; 52: 626 -632.

Clinical Cutpoints for LDL Percentile: 20 th 50 th 80 th Optimal High LDL Cholesterol Framingham Offspring 70 MESA 100 130 160 190 220 250 mg/d. L LDL Particle Number 700 1000 1300 1600 1900 Percent of Subjects 2200 2500 nmol/L

LDL Particle Number Goals Using the same approach to risk assessment and management outlined by ATP III, percentileequivalent LDL particle number goals are defined as follows: Patient Group High Risk (CHD/CHD Risk Equivalents) Moderately High Risk (Multiple Risk Factors) Low Risk (0– 1 Risk Factor) LDL-C Goal (mg/d. L) <100 (20 th percentile) LDL-P Goal (nmol/L) <1000 (20 th percentile) Small LDL-P Goal (nmol/L) < 130 (50 th percentile) < 1300 (50 th percentile) < 850 (50 th percentile) < 160 (80 th percentile) < 1600 (80 th percentile) <850 (50 th percentile)

Candidates for Quantitative Lipoprotein Testing Primary Prevention § High-risk history (family) § Isolated lipid abnormalities § High triglyceride § Low HDL cholesterol § Assess “residual risk” near NCEP values § Metabolic syndrome § Diabetes Secondary Prevention § Few or no modifiable risk factors § Assess “residual risk” near NCEP goal § Recurrent events § Diabetes § Metabolic syndrome

Treatment Considerations Combination therapy (statin + other agent[s]) may be necessary to achieve both goals. Combination agents which increase LDL size (niacin or fibrates) generally lower LDL-P more than LDL-C.