Presented By: Name Title

1. Insert Title Here Presented By: Name Title

2. Heart disease, stroke and other cardiovascular diseases are the No. 1 killer of Americans Over 2,600 Americans die of cardiovascular disease each day.1 US heart disease prevalence is projected to double in the next century. 2 Over 125 million lipid panels are done annually in U.S.1 1 Burden of Heart Disease and Stroke in the United States from Steps to a Healthier US. US Department of Health and Human Services, 2003. 2 ACC /AHA Guidelines, 2001; NHLBI Chart Book 2000; and adapted from Foot et al; JACC 2000. The Burden of Heart Disease

3. “… all abnormalities in plasma lipidconcentrations, or dyslipidemia, can be translated into dyslipoproteinemia.” “… the shift of emphasis to lipoproteins offers distinct advantages in the recognition and management of such disorders.” “…there is no single test that infallibly separates all those who have dyslipoproteinemia from those who do not….the majority oflaboratories still employ a combination of chemical measurements of plasma lipids for this purpose.” LDL-C is the focus of clinical attention for historical and analytical reasons Fredrickson et al., NEJM 1967; 276: 148

4. POLAR SURFACE COAT Phospholipid Free cholesterol Apo B This is an LDL particle NONPOLAR LIPID CORE Cholesterol Ester Triglyceride This is LDL Cholesterol LDL Cholesterol Is Not LDL!! A convenient analytic surrogate of LDL since 1972

5. LDL particles vary in cholesterol content 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

6. LDL • LDL = Low Density Lipoprotein • LDL is a multimolecular particle • LDL-C = the amount of cholesterol contained in an LDL particle • LDL-P = LDL particle concentration

7. Less cholesterol per particle Variability of LDL Cholesterol Content Has 2 Sources: LDL Size and Core Lipid Composition LDL-C at equal LDL-P =1500 nmol/L ~150 mg/dL ~125 mg/dL ~125 mg/dL ~100 mg/dL Cholesterol molecules per LDL particle (LDL-C, mmol/L  LDL-P,nmol/L) ~2600 ~2150 ~2150 ~1700

8. Small LDL Cholesterol ester Triglyceride Hepatic Lipase Small HDL Hepatic Lipase Cholesterol Carried Inside Lipoprotein Particles Is Highly Variable TG CETP CE TG CETP CE Otvos JD, Jayarajah E, Cromwell, WC. AJC 2002;90(8A):22i-29i

9. Up to 70% More Particles 100 mg/dL 100 mg/dL Cholesterol Balance Among Individuals At The Same LDL-C Level, The Number of LDL Particles Varies Large LDL Small LDL

10. Up to 40% More Particles 100 mg/dL 100 mg/dL Cholesterol Balance Among Individuals At The Same LDL-C Level, The Number of LDL Particles Varies Normal Cholesterol Carried Per Particle Less Cholesterol Carried Per Particle

11. Weight of Evidence

12. LDL and HDL Particle Subclasses Predict Coronary Events and are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT) Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, McNamara J, Bloomfield HE, Robins SJ Circulation 2006;113:1556-63

13. Alternative Measures of LDL as Predictors of CHD Events in VA-HIT p<0.001 Odds Ratio per 1-SD Increment of on-trial value p=0.17 p=0.25 p=0.31 LDL-C Non-HDL-C ApoB LDL-P Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Circulation 2006;113:1556-63

14. Alternative Measures of HDL as Predictors of CHD Events in VA-HIT p<0.001 Odds Ratio per 1-SD Decrement of on-trial value p=0.18 p=0.42 HDL-C ApoA-1 HDL-P Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Circulation 2006;113:1556-63

15. Conclusion In this nested case-control sub-study of VA-HIT, NMR-measured HDL and LDL particle numbers were significant independent predictors of incident CHD events, whereas levels of HDL and LDL cholesterol (or apolipoproteins A-1 and B) were not. Circulation 2006;113:1556-63

16. 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 Am J Cardiol. 2006;98:1599-1602

17. LDL Cholesterol and LDL ParticleNumbers in T2DM Patients with LDL-C < 100 mg/dL (n=2,355) 5th 20th 50th 80th percentile 37% (n=870) 63% (n=1485) LDL-C Percent of Subjects 70 100 130 160 (mg/dL) 7% (n=162) 31% (n=741) 38% (n=891) 16% (n=383) 8% (n=178) Percent of Subjects 24% LDL-P 700 1000 1300 1600 (nmol/L) Am J Cardiol. 2006;98:1599-1602

18. LDL ParticleNumber Distribution in T2DM Subjects 5th 20th 50th 80th percentile 1% (n=19) 24% (n=364) 43% (n=631) 21% (n=307) 11% (n=163) 32% 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) 41% LDL-C < 70 mg/dL (n=871) Percent of Subjects 700 1000 1300 1600 (nmol/L) Am J Cardiol. 2006;98:1599-1602

19. LDL treatment targets are consensus, population-based (not derived from clinical trials comparing different targets) Percentile: 20th 50th 80th Optimal Low High LDL Cholesterol Percent of Subjects Framingham Offspring 70 100 130 160 190 220 250 mg/dL LDL Particle Number Percent of Subjects MESA 700 1000 1300 1600 1900 2200 2500 nmol/L

21. Framingham Highlights • Criteria and data relevant to assessing alternative measures of LDL for risk management (treatment target), as distinguished from risk assessment (novel biomarker) • Sources and prevalence of variability in the cholesterol content of LDL particles – statin treatment implications • Alternative explanation for why non-HDL-C is more strongly related to CVD than LDL-C

22. Low LDL-P & Low LDL-C (n=1,249) High LDL-P & High LDL-C (n=1,251) Event-Free Survival Years of Follow-up Fig. 2 Survival Curves for Framingham Subjects with Concordant LDL-C and LDL-P

23. Fig. 2 Survival Curves for Framingham Subjects with Discordant LDL-C and LDL-P High LDL-C Low LDL-P (n=284) Event-Free Survival Low LDL-C High LDL-P (n=282) Years of Follow-up

24. Fig. 2 Survival Curves for Framingham Subjects with Concordant and Discordant LDL-C and LDL-P Low LDL-P & Low LDL-C (n=1,249) High LDL-C Low LDL-P (n=284) High LDL-P & High LDL-C (n=1,251) Event-Free Survival Low LDL-C High LDL-P (n=282) Years of Follow-up

25. Conclusions • LDL-C is not LDL • The cholesterol content of LDL is far more variable than generally appreciated. • Cholesterol-depleted LDL is prevalent not only in individuals with elevated TG/low HDL etc., but also in those with low LDL. • 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.

26. ADA/ACC Consensus StatementA need for better lipoprotein Management

27. Lipoprotein abnormalities are common findings in patients with CMR. Measurement of LDL cholesterol may not accurately reflect the true burden of atherogenic LDL particles, especially in those with typical lipoprotein abnormalities of CMR. Even with adequate LDL cholesterol lowering, many patients on statin therapy have significant residual CVD risk. Treatment targets and the best approach for CVD risk reduction in this population need to be better defined. Some have advocated that assessment of other lipoprotein parameters might be more helpful than assessment limited to LDL-C or non-HDL cholesterol in these populations. ADA/ACC Consensus StatementA need for better lipoprotein Management

28. ADA/ACC Consensus StatementA need for better lipoprotein Management • Since each of these risk factors increases risk of cardiovascular disease (CVD), the concept of global cardiometabolic risk (CMR) is of value. • Risk factors for type 2 diabetes and CVD often cluster, including obesity (particularly central), insulin resistance, hyperglycemia, dyslipoproteinemia, and hypertension.

29. “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).” “Many cross-sectional and prospective studies show that LDL particle number is a better discriminator of risk than is LDL cholesterol.” “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 and 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.” “ApoB and LDL particle concentration also appear to be more closely associated with obesity, diabetes, insulin resistance, and other markers of CMR than LDL cholesterol or non-HDL cholesterol.” ADA/ACC Consensus StatementKey Findings on LDL-P by NMR

30. LDL Lowering Drugs Reduce LDL-P

31. Insert case studies here (example format below) Patients clinical evaluation NMR LipoProfile test results Intervention Case StudiesInitial Presentation

32. Follow up NMR LipoProfile test results Intervention (if needed) Case StudiesFollow Up

33. If you have more than one follow up showing the effects of your intervention, please include that result as well. Case StudiesFollow Up # 2

34. 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. • Achievement of LDL-P treatment goals ensures that the patient has achieved adequate LDL reduction. • LDL size (“quality”) does not contribute to risk once LDL particle number is taken into account. • LDL-P may be lowered not only by statins, but by lifestyle change and combination drug therapy.