Insert Title Here Presented By Name Title The

Insert Title Here Presented By: Name Title

The Burden of Heart Disease • 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.

LDL-C is the focus of clinical attention for historical and analytical reasons “… all abnormalities in plasma lipid concentrations, 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 of laboratories still employ a combination of chemical measurements of plasma lipids for this purpose. ” Fredrickson et al. , NEJM 1967; 276: 148

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

LDL particles vary in cholesterol content Measured LDL-C 90 mg/d. L LDL particles 900 nmol/L Measured LDL-C 90 mg/d. L LDL NMR Signals LDL particles 1600 nmol/L

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

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

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

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

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

Weight of Evidence

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, Mc. Namara J, Bloomfield HE, Robins SJ Circulation 2006; 113: 1556 -63

Alternative Measures of LDL as Predictors of CHD Events in VA-HIT Odds Ratio per 1 -SD Increment of on-trial value p<0. 001 p=0. 25 LDL-C p=0. 17 p=0. 31 Non. HDL-C Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Apo. B LDL-P Circulation 2006; 113: 1556 -63

Odds Ratio per 1 -SD Decrement of on-trial value Alternative Measures of HDL as Predictors of CHD Events in VA-HIT p<0. 001 p=0. 18 p=0. 42 HDL-C Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Apo. A-1 HDL-P Circulation 2006; 113: 1556 -63

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

LDL Particle Number is Highly Heterogeneous Among Patients with Type 2 Diabetes Mellitus at LDL Cholesterol Target Goal <100 mg/d. L W. C. Cromwell and J. D. Otvos Am J Cardiol. 2006; 98: 1599 -1602

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

LDL Particle Number Distribution in T 2 DM Subjects 5 th 1% (n=19) 20 th 24% (n=364) 50 th 43% (n=631) 80 th 21% (n=307) percentile 11% (n=163) LDL-C 71 -99 mg/d. L 32% Percent of Subjects (n=1, 484) 700 16% (n=147) 1000 43% (n=377) 1300 30% (n=260) 1600 (nmol/L) 9% (n=76) 2% (n=15) 41% Percent of Subjects LDL-C < 70 mg/d. L (n=871) 700 1000 1300 1600 (nmol/L) Am J Cardiol. 2006; 98: 1599 -1602

LDL treatment targets are consensus, population-based (not derived from clinical trials comparing different targets) Percentile: 20 th 50 th 80 th Optimal Low 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

Framingham Highlights 1. Criteria and data relevant to assessing alternative measures of LDL for risk management (treatment target), as distinguished from risk assessment (novel biomarker) 2. Sources and prevalence of variability in the cholesterol content of LDL particles – statin treatment implications 3. Alternative explanation for why non-HDL-C is more strongly related to CVD than LDL-C

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

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

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

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.

ADA/ACC Consensus Statement A need for better lipoprotein Management

ADA/ACC Consensus Statement A need for better lipoprotein Management • 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 Statement A 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.

ADA/ACC Consensus Statement Key Findings on LDL-P by NMR • “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 apo. B 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. ” • “Apo. B 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. ” • “Apo. B 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. ”

LDL Lowering Drugs Reduce LDL-P

Case Studies Initial Presentation • Insert case studies here (example format below) • Patients clinical evaluation • NMR Lipo. Profile test results • Intervention

Case Studies Follow Up • Follow up NMR Lipo. Profile test results • Intervention (if needed)

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

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.