LDL Particle Number as Measured by NMR CPT

LDL Particle Number as Measured by NMR CPT 83704 - Coverage Decision

Agenda • Introductions • LDL Particle Number and Weight of Evidence • Questions • Next Steps

Attendees • Dr. James A. Underberg, MS, MD, FACPM, FACP, FNLA NYU Medical School - James. Underberg@nyumc. org • Dr. Jim Otvos – Chief Scientific Officer, Lipo. Science – jotvos@liposcience. com • Jim Fries – Vice President, Scientific Development, Lipo. Science – jfries@liposcience. com • Steve Adams – Manager, Payer Relations – Lipo. Science – sadams@liposcience. com

Rationale for Coverage • Aetna covers apo. B, which is a marker for LDL-P • Weight of evidence concludes that managing residual risk in the Cardiometabolic patient is best done through LDL-P • NMR as a clinical standard of care for the at risk patient helps Aetna better manage their covered lives • FDA cleared • Specific CPT code (83704) makes it easy to track

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. ” Fredrickson et al. , NEJM 1967; 276: 148

Explanation of LDL = Low Density Lipoprotein LDL-C = the amount of cholesterol contained in all LDL particles LDL-P = LDL particle concentration

Lipids vs. Lipoproteins 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

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

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

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

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

Weight of Evidence

CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study (n=3, 066) Event-Free Survival Better survival Lower risk Worse survival Higher risk High LDL-C High LDL-P (n=1, 251) Concordant Discordant Years of Follow-up Cromwell WC et al. J Clin Lipidology 2007; 1(6): 583 -592. Low LDL-C Low LDL-P (n=1, 249)

CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study (n=3, 066) Better survival Lower risk Low LDL-C High LDL-C Low LDL-P (n=1, 249) Event-Free Survival (n=284) Worse survival Higherrisk High LDL-C High LDL-P (n=1, 251) High LDL-C Low LDL-P (n=284) Low LDL-C High LDL-P (n=282) Concordant Discordant Years of Follow-up Cromwell WC et al. J Clin Lipidology 2007; 1(6): 583 -592.

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. 17 p=0. 25 LDL-C Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Non-HDL-C 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. 42 HDL-C Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes HDL-P Circulation 2006; 113: 1556 -63

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 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). ” • “Measurements of apo. B or LDL particle number by NMR may more closely quantitate the atherogenic lipoprotein load. • “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. ”

Approach to Clinical Utilization of NMR LDL-P Step 1: Assess clinical CHD risk: Very-High, Moderate-High Risk Step 2: Establish targets of therapy appropriate for degree of clinical risk present Very-High and High Risk LDL-P < 1000 nmol/L Moderately-High Risk LDL-P NMR < 1300 nmol/L Step 3: Laboratory evaluation Step 4: Clinical intervention 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

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. • The weight of clinical and scientific evidence should lead us to coverage of LDL-P (CPT 83704)

New Evidence Supporting the use of LDL-P and HDL-P

Heart Protection Study (confidential results) • Randomized trial of simvastatin vs placebo in >20, 000 high-risk adults. • NMR analyses of stored plasma samples: 10, 085 on statin; 10, 057 on placebo. Outcome • 3026 Major Coronary Events (MI, coronary death, revascularization) during 5 -yr follow-up. Confidential; unpublished data

Prediction of Major Coronary Events in HPS by LDL-Related Variables LDL-C Non-HDL-C Apo B LDL-P Improvement in Model Fit ( 2) From Cox regression models predicting 3026 MCEs (MI, coronary death, revascularization), adjusted for age, sex, smoking, SBP, prior disease, e. GFR, and treatment allocation. Confidential; unpublished data

Prediction of Major Coronary Events in HPS by HDL-Related Variables HDL-C Apo A 1 Adjusted for LDL-P HDL-P Improvement in Model Fit ( 2) From Cox regression models predicting 3026 MCEs (MI, coronary death, revascularization), adjusted for age, sex, smoking, SBP, prior disease, e. GFR, and treatment allocation. Confidential; unpublished data

Prediction of Major Coronary Events in HPS by LDL + HDL-Related Variables LDL-C + HDL-C Apo B + Apo A 1 LDL-P + HDL-P Improvement in Model Fit ( 2) From Cox regression models predicting 3026 MCEs (MI, coronary death, revascularization), adjusted for age, sex, smoking, SBP, prior disease, e. GFR, and treatment allocation. Confidential; unpublished data

Multi-Ethnic Study of Atherosclerosis (MESA) • Large NHLBI observational study of the pathogenesis and progression of subclinical atherosclerosis. • Baseline NMR measurements of entire cohort. Outcomes • 319 CVD events during 5. 5 -yr follow-up (n=5, 598). Confidential; unpublished data

Cumulative Incidence of CVD Events in MESA in Subgroups with Low LDL-C, Low LDL-P, or Both From proportional hazards regression analyses adjusted for age, sex, race, SBP, smoking, hypertension rx, BMI, and diabetes. Confidential; unpublished data