What Lipoprotein Related Parameters Should Be Measured And How Should They Be Treated in Dyslipidemic Patients with Cardiovascular Disease? Peter O Kwiterovich, MD Professor of Pediatrics and of Medicine Director, Lipid Research/Atherosclerosis Laboratory and Lipid Clinic The Johns Hopkins University School of Medicine

Peter O. Kwiterovich, MD DISCLOSURES Consulting Fees Schering-Plough Corp. / Merck & Co., Inc. Grants/Contracted Research Abbott Vascular, GlaxoSmithKline, Pfizer, Inc, Schering Plough Research Institute Honoraria

Tim Russert Residual CVD Risk April 2008 Known CAD (preclinical) on a statin LDL-C 67mg/dl, Triglycerides 300 mg/dL, HDL 32mg/dl Performed well on stress test June 2008 AMI at work, attempts to resuscitate fail Could this have been avoided? Grady D. A Search for Answers in Russert’s Death. The New York Times. June 17, 2008. Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.

Apolipoprotein B and ApoA-I Containing Lipoproteins Associated With Atherosclerosis1–5 LDL-C Apo B VLDL Number of Total &Small dense LDL particles Lp(a) lipoproteins Remnant Tg-rich lipoproteins Chylomicron remnants (Postprandial lipemia) VLDL Remnants HDL-C (inverse relationship with CAD) NonHDL-C (positive relationship with CAD) 1. Carmena R, et al. Circulation. 2004;109 (Suppl III):III-2─III7. 2. Grundy SM et al. Circulation. 2004;110:227–239. 3. Homma Y. J Atheroscler Thromb. 2004;11:265–270. 4. Botham KM et al. Curr Pharm Des. 2005;11:3681–3695. 5. Groot PHE et al. Arterioscler Thromb. 1991;11:653662.

Lipoprotein Subclasses Chylo- microns Lipoprotein Subclasses 0.95 VLDL Chylomicron Remnants 1.006 IDL Density (g/ml) 1.02 LDL 1.06 Lipoprotein particles have historically been segregated into groups based on common physical size (abscissa), density (ordinate), core cholesterol and triglyceride content, and surface apolipoproteins present. The most common class groupings appear above. The lower the hydrated density, the greater the core lipid content and size, and the lower the content of apolipoproteins. The triglyceride-rich lipoproteins chylomicrons and VLDL are large particles that are catabolized into smaller remnant particles, chylomicron remnants and VLDL remnants, such as IDL. Once most of triglyceride has been removed from the triglyceride-rich particles, the cholesterol- rich LDL remains. LDL also has subclasses that vary in size from large, medium and small. The smaller, cholesterol-rich HDL exist as at least two subclasses, HDL2 and HDL3. Lp (a) is an LDL molecule to which is attached apo (a). Each lipoprotein class is therefore composed of a continuum of individual lipoprotein particles, which span a defined range of size or density. The number of individual lipoprotein particles present within a class varies not only from one patient to another, but, can be affected in the same patient over time by development or expression of co-morbidities, diet, activity, or medication. Conventional lipid assays determine the amount of cholesterol or triglyceride carried by all particles within a lipoprotein class. While this approach allows for a generalized assessment about the lipoproteins involved in lipid transport, it does not allow for quantification of the number or characterization of the size of individual lipoprotein particles present. Methods such as nuclear magnetic resonance spectroscopy do provide an assessment of the number and size of the lipoprotein subclasses. HDL2 Lp(a) 1.10 HDL3 1.20 5 10 20 40 60 80 1000 Diameter (nm)

Genetic Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis Concentration and size of lipoproteins may be related to risk of CVD and related metabolic parameters. GWA study was performed in 17,296 women from the WGHS using 17 lipoprotein measures by NMR, LDL-C, HDL-C, TG, apoB and apoA-I Among 36 loci with GWS (p<5X10-8), 10 were novel (not reported before in GWA studies of lipids) An additional 7 loci with GWS with lipids revealed GWS with lipoprotein size and number. There are genetic effects on the distribution of LDL, HDL and VLDL particle size, and on IDL and VLDL particle #. which can not be assessed by conventional lipid measures (Chasman DI et al PLoS Genet 2009; 5:e1000730)

Prediction of Risk of CAD Comparing ApoB, LDL-P, LDL-C, and Non-HDL-C in Epidemiologic/Noninvasive/Clinical Trial Studies 1.In 5 studies: LDL-C = or >ApoB 2.In 36 studies: ApoB or LDL-P > LDL-C 3. In 8 studies: NonHDL-C = ApoB or LDL-P 4. In 13 studies: ApoB or LDL-P > Non-HDL-C Sniderman et al. in: The Johns Hopkins Textbook of Dyslipidemia, Wolters Kluwer/LWW October 2009.

Event Rates Plotted against LDL Cholesterol Levels during Statin Therapy in Secondary-Prevention Studies LaRosa, J. et al. N Engl J Med 2005;352:1425-1435

TNT Study- Residual Risk for Recurrent CAD Despite Treatment with Atorvastatin 10 or 80 mg/day Those in the lowest quintiles for HDL-C had significantly greater 5 year risk of recurrent CAD than those in the upper quintile of HDL regardless of whether the LDL-C was < 70 or < 100 mg/day. Those in the lowest quintile for HDL-C (< 37 mg/dL) had a mean apoB of 116 mg/dL and a mean TG of 170 mg/dL Thus, the persistence of the dyslipidemic triad of low HDL-C, and high apoB and TG is related to increased residual risk for CAD despite LDL-C levels < 70 mg/dL Barter P et al. N Engl J Med 2007;357:1301-1310

6/26/2018

Estimated Percentiles of LDL-C, apoB and total LDL Particle Number 5th 10th 25th 50th 75th 90th 95th LDL-C 80 90 110 130 160 180 200 Non-HDL-C 110 120 140 160 190 210 230 ApoB 60 70 80 100 120 140 150 LDL Particles 800 900 1100 1400 1800 2000 2100 LDL-C and apoB (mg/dL)Total LDL Particle Number (nmol/L) Estimates were derived from the Framingham heart Study (Freedman et al Clin Chem 2004: 50- 1189-1200) (Schaefer et al J Lipid Res 1994; 779-792). Men and women were combined. Mudd JO et al J Am Coll Cardiol 2007;50:1735-41

6/26/2018

CASE: 66 yr old man with dyslipidemia, intolerant to statins, niacin and fish oils , bad diet, obesity, fatty liver, and IGT. No CAD. Father had MI at 47 and mother at 70 Rx: None TC 274 LDL-C 199 (95th %) NonHDL-C 250 (>95th %) HDL-C 24 TG 254 ApoB 170 (> 99th %) LDLP 3524 (>99th %) SLDL 3319 (>99th %) Rx: Rosuvastatin 2.5 TC 175 LDL-C 108 (25th %) NonHDL-C 141 (25th %) HDL-C 34 TG 164 ApoB 130 (83th %) LDLP 1977 (90th %) SLDLP 1632 (> 90th %)

Summary Approach to Reducing CAD and Residual Risk for CAD 1. Minimal baseline measurement includes TC, LDL-C, HDL-C, Non-HDL-C, TG, ApoB. 2. After maximum treatment of LDL-C (goal < 70 mg/dL) with a statin (+ ezetimibe or BAS), assess ApoB. ApoB should be lowered to same level as LDL-C. 3. If HDL-C is low (< 40 mg/dL) and/or TG too high (>150 mg/dL) add niacin or a fibrate. 4. To determine if the numbers of total and small LDL particles are still elevated, NMR spectroscopy can be performed. 2/23/2010