Atherosclerosis, Plaque Imaging LDL-C or non-HDL-C as Target for CAD Prevention in Patients with Elevated Triglycerides (Diabetes Mellitus) Atherosclerosis, Plaque Imaging and Lipid Therapy February 25, 2013 Washington, D.C.

Consulting: Bristol-Myers Squibb W. Virgil Brown, MD Consulting: Bristol-Myers Squibb

The non–HDL-C goal is 30 mg/dL higher than the LDL-C goal.2 Key Points: Non–HDL-C has remained a secondary target of therapy in the NCEP ATP III guidelines, both in the 2001 and 2004 publications.1,2 Non–HDL-C was added as a secondary target of therapy to take into account the atherogenic potential associated with remnant lipoproteins in patients with high TG (≥200 mg/dL).2 The non–HDL-C goal is 30 mg/dL higher than the LDL-C goal.2 1. NCEP ATP III. JAMA. 2001;285:2486–2497. 2. Grundy SM et al. Circulation. 2004;110:227–239. 3

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Text in sub bullet 1 under bullet 1 was revised so that no permission will be necessary. Key Points: Based on data from the Framingham Heart Study, non–HDL-C appeared to be a better predictor of CHD incidence than LDL-C was.1 No association was detected between LDL-C and the risk for incident CHD within a given level of non–HDL-C.In contrast, a graded positive association was noted for non–HDL-C and risk for CHD incidence within each level of LDL-C.1 Additional Information: Data from a pooled analysis of 5,794 subjects (2,693 men, 3,101 women) from the Framingham Cohort and the Framingham Offspring Studies were used to investigate how much non–HDL-C contributed compared with LDL-C in predicting CHD risk.1 The average follow-up time was about 15 years, during which a total of 990 incident CHD events (618 in men, 372 in women) were recorded.1 All lipid parameters were strongly associated with CHD risk in men and women. Because the results for men and women were so similar, men and women were grouped together for all analyses.1 1. Liu J et al. Am J Cardiol. 2006;98:1363–1368. 5

Key Points: A target goal for non–HDL-C was first noted in the 2001 NCEP Adult Treatment Panel III guidelines, which identified non–HDL-C as a secondary target of therapy in patients with high TG (≥200 mg/dL).1 Subsequent to the 2001 NCEP ATP III guidelines, a number of other lipid management guidelines adopted the ATP III recommendation for non–HDL-C. 2–6 1. NCEP ATP III. JAMA. 2001;285:2486–2497. 2. Smith SC Jr et al. Circulation. 2001;104:1577–1579. 3. Grundy SM et al. Circulation. 2004;110:227–239. 4. Grundy SM et al. Circulation. 2005;112:2735–2752. 5. Smith SC Jr et al. Circulation. 2006;113:2363–2372. 6. Brunzell JD et al. J Am Coll Cardiol. 2008;51:1512–1524. 6

Prevalence of Elevated TG (1999-2008) 20+ yrs 150 200 > 500 Overall 31% 16% 1.1% Men 35% 20% 1.8% Women 27% 13% 0.5% Heritage Mexican 1.4% African 8% 0.4% European 33% 18% Miller M, et al. Circulation. 2011;123:2292-2333

Metabolic Consequences of Hypertriglyceridemia Metabolic Consequences of Type 2 Diabetes Mellitus Metabolic Consequences of Hypertriglyceridemia TG HTGL Small, dense HDL Apo A-I Apo A-I Insulin Resistance HDL HDL  FFA TG CE CETP VLDL Apo B-100 TG VLDL TG DGAT TG TG LPL HyperTG resulting from either increased production or decreased catabolism of TRL directly influences LDL and HDL composition and metabolism. For example, the hyperTG of IR is a consequence of adipocyte lipolysis resulting in FFA flux to the liver and increased VLDL secretion. Higher VLDL-TG output activates cholesteryl ester transfer protein (CETP) resulting in TG-enrichment of LDL and HDL. The TG content within these particles is hydrolyzed by HTGL resulting in small, dense LDL and HDL particles. Experimental studies suggest that hyperTG HDL may be dysfunctional, that small dense LDL particles may be more susceptible to oxidative modification and that increased number of atherogenic particles may adversely influence CVD risk. TG CETP TG CE CE Glycerol TG HTGL Apo B-100 LDL Apo B-100 LDL Liver Small, dense LDL Miller M, et al. Circulation. 2011;123:2292-2333

Non–HDL-C is calculated as total cholesterol minus HDL-C.1 Key Points: Non–HDL-C is calculated as total cholesterol minus HDL-C.1 Non–HDL-C consists of all lipoproteins that contain apoB,1 and includes2: Chylomicrons and chylomicron remnants Very low-density lipoproteins Intermediate-density lipoproteins Large, buoyant LDL Small, dense LDL Lipoprotein (a) 1. NCEP ATP III. Circulation. 2002;106:3143–3421. 2. Rana JS et al. Curr Opin Cardiol. 2010;25:622–626. 9

In patients with LDL-C < 100 mg/dL, what percent have Non-HDL-C within Goal ( <130 mg/dL):? 97% if TG < 93 g/dL 84% if TG 94 to 166 mg/dL 43% if TG > 167 mg/dL that is 57% are above goal. L D L - C Non-HDL-C mg/dL Study of 1590 patients referred to a university lipid clinic in Spain. Direct LDL and apoB measured by immunochemical methods. Non-HDL-C isolated by UC Masana L, Ibarretxe D, Heras M, et al. Atherosclerosis 2013; 225:471-475.

TG 27- 93 mg/dL How does LDL-C relate to Non-HDL-C in groups with differing triglyceride values? TG 94-166 mg/dL TG >167mg/dL TG >400 mg/dL Study of 1590 patients referred to a university lipid clinic in Spain. Direct LDL and apoB measured by immunochemical methods. Non-HDL-C measured in VLDL and IDL isolated by UC. Masana L, Ibarretxe D, Heras M, et al. Atherosclerosis 2013; 225:471-475.

Non-HDL-C may not be the final word. Sniderman, et al. Journal of Clinical Lipidology v4: p152 High variance in particle number (apoB) occurs at any given non-HDL-C concentration. The probability of a major vascular event is predicted by both measures when elevated and these are not tightly linked. Both measures may be necessary to choose the final goal in a given patient. This hypothesis needs to be tested in a large clinical trial.

Statins Change Relationships Non-HDL-C and ApoB before (A) and after (B) statin treatment. Lunar Study; Ballantyne et al. AJC (2013) 111:506-509.

Statins Change Relationships: Lunar Study; Ballantyne et al. AJC (2013) 111:506-509. Current Goals: LDL-C Non_HDL-C ApoB <100 mg/dL <130 mg/dL <90 mg/dL <70 mg/dL <10 0 mg/dL <80 mg/dL ApoB and Non-HDL-C at baseline and during statin therapy in patients with ACS. Triglycerides (mg/dL) R2 Non-HDL-Cholesterol ApoB ApoB 90 mg/dL 80 mg/dL Baseline < 200 0.85 121 109 > 200 0.80 128 117 Statin therapy < 200 0.93 105 92 > 200 0.92 104 92

Clinical Outcome Studies Evaluating High TG Subgroups Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Primary Endpoint: Subgroup HHS (Gemfibrozil) -34% (0.02) TG > 204 mg/dL LDL-C/HDL-C > 5.0 -71% (0.005) BIP (Bezafibrate) -9.4% (0.26) TG > 200 mg/dL HDL-C <35 mg/dL -42% (0.02) FIELD (Fenofibrate) -11% (0.16) TG > 150 mg/dL -12% (0.07) Statin add-on ACCORD ( Fenofibrate/simva) -8% (0.32) HDL-C < 34 mg/dL -31% (0.0567) JELIS (ethyl EPA) (simva & prava) -19% (0.011) HDL-C < 40 mg/dL -53% (0.043) Pre-statin Some statin use 15 15

Summary: Non-HDL-C is an imperfect predictor of particle number. A separate measure of particle number [apoB or NMR] may provide additional information regarding higher risk than revealed by cholesterol measures alone. 16