1. New (U.S.) Lipid Guidelines (The Good and Bad) Robert A. Vogel, MD Clinical Professor of Medicine University of Colorado Denver Disclosures: National Coordinator ODYSSEY Trial (Sanofi)

2. ATP-3ATP-4 Patient Risk Lipid Profile Meds to improve lipid profile, Lifestyle Patient Risk Statins, Lifestyle RCTs

3. Major Statin TrialsTNT Trial CVE On-treatment LDL-C JUPITER % CVE Reduction

4. Dal-Outcomes: Incidence of the Primary End Point (CHD Death, Nonfatal MI, USA, Cardiac Arrest) Schwartz GG et al. N Engl J Med 2012. DOI: 10.1056/NEJMoa1206797 Years Primary End Point (%) HDL-C: ↑33%, LDL-C: no ∆

5. ACCORD Trial in High-Risk Subjects with Type 2 Diabetes Mellitus: Fenofibrate vs. Placebo MACE Total Mortality

6. NEJM 2011;365:2255 AIM-HIGH Study: Niacin 1.5-2.0g in 3414 Subjects with CHD and LDL-C 40-80 mg/dl LDL-C: 74→62 HDL-C: 35→42 TG: 164→122

7. 2013 ACC/AHA/NHLBI Cholesterol Guidelines No specific LDL-C targets 4 Statin Groups: ASCVD LDL-C >190 (FH) DM, 40-75 years old, LDL-C 70-189 10-year ASCVD risk >7.5% Race- and sex-specific pooled cohort equations If risk uncertain, consider using family history, CRP, CAC, ABI Consider 30-year or lifetime risk in adults 20-59 years old who are not at short-term risk High-intensity statin therapy Moderate-intensity statin therapy

8. High- and Moderate-Intensity Statin Therapy

9. Q: Why have the guidelines been changed? A: Because the data don’t support LDL-C treatment goals. Q: How do you judge treatment if you don’t consider on-treatment LDL-C? A: By statin usage and dose

10. Pooled Cohort Equation vs. FRS 10-Year CHD/ASCVD Event Rates for a nonsmoking, non diabetic, non hypertensive male with TC 200 mg/dl, HDL 45 mg/dl, and SBP 130 mmHg

11. Lomitapide (Juxtapid) Microsomal transfer protein (MTP) inhibitor of VLDL synthesis Approved for treatment HoFH only Reduces LDL-C 70-80% and TG 30-40% Increases hepatic fat 1%→6%, ALT or AST >3x ULN 34% 17% intolerance: diarrhea, nausea, vomiting, dyspepsia, abdominal pain Starting dose 5 mg QD with water 2 hrs after evening meal Increase dose after 2 wks to 10, 20, 40, 60 mg (4 wks) Max dose 30 mg with use of CYP3A4 inhibitors (e.g. atorva, amlo, warfarin) Obtain LFT’s prior to increasing dose, ↓dose if LFT’s >3x ULN, D/C if >5x ULN Low-fat diet, ? ezetimibe Supplements: vitamin E 400 IU, linoleic acid 200 mg, alpha-linolenic acid 210 mg, EPA 110 mg, DHA 80 mg

12. Mipomersen (Kynamro) Antisense oligonuclide (ASO) to ApoB messenger RNA Approved for treatment HoFH only Weekly 200mg S.C. injections Reduces LDL-C 25 – 65%, Lp(a) 25% Increases hepatic fat: 12% LFT’s >3x ULN, 3% >5x ULN (LFT monitoring required) 84% injection site reactions, 30% flu-like symptoms 2 days post injection

13. 13 LDL-R Synthesis, Cycling, and Degradation Degradation of LDL-R

14. Varbo et al, Circulation 2013;128:1298 Mendelian Study of the Associations Between Remnant and LDL Cholesterol and CHD and Inflammation in 60,608 Subjects in the Copenhagen General Population, City Heart Disease, and IHD Studies HR per 1 mmol/L Increase No significant association between CRP and CHD

15. 2014 Lipid Management Evaluate disease not lipid profile risk Use statins at evidence-based dosage Lifestyle is important PCSK9 and Apo C-III inhibitors are promising