Disclosures. Objectives 2/11/2017

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1 Role of Non-Statin Therapy in CV Risk Reduction James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA,FASPC Clinical Assistant Professor of Medicine NYU School of Medicine NYU Langone Center for Cardiovascular Disease Prevention Director,Bellevue Hospital Lipid Clinic, New York,NY President-Elect National Lipid Association Disclosures Speaker Bureau: Amgen, Sanofi, Regeneron, Amarin, True Health Diagnostics. Alexion, Kastle Research Funding: Pfizer, Aegerion Advisory Boards: Amgen, Sanofi, Regeneron, Kastle, Invitae, Akcea Consulting: Amgen, Amarin Objectives At the end of this session attendees will be able to Understand how different guideline and recommendation statements differ and concur on the use of Non-Statin Medications for lipid lowering Utilize Non-Statin medications in high risk ASCVD patients Be familiar with the data on the addtionof Non-Statin medications to statins for CV risk reduction in high risk ASCVD patients 1

2 Treated CHD Patients Achieving LDL-C <100 mg/dl and <70 mg/dl According to Three Data Sources As Percent of All Treated Patients As Percent of All Treated High-Risk Patients As Percent of All Treated CHD Patients 71.0 Patients (%) High-Risk Patients CHD Patients CHD Patients at LDL-C Goal (<100 mg/dl) CHD Patients at LDL-C Goal (<70 mg/dl) CHD Patients at LDL-C Goal (<100 mg/dl) CHD Patients at LDL-C Goal (<70 mg/dl) National Health & Nutrition Administrative Claims Data 2003-Sept 2010 Examination Survey Electronic Medical Records 2003-Sept 2010 Jones PH, et al. J Am Heart Assoc. 2012; doi /JAHA LDL-C Goal Attainment in FH 100 Treated LDL-C <100 mg/dl 100 Reduction in LDL-C 50% Percent Percent CASCADE- FH UK 2008 The Netherlands CASCADE- FH UK 2008 The Netherlands 2010 FH = familial hypercholesterolemia. Pijlman AH, et al. Atherosclerosis. 2010;209: Hadfield SG, et al. Ann Clin Biochem. 2008;45:199. Conclusion : Clinicians could consider using lower-intensity statin combined with bile acid sequestrant or ezetimibe among high-risk patients intolerant of or unresponsive to statins; however, this strategy should be used with caution given the lack of evidence on long-term clinical benefits and harms. Gudzuneet al. Ann Intern Med. 2014;160:

3 Drugs That Provide Additional LDL-C Lowering in Combination with Statin* 1. Ezetimibe 2. Bile-acid resins 3. Niacin 4. PCSK9 inhibitors 5. Lomitapide 6. Mipomersen Evidence for Drugs That Provide Additional LDL-C Lowering in Combination with Statin* 1. Ezetimibe: 1 positive trial 2. Bile-acid resins: no trials 3. Niacin: 2 negative trials 4. PCSK9 inhibitors: 4 ongoing trials *Lomitapide and mipomersenare restricted to homozygous FH IMPROVE-IT: Primary Endpoint ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke HR CI (0.887, 0.988) p=0.016 Simva 34.7% 2742 events NNT= 50 EZ/Simva 32.7% 2572 events 7-year event rates EZ, ezetimibe; Simva, simvastatin Cannon CP, et al. N EnglJ Med. 2015;372:

4 AIM-HIGH: Primary Outcome AIM-HIGH Investigators. N EnglJ Med. 2011;365: HPS2-THRIVE: Effect of ERN/LRPT on MAJOR VASCULAR EVENTS ERN, extended-release niacin; LRPT, laropiprant HPS2-THRIVE Collaborative Group. N EnglJ Med. 2014;371: PCSK9 Outcome Trials ODYSSEY Outcomes (alirocumab) N = 18,000 Duration 5 6 years FOURIER (evolocumab) N = 22,500 Duration 5 years SPIRE-1 (bococizumab)* N = 12,000, LDL-C 70 and <100 mg/dl SPIRE-2 (bococizumab)* N = 6,300, LDL-C 100 mg/dl *Studies halted due to discontinuation of drug development 4

5 Comparison of Recent Major Guidelines Up to 2013 Guideline Treat Based On ACC/AHA (2013) Treat to Specific Target First Line Therapy Alternativeor Add-On Therapies Risk Group No Statin Evidence based, high risk ADA (2013) Risk Group Yes (LDL-C) Statin Generally Not Recommended ESC/EAS (2011) IAS (2013) Risk Group and LDL-C Yes (LDL-C +/- nonhdlc or ApoB) Statin BAS, CAI, nicotinic acid, fibrate, omega 3 Risk Group No Statin BAS,CAI, nicotinic acid, fibrate BAS = Bile Acid Sequestrant CAI = Cholesterol Absorption Inhibitor Lipid Recommendations & Guidelines Flink L, Underberg JA, Newman JD, Gianos E Curr Atheroscler Rep (2015) 17:15 5

6 Journal of Clinical Lipidology (2015) 9, S1 S122 Range of LDL cholesterol concentrations in severe hypercholesterolaemia, according to monogenic defects Lancet Diabetes-Endocrinol 2016 Published Online 5/27, S (16) Lipid Clinic Heart Institute 6

7 Algorithm for Non-StatinRx Lancet Diabetes-Endocrinol 2016 Published Online 5/27, S (16) Lipid Clinic Heart Institute NLA Part 2: PSCK9 Inhibitors Until outcomes are available, consider use primarily in the following patients who despite maximally tolerated statin therapy (+/- ezetimibe) have: 1) ASCVD: LDL-C 100 mg/dl or nonhdl-c 130 mg/dl 2) FH: LDL-C 130 mg/dl or nonhdl-c 160 mg/dl Also mayconsider in: 1) highly selective high risk patients with ASCVD who remain above goal LDL-C or non-hdl-c despite maximally tolerated statin therapy 2) Selected high and very high risk patient who are truly statin intolerant and require substantial additional atherogenic lipid lowering Journal of Clinical Lipidology (2015);9S1-S ESC/EAS Guidelines on the Management of Dyslipidemias: Treatment Goals for LDL-C Task Force for the Management of Dyslipidaemias of the ESC and EAS. EurHeart J prepub. 7

8 2016 ESC/EAS Guidelines on the Management of Dyslipidemias: Pharmacological Treatment of Hypercholesterolemia Task Force for the Management of Dyslipidaemias of the ESC and EAS. EurHeart J prepub. ENDOCRINE PRACTICE Rapid Electronic Article in Press DOI: /EP GL Lipid Goals ENDOCRINE PRACTICE Rapid Electronic Article in Press DOI: /EP GL 8

9 LDL-C: Target, Goals, and Thresholds for Non statin Therapy LDL-C target:the target of therapy is reduction in atherogenic lipoproteins assessed by levels of LDL-C LDL-C goal:number that is used to assess success of therapy LDL-C threshold:% reduction or number to evaluate potential net ASCVD benefit in conjunction with absolute risk of the individual patient 9

10 J A C C V O L. 6 8, N O. 1, Lloyd-Jones et al.j U L Y 5, : Lipid Pathway J A C C V O L. 6 8, N O. 1, Lloyd-Jones et al.j U L Y 5, : Lipid Pathway J A C C V O L. 6 8, N O. 1, Lloyd-Jones et al.j U L Y 5, : Lipid Pathway 10

11 J A C C V O L. 6 8, N O. 1, Lloyd-Jones et al.j U L Y 5, : Lipid Pathway J A C C V O L. 6 8, N O. 1, Lloyd-Jones et al.j U L Y 5, : Lipid Pathway J A C C V O L. 6 8, N O. 1, Lloyd-Jones et al.j U L Y 5, : Lipid Pathway 11

12 Conclusions: As documented for low- and moderate-intensity regimens, variability in % LDL- C reduction following high-intensity statin therapy is wide yet the magnitude of this % reduction directly relates to efficacy. These data support guideline approaches that incorporate % reduction targets for statin therapy as well as absolute targets, and might provide a structure for the allocation of emerging adjunctive lipid-lowering therapies such as PCSK9 inhibitors should these agents prove broadly effective for cardiovascular event reduction. Ridker PM, et al. Eur Heart J doi: /eurheartj/ehw046. LDL-C Change in LDL-C on Statin and Event Rates Placebo No Reduction/Increase <50% Reduction 50% Reduction Change in LDL-C (%) (High Intensity Statin) Event Rate / 1000 Person-Years Individual Observations (N=7856) Ridker PM, et al. Eur Heart J doi: /eurheartj/ehw046. LDL-C Response Variability to High-Intensity Statin Therapy and Implications for the Allocation of PCSK9 Inhibitors PCSK9 Inhibitor Greatest Theoretical Benefit PCSK9 Inhibitor Intermediate Theoretical Benefit PCSK9 Inhibitor Least Theoretical Benefit Change in LDL-C (%) (High Intensity Statin) N=2734 (34.8%) N=3549 (45.2%) N=1573 (20.0%) Individual Observations (N=7856) Ridker PM, et al. Eur Heart J doi: /eurheartj/ehw046. No Reduction/ Increase in LDL-C <40% Reduction in LDL-C 40-60% Reduction in LDL-C >60% Reduction in LDL-C 12

13 From: Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Metaanalysis Silverman MG, et al. JAMA. 2016;316(12): Determining When to Add NonstatinTherapy: A Quantitative Approach Robinson, J.G. et al. J Am Coll Cardiol. 2016;68(22): Robinson, J.G. et al. J Am Coll Cardiol. 2016;68(22):

14 Top Line Results for Fourier Trial Released Meets primary and secondary endpoints Full Results to be presented at ACC In March Conclusions/Take Home Message High risk patients are often unable to achieve desired lipid goals Statins remain a constant for high risk patients across all guidelines and recommendations Non-Statin therapy with medications shown to be safe and have evidence based data showing benefit when added to statins in integral to achieving lipid goals As new data is revealed and as new theraputic agents progress through development guidelines and recommendations will need to be adjusted. 14