Lipids: Guidelines & Best Treatment Options

Transcription

1 Lipids: Guidelines & Best Treatment Options Michael Miller, MD, FACC, FAHA, FNLA Professor of Cardiovascular Medicine University of Maryland School of Medicine

2 Michael Miller, MD, FACC, FAHA, FNLA Professor of Cardiovascular Medicine, Epidemiology & Public Health University of Maryland School of Medicine Director, Center for Preventive Cardiology University of Maryland Medical Center Baltimore, MD Disclosures Advisory Board: Amarin: Steering Committee for the REDUCE-IT trial

3 General Principles of the 2013 ACC/AHA Cholesterol Guidelines All adults should adhere to a healthy lifestyle. Statin therapy is recommended for adults in groups demonstrated to benefit. Engage in a clinician-patient discussion prior to initiating statin therapy, especially for primary preventionin patients with low ASCVD risk Current evidence is inadequate to support treatment to specific LDL-C and/or non-hdl-c goals. Initiate the appropriate intensity of statin therapy Stone NJ et al. Circulation Nov 12 (Epub ahead of print).

4 ACC Expert Consensus Pathway on Non-statin Therapies Stable ASCVD with comorbidities on statin for 2 o prevention Clinician-patient discussion factors to consider 1. Potential for additional ASCVD risk reduction from addition of non-statin therapy. 2. Potential for adverse events or drug-drug interactions from addition of nonstatin therapy. 3. Patient preferences. Consider ezetimibe 1 st * 1 Optional non-statin 2 meds to consider Consider adding or replacing with PCSK9 inhibitor 2 nd Patient has 50% LDL-C reduction (may consider LDL-C <70 mg/dl or non-hdl-c <100 mg/dl) on maximally tolerated statin/other medications No Yes Decision for no additional medication Monitor adherence to meds & lifestyle, & LDL-C response *May consider bile acid sequestrant (BAS) if ezetimibe intolerant and triglycerides <300 mg/dl. Consider only if on maximally tolerated statin and either ezetimibe or BAS with persistent <50% LDL-C reduction or LDL-C 70 mg/dl. Lloyd-Jones DM et al. J Am Coll Cardiol. 2016;68:

5 Beyond Statins: Status of Add-on Therapies Ezetimibe PCSK9i OM3 Apo C-III antisense antibodies Anti-inflammatory Compounds (Methotrexate, IL-1B)

6 IMPROVE IT Trial: Effect on LDL-C Ezetimibe (EZ) + Simvastatin vs Simvastatin Alone Mean LDL-C (mg/dl) yr mean LDL-C TC TG HDL-C hscrp Simvastatin EZ/Simvastatin Δ in mg/dl Simvastatin Median Time avg 69.5 vs 53.7 mg/dl 50 EZ/Simvastatin 40 Time since randomization (months) R Study drug is administered once daily in the evening. Cannon CP et al. Am Heart J. 2008;156:

7 FDA-Approved PCSK9 Inhibitors (fully human monoclonal antibodies) Alirocumab: Indicated as adjunct to diet and 1) maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of LDL-C. Dose: Initiate 75 mg SC every 2 weeks (The majority of patients achieve sufficient LDL-C reduction with this dosage.) If LDL-C response is inadequate, may be increased to 150 mg every 2 weeks. Evolocumab: Indicated as an adjunct to diet and: 1) Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical ASCVD, who require additional lowering of LDL-C 2) Other LDL-C-lowering therapies (eg, statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C Dose: ASCVD or HeFH: 140 mg every 2 weeks or 420 mg once monthly. For HoFH: 420 mg once monthly. Note: The 420 mg dose can be administered: 1) over 9 minutes by using the single-use on-body infuser with prefilled cartridge, or 2) by SC.

8 PCSK9 Inhibitors Cardiovascular Outcomes Trials Alirocumab Evolocumab Bococizumab Sponsor Sanofi/Regeneron Amgen Pfizer Trial ODYSSEY Outcomes FOURIER SPIRE I & 2 Sample Size 18,000 28,000 27,000 Patients 4-16 weeks post-acs MI, stroke, or PAD High risk of CV event Statin Evidence-based Rx Atorvastatin 20 mg or equivalent Lipid-lowering Rx LDL-C 70 mg/dl 70 mg/dl 70-99, 100 mg/dl Dosing (SC) Every 2 weeks Every 2 or Every 4 weeks Every 2 weeks Endpoint CHD death, MI, ischemic stroke, or UA hospitalization Primary: CV death, MI, stroke, UA hospitalization or coronary revascularization Key Secondary: CV death, MI, or stroke CV death, MI, stroke, or urgent revascularization Completion February 2018 November 2016 Discontinued 11/2016 Available at: Clinicaltrials.gov.

9 Nicholls SJ, et al. JAMA. 2016;316:

10 LDL-C Percentage Change from Baseline (%) GLAGOV: Percent Change in LDL-C During Treatment Mean LDL-C 93.0 mg/dl Change from baseline 3.9% 90 mg/dl Mean LDL-C 36.6 mg/dl Change from baseline -59.8% 29 mg/dl Study Week Nicholls SJ, et al. JAMA. 2016;316:

11 GLAGOV Primary Endpoint: Percent Atheroma Volume Change in Percent Atheroma Volume (%) Mean LDL-C 93.0 mg/dl P = NS Change from baseline 3.9% P< mg/dl Mean LDL-C 36.6 mg/dl Change from baseline -59.8% Statin monotherapy P<0.001 Statinevolocumab 29 mg/dl Nicholls SJ, et al. JAMA. 2016;316:

12 FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk MS Sabatine, RP Giugliano, AC Keech, N Honarpour, SM Wasserman, PS Sever, and TR Pedersen, for the FOURIER Steering Committee & Investigators American College of Cardiology 66 th Annual Scientific Session Late-Breaking Clinical Trial March 17, 2017

13 Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Sabatine MS et al. Am Heart J. 2016;173: Follow-up Q 12 weeks

14 Baseline Characteristics Characteristic Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non-hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Median time from most recent event ~3 yrs Pooled data; no differences between treatment arms. Sabatine MS et al. Am Heart J. 2016;173:

15 Lipid-lowering Therapy & Lipid Levels at Baseline Characteristic Value Statin use (%)* High-intensity 69 Moderate-intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL-C 92 (80-109) Total cholesterol 168 ( ) HDL-C 44 (37-53) Triglycerides 133 ( ) *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. Pooled data; no differences between treatment arms. Sabatine MS et al. Am Heart J. 2016;173:

16 LDL Cholesterol (mg/dl) LDL Cholesterol LDL Cholesterol Placebo % mean reduction (95%CI 58-60), P< Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR mg/dl) Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J. 2016;173:

17 CV Death, MI, Stroke, Hosp for UA, or Cor Revasc Primary Endpoint Primary Endpoint 16% 14% 12% Hazard ratio % (95% CI, ) P< Placebo 12.6% 10% 8% 6% Evolocumab 4% 2% 0% Months from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J. 2016;173:

18 Anti-inflammatory Effects of Omega-3 through Mediator Balance Omega-3:arachiadonic acid (AA) ratio can either enhance ( ω-3:aa ratio), or inhibit ( ω-3:aa ratio) anti-inflammatory effects Omega-6 PUFAs Arachidonic acid (AA) O 6 1 Prostaglandin E2 Leukotriene B4 O O O O O Proinflammatory mediators Omega-3 PUFAs Eicosapentaenoic acid O 3 Docosahexaenoic acid O 3 3 Resolvin E1 Protectin D1 Prostaglandin E3 O Leukotriene B5 2 O Maresin Less potent inflammatory mediators Anti-inflammatory mediators Modified from Endo J, Arita M. J Cardiol. 2016;67:22-7.

19 Effect of EPA on Inflammatory Markers (Baseline to week 12, intent-to-treat population) Median Placebo-adjusted Change (%) ICAM-1 Ox-LDL Lp-PLA 2 IL-6 hscrp NS NS NS IPE MARINE 4 g/day ANCHOR 4 g/day -6.6 NS NS * *P<0.01; P<0.001; P< (vs placebo). P values for Lp-PLA2 were adjusted for multiple comparisons. hscrp=high-sensitivity C-reactive protein; ICAM-1=intercellular adhesion molecule-1; IL-6=interleukin-6; IPE=icosapent ethyl; Lp-PLA 2 =lipoprotein-associated phospholipase A2; NS=not significant; Ox-LDL=oxidized low-density lipoprotein. Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46.

20 Effects of EPA on Atherosclerotic Plaques by Imaging Modality Study Patient Population N Treatment Summary of Findings Angiography Domei et al, 2013 (J-EACH) Nagahara et al, 2016 Patients undergoing PCI 37 Patients with ACS; all were receiving statin treatment after baseline CCTA measurement Multi-detector Row Computed Tomography Shintani et al, 2012 (JELIS) Carotid Ultrasound Patients with suspected CAD and LDL-C levels <160 mg/dl 82 EPA (dose not specified) + optimal LDL-C-lowering statin therapy or statin alone EPA 1.8 g/day, EPA 0.93 g/day + DHA 0.75 g/day or control 43 EPA or ezetimibe Katoh et al, 2011 Patients with HTG 10 EPA 1.8 g/day Mita et al, 2007 Patients with T2DM 81 EPA 1.8 g/day or control Maeda et al, 2014 Takaki et al, 2011 Patients with risk factors for arteriosclerosis Patients with dyslipidemia and Hx of CAD 3 months before study Nelson JR et al. Vascul Pharmacol In press. Significant in lumen diameter (P=0.020) & % stenosis (P=0.026) in EPA+statin group vs statin-alone group EPA significantly associated with prevention of plaque progression (P=0.0061) Significant in soft-plaque volume in EPA group but not in ezetimibe group; significant improvements in EPA group in plaque significant area (P=0.017), lumen reductions area (P=0.004), & plaque in volume vs ezetimibe group (P=0.036) Significant in IMT with EPA treatment vs baseline (P<0.05); IMT correlated with blood EPA concentration and EPA/AA ratio (P<0.01) Significant annual in mean IMT (P=0.029) & maximal IMT (P=0.0008) in EPA group vs control group 46 EPA 1.8 g/day Significant in maximal IMT with EPA treatment (P<0.0001) 50 EPA 1.8 g/day + statin or statin alone EPA was associated with lumen diameter, plaque volume, and intima-media thickness No difference in change in bapwv observed between groups (P=0.29); carotid β index was in EPA + statin group vs statin-alone group (P=0.02)

21 Randomized Controlled Trials and Prospective Cohort Studies of EPA+DHA and CHD Risk Author, year Subjects with baseline LDL-C >130 mg/dl Von Schacky et al, 1999 Marchioli et al, 2001 Yokoyama et al, 2007 Einvik et al, 2010 Roncaglioni et al, 2013 SRRE: 0.86 (95% CI: ) P-H:.30; I 2 : Favors EPA+DHA RR (95% CI) Favors Control Subjects with baseline TG levels >150 mg/dl Author, year Singh et al, 1997 Von Schacky et al, 1999 Marchioli et al, 2001 Yokoyama et al, 2007 Einvik et al, 2010 Roncaglioni et al, 2013 SRRE: 0.84 (95% CI: ) P-H:.21; I 2 : 30.2 RR (95% CI) Favors EPA+DHA Favors Control Alexander DD et al. Mayo Clin Proc. 2017;92: Circles represent the RR within the individual studies; 95% CIs are represented by horizontal lines. Circle size is proportional to the weight of each study. Diamonds represent the summary relative risk estimate (SRRE). Association between EPA+DHA intake and any CHD event in prospective cohort studies Author, year RR (95% CI) Pietinen et al, 1997 Albert et al, 1998 Yuan et al, 2001 Hu et al, 2002 Mozaffarian et al, 2005 Iso et al, 2006 Jarvinen et al, 2006 Jarvinen et al, 2006 (M) Streppel et al, 2008 De Goede et al, 2010 Joensen et al, 2010 (F) Joensen et al, 2010 (M) Manger et al, 2010 Chiuve et al, 2012 Takata et al, 2013 Amiano et al, 2014 (F) Amiano et al, 2014 (M) Miyagawa et al, 2014 Bergkvist et al, 2015 Koh et al, 2015 SRRE: 0.82 (95% CI: ) P-H:.001; I 2 : Favors EPA+DHA Does not favor intake EPA+DHA intake

22 Ongoing EPA+DHA and EPA-only: CVD Outcome Studies REDUCE-IT 1 (Ongoing) STRENGTH 2 (Ongoing) Omega-3 type, Dose EPA, 4 g/day EPA+DHA (FFA), 4 g/day Population International International N ~8000 Estimated 13,000 Gender Men and non-pregnant or sterile women, ages 45 years Men or women, ages 18 years Risk Profile TG >150 mg/dl +CHD or CHD risk High CV risk (50%), prior ASCVD (50%) Follow-up 4 6 years (planned) 3-5 years (planned) Statin Use 1,2. RRR=relative risk reduction. 100% (at LDL-C goal) 100% (at LDL-C goal) Primary Endpoint Expanded major adverse cardiac event Expanded Major adverse cardiac event Result Powered for 15% RRR Powered for 15% RRR Baseline TG >200 mg/dl 200 mg/dl, <500 mg/dl

23 A Mutation in Human Apo C3 Causes Very Low TG Levels and Lower Coronary Calcium Scores Fasting TG (mg/dl) Coronary Artery Calcium score RR (CC) RX (CT) RR (CC) RX (CT) Apo C-III (relative) Age (years) RR (CC)=Noncarriers of the 19X allele; RX (CT)=Carriers of the 19X allele. Pollin TI, et al. Science. 2008;322:

24 Apo C3 Regulates Lipolysis, Inflammation, and Hepatic Remnant Lipoprotein Uptake Inflammation Liver Vascular cell Adhesion Molecule-1 Lipoprotein Lipase Lipolysis VLDL Hepatic remnant lipoprotein receptors Apo C-III Hepatic uptake Apo E TG-rich lipoprotein in plasma Apo=apolipoprotein; TG=triglyceride(s); VLDL=very-low-density lipoprotein. Libby P. Eur Heart J. 2015;36:774-6.

25 Potentiation of Vascular Risk Induced by Apo C-III Intestine Apo C-III Apo C-III TRLs Apo B CM/ VLDL Apo C-III Apo C-III LPL Apo C-III Apo C-III Remnants Apo B CMR/ VLDLR/ IDL Apo C-III Apo C-III Vascular Wall HL LPL Apo B Liver Lipoprotein Receptors Apo C-III Apo C-III LDL, sdldl Apo C-III Apo C-III NF-ĸβ VCAM1 Apo C-III Miller M. Arterioscler Thromb Vasc Biol. 2017; 37:

26 Levels of Apo C-III (APOC3), TG & HDL-C following ISIS30481 Antisense Inhibitor of APOC3 Gaudet D et al. N Engl J Med. 2015;373:

27 Meta-analysis of hscrp Levels in Healthy Individuals to Future Risks of CHD Ridker PM. Circ Res. 2016;118:

28 Testing Anti-inflammatory Interventions for CVD Risk Reduction Ridker PM. Circ Res. 2016;118:

29 Dose-dependent effects of canakinumab at 4 months for CRP, interleukin-6, and fibrinogen among 556 diabetic patients at high risk for vascular disease Ridker PM. Circ Res. 2016;118:

30 Design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Ridker PM. Circ Res. 2016;118:

31 Effects of Canakinumab, as Compared with Placebo, on Plasma Levels of High-Sensitivity C-Reactive Protein, Low-Density Lipoprotein (LDL) Cholesterol, High-Density Lipoprotein (HDL) Cholesterol, and Triglycerides. Ridker PM et al. N Engl J Med DOI: /NEJMoa

32 Cumulative Incidence of the Primary End Point and the Key Secondary Cardiovascular End Point. Ridker PM et al. N Engl J Med DOI: /NEJMoa

33 Characteristics of the Trial Participants. Ridker PM et al. N Engl J Med DOI: /NEJMoa

34 Incidence Rates and Hazard Ratios for Major Clinical Outcomes and All-Cause Mortality. Ridker PM et al. N Engl J Med DOI: /NEJMoa

35 Incidence Rates and Numbers of Serious Adverse Events and Selected Safety Laboratory Data During Treatment, Stratified According to Trial Group. Ridker PM et al. N Engl J Med DOI: /NEJMoa

36 Cardiovascular Inflammation Reduction Trial (CIRT) Primary Objective: To determine whether low dose methotrexate (target dose mg/wk) reduces MACE Inclusion criteria (n=7000) Age 18 yrs at screening Documented MI (>60 days but <5 yrs) History of T2DM or MetS Event Driven (530 events; MI, CVA, CV death) Average follow-up period: 3-4 years Everett BM et al. Am Heart J. 2013;166:

37 Cardiovascular Inflammation Reduction Trial (CIRT) Everett BM et al. Am Heart J. 2013;166:

38 CIRT: Titration Algorithm for Low-Dose Methotrexate *New & persistent stomatitis, vomiting, diarrhea, unexplained cough with fever or shortness of breath. Everett BM et al. Am Heart J. 2013;166:

39 Lipids: Guidelines & Best Treatment Options: Conclusions Statins are the mainstay for treatment of hyperlipidemia Non-statin therapies (ezetimibe, PCSK9i) that lower LDL-C are associated with improved outcomes, despite modest antiinflammatory effects Over the next 1-3 years, RCTs will examine effectiveness: TG (+/- inflammation) using OM3 Inflammation (in the absence of lipid lowering)