Managing Dyslipidemia in 2018 Glen J. Pearson, BSc, BScPhm, PharmD, FCSHP, FCCS Professor of Medicine (Cardiology) Co-Director, Cardiac Transplant Clinic; Associate Chair, Health Research Ethics Boards; Chair, Trainee Research Access Committee; Faculty of Medicine and Dentistry; University of Alberta; Mazankowski Alberta Heart Institute Vaughn Estate, Sunnybrook Health Sciences Centre Toronto, ON May 5 th, 2018 Speaker Disclosures Disclosures I have the following potential conflicts to disclose. no financial or industry disclosures member of CCS primary panel since 2007 Vice-Chair of the 2016 CCS primary panel and current chair of the 2018 panel a primary member of the Canadian Working Group for the Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance 2013 and 2016. a primary panel member of the 2018 CCS FH Guidelines panel and secondary panel member of the CCS 2014 Position Statement on Familial Hypercholesterolemia Clinician member and PI of the new Familial Hypercholesterolemia Canada Registry practitioner and research initiative. I believe in the LDL hypothesis Learning Objectives 1. To provide practicing pharmacists with a brief, up-to-date, evidence-based knowledge of 2016 treatment guidelines for the treatment of patients with dyslipidemia and those at risk for CV events. 2. To review recent evidence for the use of PCSK-9 inhibitors in treating dyslipidemia and improving CV outcomes. FOURIER (Evolocumab) ODYSSEY Outcomes (Alirocumab) 3. To briefly highlight the potential benefit of very low-ldl cholesterol levels in high risk patients. 1
Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016. DOI: 10.1016/j.cjca.2016.07.510 Pharmacological Treatment Indications & Targets Category Consider Initiating pharmacotherapy if: Target NNT Primary Prevention High (FRS 20%) Intermediate (FRS 10-19%) LDL-C < 2.0 mmol/l or > 50% 35 40 LDL-C 3.5 mmol/l or Non-HDL-C 4.3 mmol/l or Apo B 1.2 g/l or Men 50 & women 60 yrs and 1 CV risk factor Or Apo B < 0.8 g/l Statin Indicated Conditions*** Clinical atherosclerosis (CAD, CVD, PAD) Or 20 Abdominal aortic aneurysm Diabetes mellitus: 40 yrs, or >15 yrs duration & age 30 yrs (DM 1), or microvascular disease non-hdl-c < 2.6 mmol/l CKD (age 50 yrs): egfr < 60 ml/min/1.73 m 2, or ACR > 3 mg/mmol LDL-C 5.0 mmol/l >50% in LDL-C Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: 10.1016/j.cjca.2016.07.510 2
The Current Evolution (Revolution?) Speaker Disclosures in Lipid Lowering Therapy Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors PCSK-9 Inhibitors Nat Rev Cardiol 2014;11:563 75 PCSK-9 Inhibitors Nat Rev Cardiol 2014;11:563 75 3
Ongoing CV Outcomes Trials: PCSK-9 Inhibitors March 2018 Manufacturer D/C d Global Development of product Nov 1/16 2017-2018 March 2017 ACS: Acute coronary syndrome; F: Fatal; NF: Nonfatal; MI: Myocardial infarction; UA: Unstable angina Adapted from: www.clinicaltrials.gov; date last accessed: 25 th August 2015 Further Details This article was published on March 17, 2017, at NEJM.org. DOI: 10.1056/NEJMoa1615664. 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 1.8 mmol/l or non-hdl-c 2.6 mmol/l Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks Sabatine MS et al. Am Heart J 2016;173:94-101 4
Efficacy Endpoints Primary: CV death, MI, stroke, hosp. for UA, or coronary revasc Key secondary: CV death, MI or stroke Safety AEs/SAEs Events of interest incl. muscle-related, new-onset diabetes, neurocognitive Development of anti-evolocumab Ab (binding and neutralizing) TIMI Clinical Events Committee (CEC) Adjudicated all efficacy endpoints & new-onset diabetes Members unaware of treatment assignment & lipid levels Sabatine MS et al. Am Heart J 2016;173:94-101 Follow-up Randomized 27,564 patients Evolocumab (N=13,784) Placebo (N=13,780) Follow-up median 26 months (IQR 22-30) 2907 patients experienced primary endpoint 1829 experienced key secondary endpoint Premature perm. drug discontinuation 5.6%/yr 5.8%/yr Withdrew consent 0.29%/yr 0.35%/yr Lost to follow-up 5 patients 13 patients Ascertainment for primary endpoint was complete for 99.5% of potential patient-years of follow up 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 5
Lipid Lowering Therapy & Lipid Levels at Baseline Characteristic Value Statin use (%)* High-intensity 69 Moderate-intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mmol/l LDL-C 2.4 (2.1-2.8) Total cholesterol 4.35 (3.9-4.9) HDL-C 1.14 (0.96-1.37) Triglycerides 1.5 (1.13-2.06) *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 2.6 2.3 (mmol/l) 2.1 1.8 1.6 1.3 1.45 mmol/l (95% CI 142-147 1..05 0.8 0.5 0.25 median 0.78 mmol/l, IQR 0.5-1.2 mmol/l 6
Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3-yr Kaplan-Meier rate HR (95% CI) CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92) CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88) Cardiovascular death 2.5 2.4 1.05 (0.88-1.25) MI 4.4 6.3 0.73 (0.65-0.82) Stroke 2.2 2.6 0.79 (0.66-0.95) Hosp for unstable angina 2.2 2.3 0.99 (0.82-1.18) Coronary revasc 7.0 9.2 0.78 (0.71-0.86) Urgent 3.7 5.4 0.73 (0.64-0.83) Elective 3.9 4.6 0.83 (0.73-0.95) Death from any cause 4.8 4.3 1.04 (0.91-1.19) Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any 77.4 77.4 Serious 24.8 24.7 Allergic reaction 3.1 2.9 Injection-site reaction 2.1 1.6 Treatment-related and led to d/c of study drug 1.6 1.5 Muscle-related 5.0 4.8 Cataract 1.7 1.8 Diabetes (new-onset) 8.1 7.7 Neurocognitive (EBBINGHAUS study) 1.6 1.5 Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC 7
Summary for Evolocumab LDL-C by 59% Consistent throughout duration of trial Median achieved LDL-C of 0.78 mmol/l, IQR 0.5-1.2 mmol/l CV outcomes in patients already on statin therapy 15% broad primary endpoint; 20% CV death, MI, or stroke Consistent benefit, incl. in those on high-intensity statin, low LDL-C 25% reduction in CV death, MI, or stroke after 1 st year Long-term benefits consistent w/ statins per mmol/l LDL-C Safe and well-tolerated Similar rates of AEs, includiing DM & neurocognitive events w/ Evolocumab & placebo rates of evolocumab D/C low and no greater than placebo No neutralizing antibodies developed Conclusions In patients with known cardiovascular disease: 1. PCSK9 inhibition with evolocumab significantly & safely major cardiovascular events when added to statin therapy 2. Benefit was achieved with lowering LDL cholesterol well below current targets 8
LDL 1.8 mmol/l Non-HDL-C 2.6 mmol/l Apo-B 0.80 g/l 9
0.4 0.6 1.3 1.8 (mmol/l) 10
2.3 (1.9-2.7) 2.3 (1.9-2.7) 3.0 (2.6-3.5) 3.0 (2.6-3.5) 1.1 (0.95-1.3) 1.1 (0.9-1.3) 1.45 (1.05-2.05) 1.45 (1.07-2.07) (1.8 mmol/l) 11
Mean LDL C mmol/l 2.72 2.32 1.94 1.55 1.16 0.76 0.34 2.4 1.44 mmol/l 0.98 1.09 1.40 mmol/l 2.67 1.37 1.24 mmol/l 12
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LDL (mmol/l) <2.1 2.1 - <2.6 2.6 <2.1 mmol/l 2.1 - <2.6 mmol/l 2.6 mmol/l 14
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Data on LDL-C and Risk of CVD Ference BA, et al. Eur Heart J 2017. (doi: 10.1093/eurheartj/ehx144.) 16
Meta-Analysis: In-Trial Achieved LDL HR for Major CV Events ( ) On-Statin LDL-C Levels and Risk for Major Cardiovascular Events 1.00 40 0.75 0.50 0.25 10 30 20 Percent of Patients ( ) Meta-analysis of 8 statin trials (n=38,153): >40% did not reach LDL-C target (<1.8 mmol/l) on high dose statin 0 1.3 2.6 3.9 5.2 6.5 Achieved On-statin LDL Levels Patients achieving LDL-C <1.3 mmol/l are at lower CVD risk than those achieving an LDL-C of 1.9 to <2.6 mmol/l Boekholdt et al. J Am Coll Cardiol. 2014;64(5):485-495. Evolution of LDL Targets: How Much Lower is Better? LDL Target: <2.5 mmol/l (Canadian Guidelines 2000 & 2003) Evidence: CARE, 4S, AF/TexCAPS, WOSCOPS, etc. LDL c Levels LDL Target: <2.0 mmol/l (Cdn Guidelines 2006, 2009, 2012 & 2016) Evidence: TNT, IDEAL, and PROVE-IT LDL Target: <1.8 mmol/l (ESC/EAS Guidelines 2016) Evidence: IMPROVE-IT LDL Target: <1.0 (Future Guidelines??) Evidence: FOURIER (median on-treatment LDL = 0.78 mmol/l at 26 months) ODYSSEY (mean on-treatment LDL = 1.37 mmol/l at 48 months) Questions? 17