Managing Dyslipidemia in 2018 Glen J. Pearson, BSc, BScPhm, PharmD, - - PDF document

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Dyslipidemia Guidelines

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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 5th, 2018

Dyslipidemia Guidelines

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Speaker Disclosures

• I have the following potential conflicts to disclose.

– no financial or industry disclosures – member of CCS Dyslipidemia Guidelines primary panel since 2007 – Vice-Chair of the 2016 CCS Dyslipidemia Guidelines 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

Disclosures

Dyslipidemia Guidelines

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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

• utcomes.
• FOURIER (Evolocumab)
• ODYSSEY Outcomes (Alirocumab)
• 3. To briefly highlight the potential benefit of very low-LDL

cholesterol levels in high risk patients.

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Dyslipidemia Guidelines

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Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016. DOI: 10.1016/j.cjca.2016.07.510

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Category Consider Initiating pharmacotherapy if: Target NNT Primary Prevention High (FRS ≥20%) LDL-C < 2.0 mmol/L

• r > 50% ↓

Or Apo B < 0.8 g/L Or non-HDL-C < 2.6 mmol/L 35 Intermediate (FRS 10-19%) LDL-C ≥3.5 mmol/L

• r Non-HDL-C ≥4.3 mmol/L
• r Apo B ≥1.2 g/L
• r Men ≥50 & women ≥60

yrs and ≥1 CV risk factor 40 Statin Indicated Conditions*** Clinical atherosclerosis (CAD, CVD, PAD) 20 Abdominal aortic aneurysm Diabetes mellitus: ≥40 yrs,

• r >15 yrs duration & age

≥30 yrs (DM 1), or microvascular disease CKD (age ≥ 50 yrs): eGFR < 60 mL/min/1.73 m2, or ACR > 3 mg/mmol LDL-C ≥5.0 mmol/L >50% ↓ in LDL-C

Pharmacological Treatment Indications & Targets

Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: 10.1016/j.cjca.2016.07.510

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Speaker Disclosures Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors

The Current Evolution (Revolution?) in Lipid Lowering Therapy PCSK-9 Inhibitors

Nat Rev Cardiol 2014;11:563‐75

PCSK-9 Inhibitors

Nat Rev Cardiol 2014;11:563‐75

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Ongoing CV Outcomes Trials: PCSK-9 Inhibitors

• ACS: Acute coronary syndrome; F: Fatal;
• NF: Nonfatal; MI: Myocardial infarction;
• UA: Unstable angina

Adapted from: www.Clinicaltrials.gov; date last accessed: 25th August 2015

March 2017 March 2018 2017-2018

Manufacturer D/C’d Global Development of product – Nov 1/16

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Further Details

This article was published on March 17, 2017, at NEJM.org. DOI: 10.1056/NEJMoa1615664.

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Trial Design

Evolocumab SC

140 mg Q2W or 420 mg QM

Placebo SC

Q2W or QM LDL-C ≥1.8 mmol/L or non-HDL-C ≥2.6 mmol/L

Follow-up Q 12 weeks

Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

RANDOMIZED DOUBLE BLIND

Sabatine MS et al. Am Heart J 2016;173:94-101

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Endpoints

• Efficacy

– 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

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Randomized 27,564 patients Evolocumab (N=13,784) Placebo (N=13,780)

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

Follow-up median 26 months (IQR 22-30) Ascertainment for primary endpoint was complete for 99.5% of potential patient-years of follow up

Follow-up

2907 patients experienced primary endpoint 1829 experienced key secondary endpoint

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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

Pooled data; no differences between treatment arms

Median time from most recent event ~3 yrs

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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)

Pooled data; no differences between treatment arms *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.

2.6 2.3 2.1 1.8 1.6 1.3 1..05 0.8 0.5 0.25

1.45 mmol/L (95% CI 142-147 median 0.78 mmol/L, IQR 0.5-1.2 mmol/L

(mmol/L)

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Types of CV Outcomes

Endpoint Evolocumab (N=13,784) Placebo (N=13,780) HR (95% CI)

3-yr Kaplan-Meier rate

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)

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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

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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 1st 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

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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

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LDL ≥ 1.8 mmol/L Non-HDL-C ≥ 2.6 mmol/L Apo-B ≥ 0.80 g/L

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1.8 1.3 0.4 0.6 (mmol/L)

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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)

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2.4 2.67 0.98 1.09 1.37 2.72 2.32 1.94 1.55 1.16 0.76 0.34 Mean LDL‐C mmol/L ∆ 1.44 mmol/L ∆ 1.40 mmol/L ∆ 1.24 mmol/L

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LDL (mmol/L) <2.1 2.1 - <2.6 ≥2.6

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<2.1 mmol/L 2.1 - <2.6 mmol/L ≥2.6 mmol/L

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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.)

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Meta-Analysis: In-Trial Achieved LDL

Boekholdt et al. J Am Coll Cardiol. 2014;64(5):485-495.

Meta-analysis of 8 statin trials (n=38,153):

• >40% did not reach

LDL-C target (<1.8 mmol/L) on high dose statin

• 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

1.00 0.75 0.50 0.25 10 20 30 40 1.3 2.6 3.9 5.2 6.5 HR for Major CV Events ( ) Percent of Patients ( ) Achieved On-statin LDL Levels

On-Statin LDL-C Levels and Risk for Major Cardiovascular Events

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LDL –c Levels

LDL Target: <2.5 mmol/L (Canadian Guidelines 2000 & 2003) Evidence: CARE, 4S, AF/TexCAPS, WOSCOPS, etc. 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)

Evolution of LDL Targets: How Much Lower is Better?

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Questions?