“S3-13: Lipids: Looking forward to 2018”

Heart and Stroke Clinical Update 1010-1140 9 Dec 2017

Robert Hegele MD, FRCPC, FACP Distinguished University Professor Endocrinologist, University Hospital Western University, London ON [email protected]

Faculty/Presenter Disclosure

• Faculty: Rob Hegele

• Relationships with commercial interests: – Grants/Research Support: Amgen, ISIS, Pfizer, Lilly, Aegerion – Speakers Bureau/Honoraria: Valeant, Amgen, Aegerion. – Consulting Fees: Amgen, Sanofi, Valeant, Aegerion, Lilly – Other: N/A

Question 1

1. What is the current Canadian lipid target for high-risk patients?

A) LDL-C < 2.0 mmol/L B) non-HDL-C < 2.6 mmol/L C) apo B < 0.8 g/L D) all of the above

3 Question 2

2. What is the main mechanism of benefit?

A) LDL-C reduction B) anti-inflammatory C) anti-thrombotic D) endothelial relaxation E) all of the above

4 Question 3

3. What is/are the current indication(s) for PCSK9 inhibition in Canada?

A) familial hypercholesterolemia B) atherosclerotic cardiovascular disease, not controlled C) statin intolerance D) A and B only E) A, B and C

5 Objectives

1. To review current Canadian Lipid Guidelines

2. To appreciate the role of established treatments

3. To evaluate the potential of recently approved lipid treatments

7 Issues in the 2016 guidelines

• keep LDL-C targets < 2.0 mmol/L • lower is better • non-fasting lipids to screen • non-HDL-C and apo B are alternate targets • Framingham or cardiovascular age • remain foundational Rx • non-statins: OK; , less so • PCSK9-inhibitors

Anderson et al. Can J Cardiol 2016; 32:1263-1282. 2016 Lipid Guidelines

Anderson et al. Can J Cardiol 2016; 32:1263-1282. 2012 CCS Dyslipidemia Guidelines Update

Table 7. Expected Benefit of Health Behaviour Changes

Intervention (minimal dose for effect) Expected Outcome Dietary cholesterol intake98 ↓ LDL-C < 300 mg/day (NCEP step I diet) 10-12% < 200 mg/day (NCEP step II diet) 12-16% Saturated fats < 7% of daily caloric intake107 ↓ LDL-C 5-10%; ↓ CVD mortality 14% Phytosterols 1-2 g/day100 ↓ LDL-C 5-8% Soy proteins with isoflavones 25g/day101 ↓ LDL-C 3-5% Viscous fibre 10 g/day102 ↓ LDL-C 3-5% Nuts 30-67 g/day103 ↓ LDL-C 5-7%, ↓ TG 5-10% Portfolio type diet104 ↓ LDL-C 8-14% Mediterranean type diet105 ↓ LDL-C 5-10%; ↓ CVD mortality DASH (Dietary Approaches to Stop ↓ CVD mortality in those with hypertension Hypertension) diet106

Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167

14/12/2017 Copyright © 2013, Canadian Cardiovascular Society 10 2012 CCS Dyslipidemia Guidelines Update

Table 7. Expected Benefit of Health Behaviour Changes

Intervention (minimal dose effect) Expected Outcome

Moderated Alcohol intake 1-2 drinks/day ↑ HDL 5-10%, ↓ CVD events

Weight loss and reduction of abdominal obesity42 ↓ LDL-C, ↑ HDL, ↓ TG, 5-10% of body weight loss ↓cardiometabolic risk

Omega -3 - 2-4 g of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA)/day ↓ TG 25-30% in pts. with ↑ TG

Exercise109,110 30-60 min/day moderate to vigorous intensity ↑ HDL 5-10%, ↓ CVD events

Smoking cessation ↑ HDL, ↓ CVD events

Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167

14/12/2017 Copyright © 2013, Canadian Cardiovascular Society 11 2016 Lipid Guidelines

Treatment Targets: Statin Indicated Conditions • LDL-C consistently <2.0 mmol/L or (those who will benefit the most): >50% reduction • Clinical atherosclerosis* • Consider <1.8 mmol/L in patients with • Abdominal aortic aneurysm clinical atherosclerosis • Most diabetes mellitus • Apo B ≤0.80 g/L or non-HDL-C ≤2.6 • CKD (age >50 years) mmol/L be considered as alternative • LDL-C ≥5.0 mmol/L treatment targets *Clinical atherosclerosis, i.e. previous MI, or coronary revascularization by PCI or CABG surgery, other arterial revascularization procedures, angina pectoris, cerebrovascular disease including TIA, or peripheral arterial disease (claudication and/or ABI <0.9)

.

Anderson et al. Can J Cardiol 2016; 32:1263-1282. Non-fasting lipids

Langsted et al. Circulation 2008;118:2047-2056 13 Non-HDL-C as an alternate target

non-HDL-C = TC – HDL-C

14/12/2017 14

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Anderson et al. Can J Cardiol 2016; 32:1263-1282. Reduced all-cause mortality with statins

LDL 4.4 mmol/L

LDL-C 3.1 mmol/L

4S Investigators Lancet 2004; 364:771-7. Reduced all-cause mortality with statins

HR 0.80 (0.67 to 0.97, P=0.02)

LDL-C 2.8 LDLmmol/L-C 1.8 mmol/L

20 mg

N Engl J Med 2008; 359: 2195-207 HOPE-3

LDL-C 3.2 mmol/L

LDL-C 2.4 mmol/L 10 mg

N Engl J Med 2016; 374:2021-31 Reduced all-cause mortality with statins

Collins et al. Lancet. 2016 Sep 8. pii: S0140-6736(16)31357 Reduced major vascular events with statins

CTTC 2016; 25 RCTs of statins; >170,000 patients

Lancet 2016 Sep 8; doi 10.1016/S0140-6737(16)31357-5. LDL-C and CHD risk Benefits vs risks of lowering LDL-C with statins

10,000 patients receiving effective statin therapy for 5 years and lowered LDL-C by 2 mmol/L would result in:

Major Rhabdomyolysis vascular Muscle Myopathy New- (if statin not Haemorrhagic events pain or (symptoms + onset stopped upon stroke weakness CK > 10xULN) diabetes prevented myopathy)

1,000 50-100 ~ 5 ~ 1 ~ 50 ~ 5 (secondary prevention patients)

Based on CTT Collaboration meta-analyses of RCTs. Includes 22 trials (135,000 patients) comparing routine statin therapy to no routine statin therapy and 5 trials (40,000 patients) comparing more versus less intensive statin therapy.

Collins R et al (2016) Lancet pii: S0140-6736(16)31357-5. doi: 10.1016/S0140-6736(16)31357-5. [Epub ahead of print] Cholesterol Treatment Trialists’ Collaboration (2016) https://www.cttcollaboration.org/ CLINICAL ATHEROSCLEROSIS Myocardial infarction, acute coronary syndromes Stable angina, documented coronary disease by angiography (>10% stenosis) Stroke, TIA, documented carotid disease Peripheral artery disease, claudication and/or ABI <0.9

ABDOMINAL AORTIC ANEURYSM Abdominal aorta >3.0 cm or Statin Previous aneurysm surgery DIABETES MELLITUS indicated ≥40 years of age or >15 years duration and age ≥30 years or conditions Microvascular complications CHRONIC KIDNEY DISEASE >3 months duration and ACR >3.0 mg/mmol or eGFR <60 ml/min/1.73m2

LDL-C ≥5.0 MMOL/L LDL-C ≥5.0 mmol/L or Documented familial hypercholesterolemia Excluded 2nd causes

Canadian Journal of Cardiology DOI: (10.1016/j.cjca.2016.07.510) Anderson et al. Can J Cardiol 2016; 32:1263-1282. Statin doses and efficacy

Am J Cardiol 2003; 92:152-60. Statin discontinuation = reduced survival

• Side effects are the most common reason patients discontinue statins 1

• Survival is reduced in patients who discontinue, even compared to those on non-daily statin doses 2

Statin continued/daily dose

Survival (%) Survival Statin continued/non-daily dose Statin discontinued

Years 1. Cohen et al. J Clin Lipidol 2012;6:208–215. 2. Mampuya et al. Am Heart J 2013;166:597–603. Statin intolerance

1) statins not withheld on the basis of a potential, small risk of new-onset DM (Strong/Very Low). 2) evaluate purported statin-associated symptoms systematically, observe during cessation, re- initiation (same or switch), altered dosing frequency to find a tolerated, statin-based therapy. (Strong/Very Low). 3) we do not recommend vitamins, minerals or supplements for symptoms of myalgia perceived to be statin-associated. (Strong/Very Low).

Approach to the statin intolerant patient 1. Rechallenge with another statin - better tolerated: fluva, prava 2. Alternating day statin - most efficacious: rosuva 3. Use a different lipid-lowering class - CAI: ezetimibe - resin: cholestyramine, colesevalam - ? 4. Coenzyme Q10: 60 – 120 mg daily 5. Vitamin D (1000 IU daily)

Joy TR, Hegele RA. Ann Intern Med 2009; 150:85827-68 Think twice about statins

limited life expectancy limited QOL elderly/frail low CV risk end-stage renal disease end-stage CHF polypharmacy

28 Statins: summary

- proven, evidence-based, life-saving - 30+ years real-world experience - first line Rx to reach targets - 5 statin-eligible conditions + intermediate risk - benefits >>> risks in properly selected patients - encourage compliance

29 IMPROVE-IT: Primary Endpoint Intention-To-Treat Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

Hazard Ratio, 0.936 : 34.7% - 2742 events (95% CI, 0.89-0.99) Mean LDL-C = 1.8 mmol/L p=0.016 NNT*= 50

Simvastatin/Ezetimibe: 32.7% - 2572 events Mean LDL-C = 1.4 mmol/L Event Rate (%) Rate Event

7-year event rates * NNT = Number Needed to Treat Time since randomization (years)

Cannon CP et al, N Engl J Med 2015;372:2387-2397. 30 MCVE

N Engl J Med 1999;341: 410-8 ACCORD-Lipid: MACE Fibrates: patients with high TG-low HDL-C

33 N Engl J Med 2010; 363:692-695 AIM-HIGH: niacin on background statin

34 Current Combination Therapy on Top of Statins for LDL Lowering

BILE ACID • No evidence of cardiovascular benefit on top of statin SEQUESTRANTS • May improve glycemia

• Modest additional cardiovascular benefit as add-on to statin EZETIMIBE (IMPROVE-IT)

• Does not generally lower LDL • No evidence of benefit in recent large studies (FIELD, ACCORD LIPID)

• Not well tolerated; may cause infection and bleeding NIACIN • No evidence of cardiovascular benefit on top of statin (HPS2- THRIVE, AIM HIGH)

HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203–12 Keech A et al, Lancet 2005 Nov 26;366(9500):1849-61 ACCORD Study Group. N Engl J Med 2010;362:1563–74 Genest J et al, Can J Cardiol 2006; 22(10):863:868 Anderson TJ et al, Canadian Journal of Cardiology 2016; doi: 10.1016/j.cjca.2016.07.510. 35 CVD end point reduction

Drug class No background With background statin statin Bile acid resins Yes (LRC-CPPT) Not done Ezetimibe Not done Yes (SHARP; IMPROVE-IT) Fibrates Yes (HHS, VA-HIT) No (ACCORD, FIELD) Niacin Yes (CDP) No (AIM-HIGH, HPS2) PCSK9i No Yes (FOURIER, SPIRE-2) Pending ODYSSEY- OUTCOMES Case report 1

- 34 year-old truck driver, 2o CHD prevention - father & 2 uncles: fatal MIs <50 years - age 29: TC and LDL-C = 10.6 and 8.5 mmol/L - age 33: - AMI - diffuse CAD - three stents placed - Rx: 80 mg, ezetimibe 10 mg, ramipril 5 mg, clopidogrel 75 mg, metoprolol 25 mg, ASA 81 mg

Yuan et al. CMAJ 2006; 174:1124-9. On exam Case report 1 date meds TC TG LDL-C HDL-C

1997 none 10.6 1.52 8.52 1.02

2003 atorvastatin 80 mg 7.40 1.30 5.04 1.05

2004 40 mg + ezetimibe 10 mg 6.22 1.25 3.82 1.05

2007 above 2 + niacin ER 2000 mg 5.65 1.02 3.36 1.19

2011 above 3 5.50 1.08 3.18 1.14

2016 rosuvastatin 40 mg + ezetimibe 10 mg 3.36 0.79 1.34 1.08 + 140 mg q2wk Where did PCSK9 inhibitors come from?

40 Emerging lipid therapies

Proprotein Emerging lipid therapies

Proprotein Convertase Emerging lipid therapies

Proprotein Convertase Emerging lipid therapies

Proprotein Convertase Subtilisin Emerging lipid therapies

Proprotein Convertase Subtilisin Kexin Emerging lipid therapies

Proprotein Convertase Subtilisin Kexin 9 PCSK9 inhibitors

- very potent LDL-C reduction: 55-75% - non-statin mechanism - mAbs: sc q2 or q4 wk - 2 approved agents: , evolocumab - 20% reduced MACE with evolocumab Terminology of Monoclonal Antibodies

Source Mouse Chimeric Humanized Human (% human protein) (0% human) (65% human) (> 90% human) (100% human)

Generic suffix: -omab -ximab -zumab -umab

High Potential for immunogenicity Low

1. Weiner LM. J Immunother. 2006;29:1-9.; 2. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23.; 3. Lonberg N. Nat Biotechnol. 2005;23:1117-1125.; 4. Gerber DE. Am Fam Physician. 2008;77:311-319.

Alirocumab: ODYSSEY COMBO II Alirocumab Maintained Consistent LDL-C Reductions over 104 Weeks

On-treatment analysis of LDL-C levels 120 Ezetimibe Alirocumab 100

, -19.7% -17.0%

dL -21.8% 80 C, mg/

- -32.0%* -30.5%* -32.4%* 60 LS mean (SE) 40 -48.9% -52.3% -52.0% Calculated LDL

20

0 0 4 8 12 16 24 36 52 64 76 88 104 Weeks Values above and below the data points indicate the percentage reduction from baseline, with percentage differences indicated by the values by the arrows (*all comparisons were P<0.0001). Conversion factor : For values in mmol/L divide mg/dL by 38.67.

49 Shahawy et al, Presented at the National Lipid Association Scientific Sessions, May 19–22 2016, New Orleans, LA, USA. 49 ODYSSEY Long Term*: LDL Cholesterol

*All patients on background of high-dose or maximally-tolerated statin ± other lipid- lowering therapy 4 Placebo 1513.9 Alirocumab 150 mg Q2W

3.5 3.2 1373.5

/L 3.1 mmol/L mmol/L 1233.2

mmol 3

1092.8 /L (SE), 2.5

952.5 mmol 61.9% (95% CI 59.4-64.3%, p< 0,001) mean 2.1 2 81 1.5 C, LS C, mmol/L 671.7

LDL - 1.5 1.3 mmol/L 531.4

1 391.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80

Intent-to-treat (ITT) analysis Week

Robinson JG et al, N Engl J Med. 2015 Apr 16;372(16):1489-99. 50 ODYSSEY Long Term: Safety Analysis

*Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, nonfatal MI, fatal and nonfatal ischemic stroke, and unstable angina requiring hospitalisation. “Unstable angina requiring hospitalisation” is limited to the UA events with definite evidence of progression of the ischemic condition (strict criteria).

Robinson JG et al, N Engl J Med. 2015; 372:1489-1499 (suppl ): 1-76 51 ODYSSEY Long Term: Post-hoc Safety Analysis of Adjudicated Cardiovascular TEAEs†

0.06 HR = 0.52 (95% C.I 0.31 to 0.90) p<0.01

0.04

0.02 Cumulative probabilityevent of 0 0 12 24 36 52 64 78 86 Time (weeks) No. patients at risk Mean treatment duration: 70 weeks Placebo 788 776 731 700 670 653 644 597 Alirocumab 1550 1533 1445 1392 1342 1306 1266 1170

Endpoints: CHD death, MI, stroke, UA requiring hospitalization

Robinson JG et al, N Engl J Med. 2015; 372:1489-1499 (suppl ): 1-76. 52 ODYSSEY OUTCOMES: Study Design Estimated Completion: Jan 2018 Post-ACS (4-52 weeks) patients1 age ≥40 yrs (n~18,000) with LDL-C ≥1.81 mmol/L, or ApoB ≥ 0.8 g/L, or Non-HDL-C ≥ 2.59 mmol/L despite high-intensity (or maximally tolerated) statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg/daily) x ≥2 wks ± other lipid-modifying therapy (e.g., ezetimibe, fenofibrate)2

Randomization3

Alirocumab 75 mg SC Q2wks x 2 months → 150 mg SC Q2wks based upon Month Placebo SC Q2wks 1 LDL-C ≥50 mg/dL (1.29 mmol/L)4

Follow-Up: Minimum 24 months or target number of events (~1600) → estimated 11.4% rate at 4 yrs, 15% risk reduction; 90% power, 1-sided p=0.025, 1% lost

1 Elevated troponin or CK-MB or resting ECG changes + obstructive coronary disease (new/presumed new ischemia/infarction by perfusion imaging, regional wall motion abnormality, coronary stenosis ≥70% by angiography) 2 Key exclusion criteria: Uncontrolled hypertension; NYHA III-IV or LVEF<25%; prior hemorrhagic stroke; TG>4.52 mmol/L; hepatitis; eGFR<30 ml/min 3 Following ≥2 wk (+ 5 days) run-in period with placebo (1 mL volume in an autoinjector) SC Q2wks 4 Titration downwards for very low LDL

Schwartz et al Am Heart J 2014;168:682-689.e1; clinicaltrials.gov (NCT01663402) Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. 63 64 Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. Do not copy or distribute. ©2017 Amgen Canada Inc. All rights reserved. 67

LDL-C evolocumab treated patients

12

4.58+1.49 10 -64.24% p=0.0001-7 8 N=28

1.64+0.79 6 Title

4

2

0 Pre-Treatment Post-Treatment Administration

Alirocumab Administration

ALIROCUMAB • 1 injection SC q2wk, Doses: 75 mg or 150 mg* • Auto-injector ALIROCUMAB

*As per the product monograph, measure LDL-C levels within 4 to 8 weeks of initiation or titration to assess response and adjust dose if needed

Evolocumab Administration

● 1 injection SC q2wk, Dose: 140 mg ● 3 injections SC q4wk Total Dose: 420 mg ● Auto-injector

Praluent™ Product Monograph. April 2016; Repatha™ Product Monograph. September 2015 70 Individuals who may require lipid–lowering strategies beyond statins Clinical ASCVD*1,2 Familial Hypercholesterolemia (FH)3 • According to the CCS Lipid Guidelines and • Inherited conditions characterized by elevated AHA/ACC Guidelines, ASCVD may include LDL-C and resulting from mutations in genes one or more of the following:1,2 involved in LDL-C metabolism3 Coronary heart disease Heterozygous FH Homozygous FH • Acute coronary syndrome † • History of myocardial infarction • LDL-C >4.9 mmol/L • Untreated LDL-C †,‡ • Stable or unstable angina • Identification >13 mmol/L • Documented coronary disease • Elevated LDL-C with • CVD diagnosis on 3 • Coronary or other arterial physical findings or average at 20 years revascularization a family history OR Cerebrovascular disease or • DNA-based evidence transient ischemic attack

Peripheral arterial disease

Abdominal aortic aneurysm2

*ASCVD, termed “clinical atherosclerosis” per CCS guidelines; †typical levels when untreated; ‡LDL-C level indicative, lower levels do not exclude HoFH. ACC, American College of Cardiology; AHA, American Heart Association; CCS, Canadian Cardiovascular Society; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol

1. Stone NJ et al. J Am Coll Cardiol. 2014;63:2889-934; 2. Anderson TJ et al. Can J Cardiol. http://dx.doi.org/10.1016/j.cjca.2016.07.510; . 3. Genest J et al. Can J Cardiol. 2014;30:1471-1481.

REVEAL study

73 SPIRE-2 study

74 Non-statin benefits agent study duration LDL-C LDL-C Event rate placebo treated reduction ezetimibe IMPROVE-IT 2015 7 years 1.80 1.40 7% evolocumab FOURIER 2017 2.2 years 2.38 0.78 15% SPIRE-2 2017 1 year 2.82 1.24 12% REVEAL 2017 4.1 years 1.58 1.31 9%

75 Cost agent % LDL-C yearly cost per % LDL-C reduction cost reduction atorvastatin 80 mg generic 52% $ 142 $ 2.70 Lipitor 80 mg brand name 52% $ 1022 $19.65 rosuvastatin 20 mg generic 55% $ 124 $ 2.25 Crestor 20 mg brand name 55% $ 734 $13.35 ezetimibe 10 mg generic 21% $ 186 $ 8.85 Ezetrol 10 mg brand name 21% $ 788 $ 37.52 PCSK9 inhibitors 65% $ 6800 $104.62

76 Proposed algorithm

Statin indicated conditions

2016 targets LDL-C < 2.0 mmol/L *LDL-C < 1.8 mmol/L no yes Patient stable? 2016 targets

Consider lower targets LDL-C < 1.4 mmol/L IMPROVE-IT target LDL-C < 1.3 mmol/L REVEAL target Sequence: LDL-C < 1.2 mmol/L SPIRE-2 target 1) maximally tolerated statin LDL-C < 0.8 mmol/L FOURIER target (GLAGOV) 2) + ezetimibe [ + BAS ()] 3) + PCSK9i Inclisiran single dose

78 N Engl J Med 2016; Nov 13 online. 79 Effect of ISIS 304801 Treatment on Key Laboratory :Values in the Three APOC3 Study inhibitorPatients.

Gaudet D et al. N Engl J Med 2014;371:2200-2206. Take home points

1. Guidelines: - LDL-centric; non-fasting lipids OK

2. Statins: - use first

3. Non-statins: - use ezetimibe next

4. PCSK9i: - alirocumab and evolocumab approved - HeFH and ASCVD not controlled - regression study positive - outcome study positive

5. Fibrates: - TG > 10 mmol/L – pancreatitis prophylaxis - TG 5 – 9.9 mmol/L – study ongoing 81 82 Question 1

1. What is the current Canadian lipid target for high-risk patients?

A) LDL-C < 2.0 mmol/L B) non-HDL-C < 2.6 mmol/L C) apo B < 0.8 g/L D) all of the above

83 Question 1

1. What is the current Canadian lipid target for high-risk patients?

A) LDL-C < 2.0 mmol/L B) non-HDL-C < 2.6 mmol/L C) apo B < 0.8 g/L D) all of the above

84 Question 2

2. What is the main mechanism of statin benefit?

A) LDL-C reduction B) anti-inflammatory C) anti-thrombotic D) endothelial relaxation E) all of the above

85 Question 2

2. What is the main mechanism of statin benefit?

A) LDL-C reduction B) anti-inflammatory C) anti-thrombotic D) endothelial relaxation E) all of the above

86 Question 3

3. What is/are the current indication(s) for PCSK9 inhibition in Canada?

A) familial hypercholesterolemia B) atherosclerotic cardiovascular disease, not controlled C) statin intolerance D) A and B only E) A, B and C

87 Question 3

3. What is/are the current indication(s) for PCSK9 inhibition in Canada?

A) familial hypercholesterolemia B) atherosclerotic cardiovascular disease, not controlled C) statin intolerance D) A and B only E) A, B and C

88

Ultra-low issue #3: accuracy of LDL-C direct 0 0.5 1.0 1.5 2.0 2.5 3.0 2.5 2.0 1.5 1.0 0.5 0

0 0.5 1.0 1.5 2.0 2.5 3.0

calculated 90 Quispe R et al. BMC Medicine 2017 15: 83 Non-pharmacological LDL-lowering Compound Dose % LDL lowering Evidence level

Isoflavones (soy protein powder) 50-100 mg 3-11% A-I Soluble fibre 5-15 g 5-20% A-I Oatmeal 60 g 2-6% A-I Plant sterols 1.3 g 4-13% A-I AHA Step 2 diet 5-10% A-I Mediterranean diet 5-10% A-I Portfolio diet 10-20% A-I Almonds 50-80 g 5% B-I Green tea extract 1.2 g 10% B-I High carb diet 60% of calories 5-10% B-I High protein diet 25% of calories 5-10% B-I Red yeast rice 1-2 g 7-20% A-IIa Guggulipid 100 mg 12% A-IIb

Huang et al. Can J Cardiol 2011: 488-505