S3-13: Lipids: Looking forward to

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 hegele@robarts.ca

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 statin 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

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 statins remain foundational Rx non-statins: ezetimibe OK; niacin, fibrates 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) Dietary cholesterol intake 98 < 300 mg/day (NCEP step I diet) < 200 mg/day (NCEP step II diet) Expected Outcome LDL-C 10-12% 12-16% Saturated fats < 7% of daily caloric intake 107 LDL-C 5-10%; CVD mortality 14% Phytosterols 1-2 g/day 100 LDL-C 5-8% Soy proteins with isoflavones 25g/day 101 LDL-C 3-5% Viscous fibre 10 g/day 102 LDL-C 3-5% Nuts 30-67 g/day 103 LDL-C 5-7%, TG 5-10% Portfolio type diet 104 LDL-C 8-14% Mediterranean type diet 105 DASH (Dietary Approaches to Stop Hypertension) diet 106 LDL-C 5-10%; CVD mortality CVD mortality in those with hypertension 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 obesity 42 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 Exercise 109,110 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: LDL-C consistently <2.0 mmol/l or >50% reduction Consider <1.8 mmol/l in patients with clinical atherosclerosis Apo B 0.80 g/l or non-hdl-c 2.6 mmol/l be considered as alternative treatment targets Statin Indicated Conditions (those who will benefit the most): Clinical atherosclerosis* Abdominal aortic aneurysm Most diabetes mellitus CKD (age >50 years) LDL-C 5.0 mmol/l *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

Risk assessment Here's your personalized Heart & Stroke Risk Assessment. Having trouble viewing our email? View it online. Your Personalized Risk Assessment Report http://www.heartage.me/ https://ehealth.heartandstroke.ca/ Your life expectancy* is: *Based on specific lifestyle risk factors. Read more. 88 years 0 100 A Canadian male your age lives an average of 82 years. Your life expectancy is higher than other people of your age group and gender. You can still make positive changes to improve your cardiac health and protect what matters. The Heart and Stroke Foundation is here to support you and your family, every step of the way. Risk factors you cannot control Non-controllable risk factors for heart disease and stroke include your age, gender, ethnicity and family history. While our researchers find ways to stop heart disease and stroke before they happen, we've uncovered realistic ways so you can minimize your risks. FAMILY HISTORY See how your family history is affecting your life today, and how to take action with powerful steps that help break the cycle of heart disease and stroke. READ MORE 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 mmol/l LDL-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 vascular events prevented 1,000 (secondary prevention patients) Muscle pain or weakness Myopathy (symptoms + CK > 10xULN) Rhabdomyolysis (if statin not stopped upon myopathy) Newonset diabetes Haemorrhagic stroke 50-100 ~ 5 ~ 1 ~ 50 ~ 5 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 Statin indicated conditions Abdominal aorta >3.0 cm or Previous aneurysm surgery DIABETES MELLITUS 40 years of age or >15 years duration and age 30 years or Microvascular complications CHRONIC KIDNEY DISEASE >3 months duration and ACR >3.0 mg/mmol or egfr <60 ml/min/1.73m 2 LDL-C 5.0 MMOL/L LDL-C 5.0 mmol/l or Documented familial hypercholesterolemia Excluded 2 nd 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 Survival (%) Statin continued/daily dose 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, reinitiation (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 - fibrate? 4. Coenzyme Q10: 60 120 mg daily 5. Vitamin D (1000 IU daily) Joy TR, Hegele RA. Ann Intern Med 2009; 150:858-68 27

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 (95% CI, 0.89-0.99) p=0.016 Simvastatin: 34.7% - 2742 events Mean LDL-C = 1.8 mmol/l NNT*= 50 Event Rate (%) Simvastatin/Ezetimibe: 32.7% - 2572 events Mean LDL-C = 1.4 mmol/l * NNT = Number Needed to Treat Time since randomization (years) 7-year event rates Cannon CP et al, N Engl J Med 2015;372:2387-2397. 30

Gemfibrozil 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 SEQUESTRANTS No evidence of cardiovascular benefit on top of statin May improve glycemia EZETIMIBE FENOFIBRATE NIACIN Modest additional cardiovascular benefit as add-on to statin (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 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 statin Bile acid resins Yes (LRC-CPPT) With background statin 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, 2 o 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: atorvastatin 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 rosuvastatin 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 + evolocumab 140 mg q2wk 3.36 0.79 1.34 1.08

Where did PCSK9 inhibitors come from? 40

Emerging lipid therapies Proprotein

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: alirocumab, evolocumab - 20% reduced MACE with evolocumab

Terminology of Monoclonal Antibodies Source (% human protein) Mouse (0% human) Chimeric (65% human) Humanized (> 90% human) 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 120 On-treatment analysis of LDL-C levels Ezetimibe Alirocumab Calculated LDL-C, mg/dl, LS mean (SE) 100 80 60 40 20-21.8% -19.7% -30.5%* -32.4%* -52.3% -52.0% -17.0% -48.9% -32.0%* 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 lipidlowering therapy 4 Placebo 151 3.9 LDL-C, LS mean (SE), mmol/l 3.5 3 2.5 2 1.5 Alirocumab 150 mg Q2W 3.1 mmol/l 61.9% (95% CI 59.4-64.3%, p< 0,001) 1.3 mmol/l 3.2 mmol/l 1.5 mmol/l 137 3.5 123 3.2 109 2.8 95 2.5 81 2.1 67 1.7 53 1.4 mmol/l 1 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 39 1.0 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 No. patients at risk Cumulative probability of event 0.06 0.04 0.02 Placebo Alirocumab 0 0 12 24 36 52 64 78 86 Time (weeks) 788 1550 HR = 0.52 (95% C.I 0.31 to 0.90) p<0.01 776 1533 731 1445 700 1392 670 1342 653 1306 Mean treatment duration: 70 weeks 644 1266 597 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) patients 1 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 Randomization 3 Alirocumab 75 mg SC Q2wks x 2 months 150 mg SC Q2wks based upon Month 1 LDL-C 50 mg/dl (1.29 mmol/l) 4 Placebo SC Q2wks 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)

LDL-C evolocumab treated patients 12 10 4.58+1.49-64.24% Title 8 6 p=0.0001-7 N=28 1.64+0.79 4 2 0 Pre-Treatment Post-Treatment

Administration Alirocumab Administration 1 injection SC q2wk, Doses: 75 mg or 150 mg* Auto-injector ALIROCUMAB 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 AHA/ACC Guidelines, ASCVD may include one or more of the following: 1,2 Coronary heart disease Acute coronary syndrome History of myocardial infarction Stable or unstable angina Documented coronary disease Coronary or other arterial revascularization Cerebrovascular disease or transient ischemic attack Inherited conditions characterized by elevated LDL-C and resulting from mutations in genes involved in LDL-C metabolism 3 Heterozygous FH LDL-C >4.9 mmol/l Identification Elevated LDL-C with physical findings or a family history OR DNA-based evidence Homozygous FH Untreated LDL-C >13 mmol/l, CVD diagnosis on average at 20 years 3 Peripheral arterial disease Abdominal aortic aneurysm 2 *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 placebo LDL-C treated ezetimibe IMPROVE-IT 2015 7 years 1.80 1.40 7% evolocumab FOURIER 2017 2.2 years 2.38 0.78 15% bococizumab SPIRE-2 2017 1 year 2.82 1.24 12% anacetrapib REVEAL 2017 4.1 years 1.58 1.31 9% Event rate reduction 75

agent Cost % LDL-C reduction yearly cost cost per % LDL-C 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 no 2016 targets LDL-C < 2.0 mmol/l *LDL-C < 1.8 mmol/l Patient stable? yes 2016 targets Consider lower targets LDL-C < 1.4 mmol/l IMPROVE-IT target LDL-C < 1.3 mmol/l REVEAL target LDL-C < 1.2 mmol/l SPIRE-2 target LDL-C < 0.8 mmol/l FOURIER target (GLAGOV) Sequence: 1) maximally tolerated statin 2) + ezetimibe [ + BAS (colesevelam)] 3) + PCSK9i

Inclisiran single dose 78 N Engl J Med 2016; Nov 13 online.

Effect of ISIS 304801 Treatment on Key Laboratory Values in the Three Study Patients. Volanesorsen: APOC3 inhibitor 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

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

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