ESC, ACC/AHA and Malaysian CPG Guidelines on lipids Statins Introduction to non-statins Guideline recommendations for non-statins Clinical trials of

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2 ESC, ACC/AHA and Malaysian CPG Guidelines on lipids Statins Introduction to non-statins Guideline recommendations for non-statins Clinical trials of non-statin drugs Non-statin vs placebo Non-statin vs placebo (on background of statin-based lipid-lowering therapy) Non-statin + statin vs placebo Non-statins on the horizon Conclusions

3 25-year-old lady, presented at 12 weeks of pregnancy with NSTEMI in Feb She declined termination of pregnancy despite being advised by the feto-maternal specialist. Past history: Coronary Angiogram (Jan 2014): severe ostial LMS and severe RCA stenosis ECHO: EF 69%, Supravalvular AS, calcified aortic cusps (AVA: 1.0cm2) Planned for CABG in Feb 2014, but patient defaulted. Premorbid medical history : Homozygous Familial Hypercholesterolemia - (Total chol: 17.7, LDL: 15.3) Hypertension Family history :Father - CABG 48yr and sister- PCI RCA 31yr

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5 Tight LMS Tight ostial RCA

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9 More emphasise on diet and healthy lifestyle Statin remains the mainstay treatment, then combination therapy with ezetimibe, and as a third line the new PCSK9 inhibitors.

10 Focus on ASCVD risk reduction: 4 statin benefit groups Clinical ASCVD LDL-C level >190mg/dl Diabetes, aged years, with LDL-C mg/dl Estimated 10-year risk of ASCVD of >7.5%,aged years, with LDL-C mg/dl ASCVD, atherosclerotic cardiovascular disease; LDL-C, Low-density lipoprotein cholesterol. Stone NJ, Robinson J, Lichtenstein AH, et al ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol

11 ASCVD Statin Benefit Groups Heart healthy lifestyle habits are the foundation of ASCVD prevention Clinical ASCVD LDL-C 4.9 mmol/l Diabetes; age years* Estimated 10-yr ASCVD risk 7.5% ; age years* High-Intensity statin (age 75 years) Moderate-intensity statin if >75 years or not a candidate for high-intensity statin High-intensity statin Moderate-intensity statin if not a candidate for highintensity statin Moderate-intensity statin High-intensity statin if estimated 10 year ASCVD risk 7.5% Moderate- to highintensity statin ASCVD prevention benefit of statin therapy may be less clear in other groups. Consider additional factors influencing ASCVD risk, potential ASCVD risk benefits and adverse effects, drug-drug interactions, and patient preferences for statin treatment. 11 * With LDL-C of mg/dl Estimated using the Pooled Cohort Risk Assessment Equations Stone NJ, et al. J Am Coll Cardiol. 2013: doi: /j.jacc Available at: Accessed November 13, 2013.

12 Look at: 1. Family history of premature ASCVD 2. LDL-C >160 mg/dl (4.2mmol/L) 3. hscrp 2 mg/dl 4. Calcium score 300 Agatston units or 75 th % 5. Sex 6. Ethnicity 7. Ankle-brachial index < Elevated lifetime risk of ASCVD

13 High, Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)* High-Intensity Statin Therapy Daily dose lowers LDL C by approximately 50% Atorvastatin (40 ) 80 mg Rosuvastatin 20 (40) mg Moderate-Intensity Statin Therapy Daily dose lowers LDL C by approximately 30% to <50% Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2 4 mg Low-Intensity Statin Therapy Daily dose lowers LDL C by <30% Simvastatin 10 mg Pravastatin mg Lovastatin 20 mg Fluvastatin mg Pitavastatin 1 mg Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47). Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. Stone NJ, Robinson J, Lichtenstein AH, et al ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol

14 Treat patients aggressively with the right statin dose and intensity for the patients that s been proven to benefit most from statin treatment LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment. Treat to reduce the CV risk, and not just the LDL-C numbers alone.

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18 The STELLAR study 0 Dose, mg (log scale) Change in LDL-C from baseline (%) * X * X X n = 485 n = 473 X n = 648 n = 634 X Rosuvastatin Atorvastatin Simvastatin Pravastatin *P<.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg. P<.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg. P<.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg. Jones P, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003;92:

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20 1.00 Simvastatin 0.95 Proportion alive Placebo Log rank P = Years since randomisation 6 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:

21 Cholesterol absorption inhibitors (ezetimibe) Fibrates Omega-3 polyunsaturated fatty acids (PUFAs) Niacin Emerging products PCSK9 inhibitors Cholesterylester transfer protein (CETP) inhibitors Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD) This presentation surveys the clinical evidence to date

22 ACC/AHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins 1 Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against non-statins 2,3 No evidence of benefit ESC/EAS guidelines (2012) recommend non-statins in limited situations 4 Lipid target not reached with maximally tolerated statin Statin not tolerated 1. Stone NJ et al. J Am Coll Cardiol 2014;63: ; 2. Rabar S, et al. BMJ 2014;349:g4356 doi: /bmj.g4356; 3. National Institute for Health and Care Excellence. Lipid modification July Fifth Joint Task Force on CVD Prevention in Clinical Practice. Eur Heart J 2012;33:

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24 Clinical trials of non-statin treatments 1. Non-statin vs placebo 2. Non-statin vs placebo (on background of statin-based lipid lowering therapy) 3. Non-statin + statin vs placebo

25 FIELD: Fenofibrate did not reduce primary outcome (CHD death or nonfatal MI) in patients with diabetes Mean lipid level (mmol/l) Rate/1000 person-years FIELD: fenofibrate 200 mg/d vs placebo in 9795 patients with type 2 diabetes Median follow-up: 5 years HR % CI 0.75 to 1.05 p= Placebo, baseline Placebo, study end LDL-C HDL-C TGs Keech p7 1E p= Fenofibrate HR % CI 0.62 to 0.94 p= Placebo p= Fenofibrate, baseline Fenofibrate, study end p= HR % CI 0.68 to 0.93 p= *CHD mortality or nonfatal MI; Primary outcome* CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization ARR over course of study=0.7%; NNT=143 NNT, number needed to treat Keech A, et al. Lancet 2005;366:

26 Meta-analysis: Fibrates may reduce CV events but not all-cause mortality Meta-analysis of 18 placebo-controlled fibrate trials ( patients) Major CV events* Coronary event Nonfatal coronary events All-cause mortality Number of studies included Favors fibrate 1.0 Relative risk (95% CI) 1.5 Favors placebo Relative risk (95% CI) 0.90 (0.82 to 1.00); p=0.048 I 2 =47.0%, p for heterogeneity= (0.81 to 0.93); p< I 2 =22.1%, p for heterogeneity= (0.75 to 0.89); p< I 2 =14.5%, p for heterogeneity= (0.93 to 1.08); p=0.918 I 2 =19.4%, p for heterogeneity=0.237 *MI and stroke Jun M, et al. Lancet 2010;362: Reprinted from The Lancet, Volume 362, Jun M, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis, , Copyright 2010, with permission from Elsevier.

27 Omega-3 fatty acids Docosahexenoic acid (DHA) Eicosapentenoic acid (EPA) PUFAs Found in fish oil and Mediterranean diet 1 Have been used to lower TG 1 EPA 1 Marketed omega-3 fatty acids include Vascepa (ethyl-epa) 2 Lovaza (mixture of ethyl-esterified EPA, DHA, and other fish oils) 3 1. Fifth Joint Task Force on CVD Prevention in Clinical Practice. Eur Heart J 2012;33: ; 2. Vascepa Prescribing Information Lovaza Prescribing Information.

28 Placebo-controlled trials of omega-3 fatty acids have reported beneficial effects on CV outcomes Study Population Regimen follow-up Lipid effects CV endpoints Non-statin vs placebo DART 1 Men, previous MI (n=2033) Dietary fish intake Mean 2 years No significant change in total-c over 2 years All-cause mortality 29% (p<0.05) GISSI-P 2 * Recent MI (n=11 324) Omega-3 PUFA 1 g/d vs control Mean 3.5 years LDL-C 9.9% (p=0.002); HDL-C 8.8% (p=ns); TGs 3.4% (p=0.001) Death, nonfatal MI or nonfatal stroke 10% (p=0.048) GISSI-HF 3 ** Chronic HF (n=6975) Omega-3 PUFA 1 g/d vs placebo Median 3.9 years TGs from 1.42 to 1.34 mmol/l over 3 years with PUFA (p< vs placebo) All-cause death 9% (p=0.041) All-cause death or CV hospitalization 8% (p=0.009) *Statin use was 5% at study baseline, rising to 46% after 42 months follow-up **Patients were also randomized to rosuvastatin or placebo; no interaction was recorded between PUFA and statin 1. Burr ML, et al. Lancet 1989;2: ; 2. GISSI-Prevenzione Investigators. Lancet 1999;354: ; 3. GISSI-HF Investigators. Lancet 2008;372:

29 Clinical trials of non-statin treatments 1. Non-statin vs placebo 2. Non-statin vs placebo (on background of statin-based lipid lowering therapy) 3. Non-statin + statin vs placebo

30 Ezetimibe Cholesterol absorption inhibitor

31 ENHANCE: Simvastatin + ezetimibe did not significantly reduce intima-medial thickness vs simvastatin alone Mean LDL-C (mg/dl) ENHANCE: ezetimibe 10 mg/d vs placebo (added to simvastatin 80 mg/d*) in 720 patients with familial hypercholesterolemia (follow-up 24 months) 1 Simvastatin + placebo Simvastatin + ezetimibe Baseline Month 24 p<0.01 Mean HDL-C (mg/dl) Simvastatin + placebo Simvastatin + ezetimibe Baseline Month 24 p=0.78 Median TGs (mg/dl) Simvastatin + placebo Simvastatin + ezetimibe Baseline Month 24 p< p=0.29 Difference from baseline at Month 24 (mm) Simvastatin + ezetimibe Simvastatin + placebo Primary endpoint: Change in carotid intima-medial thickness at Month 24 *No longer a recommended dose of simvastatin 2 1. Kastelein JJP, et al. N Engl J Med 2008;358: Zocor (simvastatin calcium) Prescribing Information. Merck Sharp & Dohme Ltd, October 2012

32 Fibrates

33 ACCORD: Fenofibrate had no significant effect on CV endpoints when added to a statin in patients with diabetes ACCORD: fenofibrate (starting dose 160 mg/d) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 4.7 years) Mean HDL-C cholesterol (mg/dl) Placebo Fenofibrate p=0.01 Mean TGs (mg/dl) Placebo Fenofibrate p< Outcome rate/yr (%) Baseline Study end Fenofibrate 1.32 Placebo Baseline p=ns for all endpoints (Primary outcome: HR 0.92; 95% CI 0.79 to 1.08; p=0.32; ARR 0.17 per year; NNT 588 to avoid one event over 1 year) 1.47 Study end *Nonfatal MI, nonfatal stroke or CV death Fatal coronary event, nonfatal MI, or unstable angina Primary outcome* Major coronary event Nonfatal MI Stroke All-cause mortality Ginsberg HN, et al. N Engl J Med 2010;362:

34 Niacin

35 AIM-HIGH trial of niacin: Discontinued early due to lack of efficacy AIM-HIGH: extended-release niacin mg/d vs placebo (added to simvastatin ± ezetimibe) in 3414 patients with established CV disease. Stopped after mean follow-up 3 yr Median LDL-C (mg/dl) Statin + placebo Statin + niacin Baseline Year 3 Median HDL-C (mg/dl) Statin + placebo Statin + niacin p<0.001 Baseline Year 3 Median TGs (mg/dl) Statin + placebo Statin + niacin Baseline Year 3 Patients (cumulative %) p= Statin + placebo Statin + niacin Primary endpoint* Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularization *Death from CHD, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization Symptom-driven coronary or cerebral revascularization Boden WE, et al. N Engl J Med 2011;365:

36 HPS-2-THRIVE: Niacin laropiprant had no effect on major vascular events and increased serious AEs HPS-2-THRIVE: extended-release niacin 2000 mg/d + laropiprant 40 mg/d vs placebo (added to simvastatin ± ezetimibe) in patients with vascular disease. Median follow-up: 3.9 year Change in lipids: niacinlaropiprant vs placebo (mg/dl) Patients with outcome (%) Lipid levels 6 LDL-C HDL-C TGs HR % CI p= ARR 0.5% NNT 200 over 3.9 years Statin + placebo 5.4 Patients with serious AE (%) p= p< Statin + niacin-laropiprant p= Primary outcome* Any major coronary event Any stroke Any revascularization 4.8 Statin + placebo p< p= Statin + niacin-laropiprant p<0.001 Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes HR % CI p=0.03 p< p< *Major vascular event (nonfatal MI, death from coronary causes, stroke, or arterial revascularization Haynes R, et al. N Engl J Med 2014;371:

37 Omega-3 fatty acids

38 Omega-3 fatty acids do not appear to augment the beneficial effects of statins on CV outcomes Study Population Regimen follow-up Lipid effects CV endpoints Non-statin + statin vs statin alone , JELIS 1 total-c >6.5 mmol/l Statin + EPA 1.8 g/d vs statin + placebo Mean 4.6 years LDL-C 25% in both groups TGs 9% vs 4% (p<0.0001) Major coronary events 19% (p=0.011) No difference for coronary or sudden cardiac death OMEGA 2 Prior MI (n=3851) Omega-3 PUFA 1 g/d vs placebo Mean 1 year 94% taking statin TGs 1.37 vs 1.43 mmol/l at study end (p<0.01) LDL-C 2.46 mmol/l in both groups Sudden cardiac death 1.5% in both groups (p=ns) Alpha- Omega 3 Prior MI (n=4837) EPA DHA 400 mg/d vs placebo Median 3.4 years 86% taking lipid-lowering drugs (mainly statins) No significant differences in TGs or other risk markers Fatal and nonfatal CV events and cardiac interventions: 14.0% vs 13.8% (p=0.93) Dysglycemia + ORIGIN 4 high CV risk (n=12 536) Omega-3 ethyl esters 1 g/d vs placebo Median 6.2 years 54% taking statin TGs 23.5 mg/dl with PUFA vs 9.0 with placebo (p<0.0001) Other lipids NS Death from CV causes: 9.1% vs 9.3% (p=0.72) 1. Yokoyama M, et al. Lancet 2007;369: ; 2. Rauch B, et al. Circulation 2010;122: ; 3. Kromhout D, et al. N Engl J Med 2010;363: ; 4. Bosch J, et al. N Engl J Med 2012;367:

39 Clinical trials of non-statin treatments 1. Non-statin vs placebo 2. Non-statin vs placebo (on background of statin-based lipid lowering therapy) 3. Non-statin + statin vs placebo

40 Ezetimibe

41 SHARP: Simvastatin + ezetimibe reduced major atherosclerotic events compared with placebo in CKD SHARP: simvastatin 20 mg/d + ezetimibe 10 mg/d or placebo in 9270 patients with CKD Median follow-up: 4.9 years LDL-C absolute change (mmol/l) Placebo Simvastatin + ezetimibe Time (months) People suffering events (%) Primary endpoint*, 1 Rate reduction 17% (95% CI 6 to 26%) Log-rank p= ARR 2.1%; NNT 48 over 4.9 years Simvastatin + ezetimibe Placebo Time (years) 10 Placebo Simvastatin + ezetimibe Patients (%) p= Risk ratio % CI 0.60 to 0.94 p= Risk ratio % CI 0.68 to 0.93 p= Any major coronary event Any non-hemorrhagic stroke Any revascularization *Nonfatal MI or coronary death, non-hemorrhagic stroke, or any arterial revascularization procedure 1 Figure reprinted with permission from Elsevier (The Lancet 2011;377: ) Baigent C, et al. Lancet 2011;377:

42 SEAS: Simvastatin + ezetimibe did not reduce major CV events in patients with asymptomatic aortic stenosis SEAS: simvastatin 40 mg/d + ezetimibe 10 mg/d vs placebo in 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. Median follow-up: 52.2 months Reduction in LDL-C (%) Placebo 3.8 Simvastatin + ezetimibe p< Change in peak aortic flow velocity (m/sec) Placebo Simvastatin + ezetimibe p= Patients (%) HR % CI 0.83 to 1.12 p= ARR 2.9% NNT 34 over 1 year p= Placebo Simvastatin + ezetimibe p= Primary outcome* Death from CV causes Aortic valve replacement Nonfatal MI CABG 28.3 p= HR % CI 0.50 to 0.93 p= *Death from CV causes, aortic valve replacement, nonfatal MI, hospitalization for acute angina, HF, coronary artery bypass grafting, percutaneous coronary intervention, and non-hemorrhagic stroke Rossebø A, et al. N Engl J Med 2008;359:

43 Non-statin trials: Summary

44 Clinical trials of fenofibrate have reported limited effects on CV endpoints Study FIELD 1 ACCORD 2 Population Type 2 diabetes (n=9795) Type 2 diabetes, receiving simvastatin (n=5518) Regimen follow-up Lipid effects CV endpoints Fenofibrate 200 mg Placebo Median 5 years Non-statin vs placebo Final TGs Fenofibrate 1.47 mmol/l Placebo 1.87 mmol/l Non-statin + statin vs statin alone Fenofibrate 160 mg Placebo Mean 4.7 years Final TGs Fenofibrate 122 mg/dl Placebo 144 mg/dl CHD mortality or nonfatal MI 11% (p=0.16) Nonfatal MI 24% (p=0.01) Coronary revascularizaion 21% (p=003) Major CV event 8% (p=0.32) Major coronary event 8% (p=0.26) All-cause mortality 9% (p=0.33) 1. Keech A, et al. Lancet 2005;366: ; 2. Ginsberg HN, et al. N Engl J Med 2010;362:

45 Clinical trials of ezetimibe have reported inconsistent effects on CV events Study Population Regimen follow-up Lipid effects CV endpoints Non-statin + statin vs statin alone ENHANCE 1 FH (n=720) Receiving simva-statin 80 mg Ezetimibe 10 mg Placebo 24 months Final LDL-C Ezetimibe 141 mg/dl Placebo 193 mg/dl Change in carotid IMT vs mm (p=0.29) IMPROVE-IT 2,3 Post-ACS (n=18 144) Receiving simva-statin mg Ezetimibe 10 mg Placebo 6 years Final LDL-C Ezetimibe 53.2 mg/dl Placebo 69.9 mg/dl Primary endpoint 6.4% (p=0.016) Non-statin + statin vs placebo SHARP 4 CKD (n=9270) Ezetimibe 10 mg + simvastatin 20 mg Placebo Median 4.9 years LDL-C (months 44 49) E/S 0.84 mmol/l Placebo 0.08 mmol/l Major atherosclerotic events 17% (p=0.0021) SEAS 5 Aortic stenosis (n=1873) Ezetimibe 10 mg + simvastatin 40 mg Placebo Median 52.2 months LDL-C E/S 53.8% Placebo 3.8% Primary CV endpoint 4% (p=0.59) 1.Kastelein JJP, et al. N Engl J Med 2008;358: ; 2. Blazing MA, et al. Am Heart J 2014;168: ; 3. Cannon C. AHA, Chicago, IL, November ; 4. Baigent C, et al. Lancet 2011;377: ; 5. Rossebø A, et al. N Engl J Med 2008;359:

46 Large endpoint trials of niacin reported no significant effect on primary CV endpoints Study AIM-HIGH 1 HPS2-THRIVE 2 Population Established CVD (n=3414) Established vascular disease (n=25,673) Regimen follow-up Lipid effects CV endpoints Non-statin + statin ± ezetimibe vs statin ± ezetimibe alone Niacin mg Placebo Added to simvastatin ± ezetimibe Mean 3 years Niacin 2000 mg + laropiprant 40 mg/d Placebo Added to simvastatin ± ezetimibe Median 3.9 years Final HDL-C Niacin 42 mg/dl Placebo 37 mg/dl HDL-C 6% vs placebo Primary CV endpoint 2% (p=0.80) Major vascular events 4% (p=0.29) 1. Boden WE, et al. N Engl J Med 2011;365: ; 2. Haynes R, et al. N Engl J Med 2014;371:

47 Non-statins on the horizon

48 Non-statins on the horizon PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL 1 Loss of PCSK9 reduces LDL-C and protects against CHD 1 Monoclonal antibodies against PCSK9 are under development 1 Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins 2 Marked reduction of LDL-C Potential decrease in CV events CETP inhibitors 1 Torcetrapib: withdrawn due to excess CV events Dalcetrapib: no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib, evacetrapib) Mipomersen 1 Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia 1. Tomkin GH, et al. Expert Opin Investig Drugs 2014;23: ; 2. Robinson JG, et al. ESC Congress 2014

49 Supplements

50 Supplements are not primary treatment Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed, which may be partly due to the presence of flavonoids, especially naringenin 1 Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2 The few whole-grain studies show improvements in biomarkers blood lipid improvement3 Algae: Antihypertensive and antihypercholesterolemic activities were found in some green, brown and red algae seaweeds4 Spirulina: Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5 1 Belguith-Hadriche O 1, Bouaziz M, et. al. Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats. J Agric Food Chem Feb 24;58(4): ;2. 2.Jusith AM, Kathryn Bhet/ al/ Mechanisnm of serumcholesterol reduction by oat bran. Hepatology (1994);20 (6), pages ,. 3..Joanne Slavin. Why whole grains are protectrive:biological mechanisms. Proceedings of the Nutrition Society (2003), 62, Dalin R, Hiroyuki N et. al. Study on antihypertensive and antihyperlipidemiceffects of marine algae. Fisheries science(1994) ;60 (1): Amha B. Yoshimichi O. et/. Al. Current knowledge on potential health benefits of spirulina. Journal of Applied Phycology (1993);5 (2):

51 Conclusions The primary objective of lipid-modifying therapy is to reduce CV events Guidelines recommend statins as first-line drugs for lipid-modifying therapy 1 3 Guidelines do not recommend non-statins, except in very limited circumstances 1 3 In patients at high risk or with established CVD, high-intensity statin is recommended rather than addition of a non-statin 1,2 There are no data from RCTs supporting routine use of fibrates, niacin, or omega-3 fatty acids added to statin therapy to further reduce ASCVD 1,2 Addition of ezetimibe to a moderate-intensity statin produces a modest further reduction in ASCVD events after ACS 4 1. Stone NJ, et al. J Am Coll Cardiol 2014;63: ; 2. Rabar S, et al. BMJ 2014; 349:g4356 doi: /bmj.g4356; 3. Fifth Joint Task Force. Eur Heart J 2012;33: ; 4. Cannon C. AHA, Chicago, IL, November ; LBCT.02; 5. Sever PS, et al. Lancet 2003;361: ; 6. Koren MD, et al. J Am Coll Cardiol 2004;44: ; 7. Colhoun HM, et al. Lancet 2004;364: ; 8. LaRosa JC, et al. N Engl J Med 2005;352: ;9. Cannon CP, et al. N Engl J Med 2004;350: ; 10. Newman C, et al. Am J Cardiol 2006;97:61 67