Fish oil and cardiovascular science supporting global regulatory efforts

Fish oil and cardiovascular science supporting global regulatory efforts Dr Harry Rice Your essential event for networking and information

Fish Oil and Cardiovascular Science Supporting Global Regulatory Efforts Harry B. Rice, PhD Vice-President Regulatory & Scientific Affairs 24 October 2017

Reactive Versus Proactive For many years, GOED reacted to a wave of neutral studies that received widespread media attention. While we still react when necessary, we have shifted to being more proactive.

GOED Co-Authored or Sponsored Publications Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. Epub ahead of print 2017 Aug 2. Bannenberg G, Mallon C, Edwards H, Yeadon D, Yan K, Johnson H, Ismail A. Omega-3 Long-Chain Polyunsaturated Fatty Acid Content and Oxidation State of Fish Oil Supplements in New Zealand. Sci Rep. 2017 May 3;7(1):1488. doi: 10.1038/s41598-017-01470-4. Rice HB, Bannenberg G, Harwood M, Ismail A. Determining the potential effects of oxidized fish oils in pregnant women requires a more systematic approach. Am J Physiol Regul Integr Comp Physiol. 2017; 312(2):R263. Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC. A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 2017 Jan;92(1):15-29. Ismail A, Bannenberg G, Rice HB, Schutt E, MacKay D. Oxidation in EPA- and DHA-rich oils: an overview. Lipid Technol. 2016 28:55-59. http://onlinelibrary.wiley.com/doi/10.1002/lite.201600013/epdf Rice HB, Bernasconi A, Maki KC, Harris WS, von Schacky C, Calder PC. Conducting omega-3 clinical trials with cardiovascular outcomes: Proceedings of a workshop held at ISSFAL 2014. Prostaglandins Leukot Essent Fatty Acids. 2016; 107:30-42. Alexander DD, Bassett JK, Weed DL, Barrett EC, Watson H, Harris W. Meta-Analysis of Long-Chain Omega-3 Polyunsaturated Fatty Acids (LCω-3PUFA) and Prostate Cancer. Nutr Cancer. 2015;67(4):543-54. Miller PE, Van Elswyk M, Alexander DD. Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am J Hypertens. 2014;27(7):885-96.

Blood Pressure

Blood Pressure (BP) Meta-Analysis Systolic Model # Data Points WGMD Lower 95% CI Upper 95% CI All 93-1.52-2.25-0.79 Hypertensives 15-4.51-6.12-2.83 Normotensives 73-1.25-2.05-0.46 Diastolic Model # Data Points WGMD Lower 95% CI Upper 95% CI All 92-0.99-1.54-0.44 Hypertensives 15-3.05-4.35-1.74 Normotensives 72-0.62-1.22-0.02 Miller PE Van Elswyk M and Alexander DD (2014). Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am J Hypertens. 27:885-896. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4054797/

BP Meta-Analysis Summary and Conclusions Convincing scientific evidence indicates that EPA+DHA help lower BP in general population, with comparable reductions to those achieved with other diet and lifestyle interventions (e.g. reducing dietary sodium -3.6 mm Hg; increasing physical activity -4.6 mm Hg; decreasing alcohol consumption -3.8 mm Hg). 2 g/d EPA+DHA reduced both SBP and DBP, with the strongest benefits observed among hypertensive individuals who were not on antihypertensive medication. A lower dose (1-2 g/d) reduced SBP but not DBP. From a clinical and public health perspective, provision of EPA+DHA may lower BP and ultimately reduce the incidence of associated chronic diseases. Miller PE Van Elswyk M and Alexander DD (2014). Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am J Hypertens. 27:885-896. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4054797/

Leveraging BP Meta-Analysis In the U.S., like many countries, health claims need to be approved/authorized. It has been over 13 years since the FDA announced that it would allow the use of Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease on foods and dietary supplements with EPA and DHA. In 2004, when the FDA responded to the health claim petitions, high blood pressure was recognized as a surrogate endpoint for coronary heart disease (CHD). GOED submitted its initial health claim petition in November 2013. Miller PE Van Elswyk M and Alexander DD (2014). Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am J Hypertens. 27:885-896. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4054797/

Coronary Heart Disease (CHD)

CHD Meta-Analysis RCTs Model Studies (n) RR 95% CI CHD Risk all studies 18 0.94 0.85 1.05 CHD Risk LDL > 130 mg/dl 5 0.86 0.76 0.98 CHD Risk TGs > 150 mg/dl 6 0.84 0.72 0.98 Coronary Death all studies 5 0.81 0.65 1.00 Coronary Death (2 prevention) 4 0.80 0.64 0.99 Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC (2017). A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 92:15-29. http://www.mayoclinicproceedings.org/article/s0025-6196(16)30681-4/fulltext

CHD Meta-Analysis Prospective Cohorts Model Studies (n) RR 95% CI CHD Risk 17 0.82 0.74-0.98 Fatal Events 14 0.77 0.66-.0.90 Coronary Death 9 0.82 0.69-0.98 Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC (2017). A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 92:15-29. http://www.mayoclinicproceedings.org/article/s0025-6196(16)30681-4/fulltext

CHD Meta-Analysis Summary and Conclusions To date, this is the most comprehensive quantitative assessment of the relationship between EPA+DHA intake and CHD risk. Study inclusion criteria were specific to CHD. Previous meta-analyses included a mixture of cardiovascular events. Results are consistent with previous meta-analyses, and consistent between RCT and prospective cohort studies. Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC (2017). A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 92:15-29. http://www.mayoclinicproceedings.org/article/s0025-6196(16)30681-4/fulltext

Cardiac Death

Cardiac Death Meta-Analysis The outcome for which both the observational evidence of EPA+DHA intake or status and RCTs of supplementation appears to demonstrate the most consistent association is cardiac death. Until now, no meta-analysis had considered cardiac death as a primary outcome. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. Epub ahead of print 2017 Aug 2. http://www.lipidjournal.com/article/s1933-2874(17)30395-1/fulltext

Cardiac Death Meta-Analysis Model SRRE Lower 95% CI Upper 95% CI All Subjects 0.920 0.863 0.981 >1 g/day EPA+DHA 0.709 0.508 0.990 LDL > 130 mg/dl 0.828 0.725 0.946 TGs > 150 mg/dl 0.826 0.723 0.944 Seconary prevention 0870 0.801 0.945 <40% statin use 0.871 0.801 0.948 Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. Epub ahead of print 2017 Aug 2. http://www.lipidjournal.com/article/s1933-2874(17)30395-1/fulltext

Cardiac Death Meta-Analysis Summary & Conclusions EPA+DHA supplementation is associated with a statistically significant reduction in risk of cardiac death. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. Epub ahead of print 2017 Aug 2. http://www.lipidjournal.com/article/s1933-2874(17)30395-1/fulltext

Results of Past Cardiac Death Meta-Analyses Meta-Analysis # Studies CHD Death Risk Reduction Wen et al, 2014 14 12% Casula et al, 2013 11 32% Trikalinos et al, 2012 14 11% Kotwal et al, 2012 20 14% Rizos et al, 2012 20 9% Kwak et al, 2012 14 9% Delgado-Lista et al, 2012 21 9% Chen et al, 2011 10 19% Marik et al, 2009 11 13% Zhao et al, 2009 8 29% Leon et al, 2008 11 20% Wang et al, 2006 4 35%

Leveraging CHD & Cardiac Death Meta- Analyses to Support Dietary Reference Intake (DRI) Work being considered in Canada and the U.S. Chronic disease risk reduction, not essentiality Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC (2017). A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 92:15-29. http://www.mayoclinicproceedings.org/article/s0025-6196(16)30681-4/fulltext Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. Epub ahead of print 2017 Aug 2. http://www.lipidjournal.com/article/s1933-2874(17)30395-1/fulltext

Leveraging CHD & Cardiac Death Meta-Analyses to Support Codex Work Codex is a standard setting, not regulatory, body, but many governments adopt CAC standards as regulation. In 2015, Codex approved new work to establish a Nutrient Reference Value Non-Communicable Disease (NRV-NCD) for EPA+DHA. The WHO agreed to investigate the relationship between EPA+DHA and the CHD mortality. Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC (2017). A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 92:15-29. http://www.mayoclinicproceedings.org/article/s0025-6196(16)30681-4/fulltext Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. Epub ahead of print 2017 Aug 2. http://www.lipidjournal.com/article/s1933-2874(17)30395-1/fulltext

WHO NUGAG Results RCTs #Studies N RR 95% CI EPA+DHA on CHD deaths 21 73,491 0.93 0.79-1.09 EPA+DHA on CHD deaths, omitting studies only reporting cardiac death 21 65,325 0.83 0.74-0.94 Prospective Cohort Studies #Studies N RR 95% CI Fatal CHD 9 5,904 0.81 0.68 to 0.97

WHO NUGAG Results While NUGAG positions their findings (i.e. RCTs) in a manner that would suggest relevant analyses result only in null findings, the results clearly demonstrate an association between EPA+DHA intake and reduced risk of CHD mortality from observational trials, and confirms that the effect can be observed in RCTs for particular pre-planned subgroup analyses, e.g. coronary death. GOED s commissioned meta-analyses compliment NUGAG s efforts. Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC (2017). A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 92:15-29. http://www.mayoclinicproceedings.org/article/s0025-6196(16)30681-4/fulltext Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. Epub ahead of print 2017 Aug 2. http://www.lipidjournal.com/article/s1933-2874(17)30395-1/fulltext

RCT Research in Progress

Reduction of Cardiovascular Events With EPA - Intervention Trial (REDUCE-IT) Objective: to evaluate whether Vascepa (icosapent ethyl), combined with a statin therapy, is superior to statin therapy alone, when used as a prevention in reducing long-term cardiovascular events in high-risk patients with mixed dyslipidemia Estimated Completion Date: December 2017 Source: https://clinicaltrials.gov/ct2/show/nct01492361

A Study of Cardiovascular Events in Diabetes (ASCEND) Objective: to determine aspirin versus placebo and/or supplementation with 1 gram daily omega-3 fatty acids or placebo prevents "serious vascular events" in diabetic subjects not known to have occlusive arterial disease Timeframe: results expected mid-2018 Concern: Benefits may not be demonstrated because dosage is relatively low Source: https://clinicaltrials.gov/ct2/show/nct00135226

VITamin D and OmegA-3 Trial (VITAL) Objective: to determine if taking daily dietary supplements of vitamin D 3 (2000 IU) or Omacor (omega-3 fatty acid ethyl esters), 1 g/d, reduce the risk for developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses? Timeframe: initial results expected 2018 Concern: Benefits may not be demonstrated because dosage is relatively low and subjects are at low average risk Sources: https://www.vitalstudy.org/ https://clinicaltrials.gov/ct2/show/nct01169259

Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH) Objective: to determine the efficacy of EPANOVA on cardiovascular outcomes in combination with statin therapy in patients with mixed dyslipidemia at increased risk of CVD; primary outcome is time to 1 st occurrence of any component of the composite endpoint (includes cardiovascular death) Estimated Completion Date: November 2019 Source: https://clinicaltrials.gov/ct2/show/nct02104817

Neutral Results Can Be Explained Bowen KJ, Harris WS, Kris-Etherton PM. Omega-3 Fatty Acids and Cardiovascular Disease: Are There Benefits? Curr Treat Options Cardiovasc Med. 2016;18:69. Harris WS. Are n-3 fatty acids still cardioprotective? Curr Opin Clin Nutr Metab Care. 2013;16:141-9. James MJ, Sullivan TR, Metcalf RG, Cleland LG. Pitfalls in the use of randomised controlled trials for fish oil studies with cardiac patients. Br J Nutr. 2014;112:812-20. Marchioli R, Levantesi G. n-3 PUFAs in cardiovascular disease. Int J Cardiol. 2013;170:S33-8. Rice HB, Bernasconi A, Maki KC, Harris WS, von Schacky C, Calder PC. Conducting omega-3 clinical trials with cardiovascular outcomes: Proceedings of a workshop held at ISSFAL 2014. Prostaglandins Leukot Essent Fatty Acids. 2016;107:30-42. von Schacky C. Omega-3 fatty acids in cardiovascular disease--an uphill battle. Prostaglandins Leukot Essent Fatty Acids. 2015;92:41-7. Wu JH, Mozaffarian D. omega-3 fatty acids, atherosclerosis progression and cardiovascular outcomes in recent trials: new pieces in a complex puzzle. Heart. 2014;100:530-3.

Questions? harry@goedomega3.com