Reducing cardiovascular disease risk with omega-3s

Cardiovascular disease (CVD) remains the number one killer of Americans, and by 2030, nearly 44 percent of U.S. adults will have some form of the disease. [1] It has long been recognized that consumption of omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can help reduce the risk of CVD. [2,3]  Indeed, joint recommendations from the American College of Cardiology (ACC) and the American Heart Association (AHA), [4] and the 2015-2020 Dietary Guidelines for Americans [5] advise dietary patterns that include fish and/or an increased intake of EPA and DHA.

Reducing CVD Risk: Recent Findings

Numerous clinical studies and meta-analyses link intake of omega-3 fatty acids with reduced risks for CVD-related events and death. [6,7,8,9,10,11,12,13]  The most comprehensive assessment of the relationship of EPA and DHA (since both are typically found in fish, fish oil, and algal oil supplements) and coronary heart disease (CHD) was recently reported in the Mayo Clinic Proceedings . [14]  Drawing from more than 3,800 studies published from 1947 to 2015, the researchers identified 18 randomized controlled trials (RCTs) and 16 prospective cohort studies (PCSs) that reported CHD outcomes (e.g., myocardial infarction, angina, sudden cardiac death and coronary death) and met other criteria. The two groups of studies included approximately 93,000 and 732,000 participants, respectively.

Using meta-analysis models, the investigators calculated summary relative risk estimates (SRREs) for CHD outcomes. For the RCT analysis, they compared the risk of CHD events for intervention-group participants consuming EPA and DHA, primarily from supplements (a few RCTs used fatty fish), compared to control-group participants who did not; for the PCS analysis, they compared the risk of CHD events associated with high vs. low intakes of EPA and DHA from all sources, including diet and supplementation. The analysis showed EPA and DHA reduced the risk for CHD events, especially in people with high serum triglycerides or LDL cholesterol (see Figure).

“The 6 percent reduced risk among RCTs, coupled with an 18 percent risk reduction in prospective cohort studies — which tend to include more real-life dietary scenarios over longer periods — tell a compelling story about the importance of EPA and DHA omega-3s for cardiovascular health,” said lead author Dominik Alexander, PhD, MSPH, Principal Epidemiologist for EpidStat, Ann Arbor, MI. [15] An accompanying editorial in Mayo Clinic Proceedings also acknowledged the importance of the findings. [16]

Scaling Up Fish Intake

On average, Americans 19 years and older consume an average of only 23 mg EPA and 63 mg DHA per day, [17]  far below the 250 mg omega-3s per day recommended in the Dietary Guidelines for Americans. [18] Moreover, about 95.7 percent of Americans have plasma omega-3s below the concentration associated with cardiovascular protection. [19] Knowing the high prevalence of this nutrient gap should encourage practitioners to advise their patients on ways to increase omega-3 intake to recommended levels.

Dietary recommendations for omega-3 intake differ among local and regional authoritative bodies. In the US, the 2015-2020 Dietary Guidelines for Americans advises consuming about 8 ounces per week of a variety of seafood to obtain an average of approximately 250 mg per day of EPA and DHA, an amount associated with reduced cardiac deaths in people with and without preexisting CVD. [20]  The joint AHA/ACC guideline for secondary prevention recommends 1 g a day of omega-3 fatty acids from fish or fish oil capsules for CVD prevention and risk reduction in patients with coronary and other atherosclerotic vascular disease. [21]  For patients who need to lower triglyceride levels, the AHA recommends 2 to 4 g of EPA and DHA per day. [22]  Based on these recommendations, physicians should advise patients to achieve the intake of omega-3s appropriate for their health needs through simple measures, such as incorporating fish rich in omega-3s as part of a heart-healthy diet and/or taking a dietary supplement that provides adequate amounts of EPA and DHA.

To learn more about omega-3s and Know Your Ω™, an educational campaign by DSM Nutritional Products, visit www.KnowYourO.com or visit booth #1717 at the ACP Internal Medicine Meeting in San Diego, CA March 30 – April 1. The Know Your Ω™ website has helpful tools for both physicians and patients, sharing more information on how to best recommend omega-3 EPA and DHA and incorporate them into a balanced lifestyle.

                                                                                                                                                      

References

[1]Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016 Jan 26; 133(4):e38-e360. doi: 10.1161/CIR.0000000000000366.

[2]Mozaffarian D, Lemaitre Rn, King IB et al. Plasma phospholipid long-chain ?-3 fatty acids and total and cause-specific mortality in   older adults: a cohort study. Ann Intern Med. 2013;158:515-25. doi: 10.7326/0003-4819-158-7-201304020-00003.

[3]Krauss RM, Eckel RH, Howard B et al. AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the  Nutrition Committee of the American Heart Association. Circulation. 2000;102:2284–99. doi: 10.1161/01.CIR.102.18.2284.

[4]Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S76-99. doi: 10.1161/01.cir.0000437740.48606.d1.

[5]U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015. Available at: http://health.gov/dietaryguidelines/2015/guidelines/chapter-2/a-closer-look-at-current-intakes-and-recommended-shifts/.

[6]Delgado-Lista J, Perez-Martinez P, Lopez-Miranda J, Perez-Jimenez F. Long chain omega-3 fatty acids and cardiovascular disease: a systematic review. Br J Nutr. 2012;107(Suppl 2):S201-S213. doi: 10.1017/S0007114512001596.

[7]Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2012;5(6):808-818. doi: 10.1161/CIRCOUTCOMES.112.966168.

[8]Kwak SM, Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group. Ef?cacy of omega-3 fatty acid supplements  eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694. doi: 10.1001/archinternmed.2012.262.

[9]Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-1033. doi: 10.1001/2012.jama.11374.

[10]Chen Q, Cheng LQ, Xiao TH, et al. Effects of omega-3 fatty acid for sudden cardiac death prevention in patients with cardiovascular disease: a contemporary meta-analysis of randomized, controlled trials. Cardiovasc Drugs Ther. 2011; 25(3):259-265. doi: 10.1007/s10557-011-6306-8.

[11]Wen YT, Dai JH, Gao Q. Effects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease: a meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2014;24(5):470-475. doi: 10.1016/j.numecd.2013.12.004.

[12]Casula M, Soranna D, Catapano AL, Corrao G. Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: a meta-analysis of randomized, placebo controlled trials [corrected]. Atheroscler Suppl. 2013;14(2):243-251. doi: 10.1016/S1567-5688(13)70005-9.

[13]Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit  cardiovascular disease outcomes in primary- and secondary prevention studies: a systematic review. Am J Clin Nutr. 2006; 84(1):5-17. Available at: http://ajcn.nutrition.org/content/84/1/5.long.

[14]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. doi: 10.1016/j.mayocp.2016.10.018. doi: 10.1016/j.mayocp.2016.10.018.

[15]Global Organization for EPA and DHA Omega-3 (GOED). Press Release. New Study Finds EPA and DHA Omega-3s Lower Risk of Coronary Heart Disease. January 3, 2017. Available at: http://www.prnewswire.com/news-releases/new-study-finds-epa-and-dha-omega-3s-lower-risk-of-coronary-heart-disease-300384474.html.  

[16]O’Keefe JH, Jacob D, Lavie CJ. Omega-3 Fatty Acid Therapy: The Tide Turns for a Fish Story. Mayo Clin Proc. 2017 Jan;92(1):1-3. doi: 10.1016/j.mayocp.2016.11.008.

[17]Papanikolaou Y, Brooks J, Reider C, Fulgoni VL. U.S adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003-2008. Nutrition Journal. 2014;13:31. doi: 10.1186/1475-2891-13-31. doi: 10.1186/1475-2891-13-31.

[18]U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015. Available at: http://health.gov/dietaryguidelines/2015/guidelines/chapter-2/a-closer-look-at-current-intakes-and-recommended-shifts/.

[19]Murphy RA, Yu EA, Ciappio ED, Mehta S, McBurney MI. Suboptimal Plasma Long Chain n-3 Concentrations are Common among Adults in the United States, NHANES 2003–2004. Nutrients. 2015;7:10282-9. doi: 10.3390/nu7125534.

[20]U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015. Available at: http://health.gov/dietaryguidelines/2015/guidelines/chapter-2/a-closer-look-at-current-intakes-and-recommended-shifts/.

[21]Smith SC Jr, Benjamin EJ, Bonow RO et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2011 Update: A Guideline From the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124:2458-73. doi: 10.1161/CIR.0b013e318235eb4d.

[22]Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-57. doi: 10.1161/01.CIR.0000038493.65177.94.

BIO Investor Forum Interview with Regado Biosciences

BIO is very excited to be hosting the BIO Investor Forum next week in San Francisco. The BIO One-on-One Partnering System has already scheduled over 640 meetings, which is a 50% increase over last year. Investor and company registration is also trending higher, including the number of presenting companies. The One-on-One Compass has been profiling these companies slated to present at the conference, and recently spoke to the CEO of Regado Biosciences, David Mazzo. Please read below to learn more about what’s ahead for this newly public company.

regado

Tell us about Regado Biosciences.

Regado is a public (NASDAQ: RGDO) biopharmaceutical company focused on the development of novel, first-in-class, actively controllable antithrombotic drug systems for acute (hospital) and sub-acute (hospital and physician’s office) cardiovascular indications. We are pioneering the discovery and development of two-component drug systems consisting of a therapeutic aptamer and its specific active control agent. Our lead program, REG1, just began a global phase 3 trial in the indication of PCI (Percutaneous Coronary Intervention).

REG1 is Regado’s lead drug candidate. Can you describe REG1?

REG1 is an actively controllable anticoagulant system targeting coagulation Factor IXa for use in patients with a wide variety of coronary syndromes undergoing a percutaneous coronary intervention (PCI), a hospital-based procedure used to mechanically open or widen obstructed coronary arteries.

REG1 consists of pegnivacogin, an anticoagulant aptamer, and its complementary active control agent, anivamersen. Pegnivacogin is a highly specific and potent Factor IXa inhibitor. Pegnivacogin is pegylated and, as such, has a very long half-life (>24 hours). Anivamersen, the active control agent, is the Watson-Crick base pair complement of a 15 nucleotide snippet of pegnivacogin. It is a single-stranded oligonucleotide (a biological polymer consisting of a relatively small number of nucleotides chemically bound in a linear sequence that forms a chain-like structure) and, importantly, has no pharmacologic activity other than to bind to and modulate the therapeutic effect of pegnivacogin. Because anivamersen is not pegylated, it has a very short (<5 minutes) half-life by design.

Both pegnivacogin and anivamersen are administered by intravenous bolus injection using weight-based dosing. As a result, the onset of action of both agents is extremely rapid. By adjusting the dose of anivamersen relative to pegnivacogin, the anticoagulant effect of pegnivacogin can be precisely and rapidly controlled or eliminated.

The combination of the choice of Factor IXa as the target, the specificity of pegnivacogin and anivamersen and the dose of each agent administered allows physicians to achieve unprecedented levels of anticoagulation in patients that would be practically unattainable or unsafe to use with existing anticoagulants lacking active, specific control.

Can you discuss details of the REGULATE-PCI clinical trial and where it is in the clinic?

Last month, we announced the enrollment of the first patient in REGULATE-PCI clinical trial, our Phase 3, PROBE design (Prospective, Randomized, Open-label, Blinded-Endpoint) superiority study comparing the effects of Regado’s REG1 to bivalirudin in patients undergoing PCI electively or for the treatment of unstable angina or non-ST elevated myocardial infarction (N-STEMI).

REGULATE-PCI calls for the enrollment of 13,200 patients evenly divided between REG1 and the comparator, bivalirudin. The trial is expected to enroll over two years. Significantly, there are 3 interim analyses prescribed in the study design calling for safety evaluations after 1000 patients enrolled and after 25% enrollment has been achieved and a safety and efficacy analysis after 50% enrollment is attained. All three interim analyses are planned for 2014 (2Q14, 3Q14 and 4Q14, respectively). The primary endpoint of the trial is efficacy compared to bivalrudin based on a composite of death, nonfatal myocardial infarction, nonfatal stroke and urgent target lesion revascularization through day three. The principal secondary endpoint is safety compared to bivalrudin as measured by major bleeding events through day three. The trial is powered to show superiority in efficacy and non-inferiority or superiority in safety against bivalirudin. If successful, REGULATE-PCI will become the cornerstone of Regado’s international new drug applications, planned for filing in early 2016.

Why is there such a significant need for this new technology?

PCI procedures involve a significant risk of ischemic events, including death, stroke, myocardial infarction and the need for repeat revascularization of the artery. Because of this risk, powerful anticoagulant drugs are administered prior to and throughout the PCI procedure. However, anticoagulants create a significant risk of major bleeding events. As a result, interventional cardiologists are forced to make a compromising medical decision because they lack the means to simultaneously reduce the risks of ischemic and major bleeding events. Additionally, PCI procedure costs are a major expenditure for the health care system and overall PCI cost reductions (i.e., pharmacoeconomic benefits) contributed by any new anticoagulant are highly desirable.

REG1 is the first and only anticoagulant to demonstrate the ability to reduce both ischemic and major bleeding events in a clinical trial for PCI (the randomized, partially blinded, 640 subject Phase 2b “RADAR” trial) while providing pharmacoeconomic benefits.

Why should investors closely watch Regado?

REG1 has performed consistently throughout development and is expected to perform similarly in phase 3. Additionally, because of the nature of the design of REGULATE-PCI, including three key near-term value inflection points in the planned interim analyses in 2014, the trial is continuously de-risking. This trial, if successful, will result in a REG1product profile that includes superior efficacy and non-inferior or superior safety as well as significant savings to the hospital and healthcare systems. With this profile, REG1 is expected to become the new standard of care and ultimately, market leader in anticoagulant therapy in PCI.

Regado is presenting Tuesday, 10/8 at 10:30am. We look forward to seeing them at the conference! Follow our hashtag, #BIF13 for updates!

*Company snapshots and interviews are meant to be previews of presentations given at BIO events by way of answering set questions. BIO does not substantiate or validate any claims mentioned in company snapshots or presentations.