fish oil

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Fish Oils versus Statins?

Catherina Chang Martinez, PhD

Hypercholesterolemia remains a significant risk factor for cardiovascular disease. Management of hypercholesterolemia has entailed the use of statins and non-statins, such as omega-3 fatty acid supplements. Common side effects related to fish oil supplements have included reports of gastrointestinal upset and difficulty in swallowing the fish capsules. Common side effects of statin therapy have included reports of muscle aches, abdominal pain, dizziness, leading to non-adherence and termination of therapy.

The debate on the use of omega-3 fatty acids over statins in the management of blood cholesterol continues, calling for more studies.1  Day 3 of this year’s AHA Scientific Conference highlighted results from recent trials on the use of non-statins and statins in the reduction of cardiovascular events. Here are some takeaways from three studies: the STRENGTH Trial, the OMENI study, and the SAMSON study.

The STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk Patients With Hypertriglyceridemia) trial – This phase III international study evaluated the use of a medication derived from fish oil, containing the omega-3 fatty acids EPA and DHA, more than 13,000 people who had existing heart disease or who were at high risk of heart disease due to other medical conditions.2

  • The medication did not reduce the risk of cardiac events compared to a corn oil-based placebo.
  • Atrial fibrillation, an abnormal heart rhythm, occurred more frequently in participants taking the omega-3 CA medication.

The OMENI (OMega-3 fatty acids in Elderly patients with Myocardial Infarction) trial – a study of more than 1,000 patients in Norway investigated whether adding 1.8 grams of omega-3 fatty acids to standard treatment prevented further cardiovascular events among elderly participants with recent heart attacks.

  • When compared to placebo, omega-3 fatty acids supplement in addition to statin therapy and/or a blood thinner did not reduce the number of cardiac events in the participants.

The SAMSON (The Self-Assessment Method for Statin Side-effects Or Nocebo) Trial – The study, conducted in London, enrolled adults who had previously taken one or more statins but stopped taking them due to side effects. The participants had self-reported symptoms measured throughout a 12-month period of randomly alternating months of statin use, placebo, and no medications.

  • The participants who reported side effects from statins also reported the same side effects when they unknowingly took placebo pills.
  • The side effects appeared to be mostly due to psychological rather than pharmacological effects of statins since the reported symptoms were consistent when taking the placebo.

In the discussion led by Dr. Karol E. Watson, statins remain the mainstay in the reduction of Low-Density Lipoprotein (LDL) and Atherosclerotic cardiovascular disease (ASCVD) risk.  As also recommended in the 2018 AHA/ACC/ AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol, non-statin therapies should be considered in high-risk patients with LDL above thresholds.  Heart-healthy lifestyle changes should be also considered as important measures in the reduction of LDL and triglycerides in patients at risk for ASCVD. The heart-healthy lifestyle should include diet, weight control, and physical activity.4  It will be important to observe the outcome of future studies including the combined effects of heart-healthy lifestyle interventions and non-statin/statin therapy among those considered to be at high risk for ASCVD. Future discussions should also center on intervention studies to address patients’ perceptions of statin/non-statin therapies.

 

 

References

  1. Tummala R, Ghosh RK, Jain V, Devanabanda AR, Bandyopadhyay D, Deedwania P, Aronow WS. Fish Oil and Cardiometabolic Diseases: Recent Updates and Controversies. Am J Med. 2019 Oct;132(10):1153-1159. doi: 10.1016/j.amjmed.2019.04.027. Epub 2019 May 8. PMID: 31077653.
  2. Nicholls SJ, Lincoff AM, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Pedersen TR, Ridker PM, Ray K, Karlson BW, Lundström T, Wolski K, Nissen SE. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. Clin Cardiol. 2018 Oct;41(10):1281-1288. doi: 10.1002/clc.23055. Epub 2018 Sep 28. PMID: 30125052; PMCID: PMC6489732.
  3. Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Trygve Nilsen DW, Tveit A, … Effects of n-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial. Circulation. 2020 Nov. https://doi.org/10.1161/CIRCULATION AHA.120.052209Circulation.
  4. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Jun 25;73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003. Epub 2018 Nov 10. Erratum in: J Am Coll Cardiol. 2019 Jun 25;73(24):3237-3241. PMID: 30423393.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”
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Late-Breaking Highlights: Fish Oils and Frustrations in Lipid Management

Andi Shahu, MD, MHS

It was another exciting day of virtual sessions at #AHA20, led by intriguing findings from a few late-breaking trials!

 

First, the STRENGTH and OMEMI trials added nuance to ongoing discussions about the cardiovascular benefits of fish oils and cardiovascular risk reduction. The REDUCE-IT trial, published in the New England Journal of Medicine (NEJM) in 2019, showed that the highly purified fish oil icosapent ethyl improved cardiovascular outcomes in high-risk participants who had elevated triglycerides despite statin therapy. The STRENGTH and OMEMI trial, however, may temper enthusiasm about the use of fish oils in high-risk patients.

 

The STRENGTH trial randomized 13,000 participants in 22 countries to an omega-3 carboxylic acid or corn oil placebo, with a primary endpoint of cardiovascular death, myocardial infraction, stroke, coronary revascularization or hospitalization for unstable angina. The trial was stopped early due to “futility,” though it still achieved 1580 of the target 1600 endpoints needed for results to be sufficiently powered. Compared with those receiving corn oil placebo, participants in the omega-3 fatty acid group experienced a 19% reduction in triglycerides, 20% reduction in C-reactive protein and 269% increase in plasma eicosapentanoic acid (EPA; icosapent ethyl is a highly purified and stable version of this fatty acid). Despite these biochemical differences, there was no difference in the primary outcome between the two groups, 54 months after randomization. The major adverse outcome, atrial fibrillation, was significantly more likely in the treatment arm.

 

Why do STRENGTH findings differ from those of REDUCE-IT? STRENGTH and REDUCE-IT participants had similar triglyceride levels, but patients in the STRENGTH intervention arm had lower EPA levels than those in the REDUCE-IT treatment arm. Moreover, REDUCE-IT contained more participants with established CAD. Additionally, STRENGTH used a corn oil placebo, while REDUCE-IT used a mineral oil placebo. Corn oil has been shown to have a neutral effect on triglycerides and potentially some cardioprotective effects, while mineral oil may result in unfavorable increases in triglycerides and LDL. Some may argue that the use of mineral oil in REDUCE-IT might have exaggerated the efficacy of icosapent ethyl.

 

The OMEMI trial, meanwhile, randomized 1,000 elderly, 70-82 year old patients (who had had a myocardial infarction [MI] in the 2-8 weeks prior to enrollment) to 1.8 grams of omega-3 fatty acids or a matching corn oil placebo for 2 years. It excluded participants who could not tolerate fatty acids or who had diseases that would impact their ability to survive the 2 year study period. OMEMI found no difference in the composite primary outcome (non-fatal MI, unscheduled revascularization, stroke, hospitalization for heart failure or all-cause death). There were no significant differences in key clinical subgroup analyses, and there was a greater (though not statistically significant) risk of atrial fibrillation in the treatment arm. There was no difference in major bleeding.

 

Taken together, findings from STRENGTH and OMEMI complicate the picture of fish oil utilization and raise further questions about whether the cardiovascular effects of fish oils in some populations are beneficial or neutral. More work needs to be done to better elucidate the effects of fish oils on cardiovascular risk reduction in high-risk patients.

 

Nevertheless, while STRENGTH and OMEMI made waves owing to their potential practice-changing implications, I left the day feeling particularly inspired by the SAMSON trial. This ingeniously designed trial enrolled 60 participants who had stopped taking statins due to symptoms arising within two weeks. Any symptom was eligible if it was severe enough to lead to statin discontinuation in that time span. The most common symptoms were muscle aches, fatigue, and cramps. Participants were given four bottles containing atorvastatin 10 mg tablets, four bottles containing placebo pills and four empty bottles. Each month, they were randomly assigned to take the contents of one of the bottles, in a crossover fashion, with no washout between months. They were asked to rate the severity symptoms they experienced using a mobile phone app. They were also asked 6 months after the conclusion of the trial if they had resumed taking statins. Investigators combined symptom ratings, reporting average symptoms levels during “statin”, “placebo” and “no treatment” months.

 

SAMSON found that the severity of symptoms reported was substantially higher during statin months than during no treatment months; however, this was also true for placebo. Reported symptom levels during statin and placebo months were no different from each other. The nocebo proportion was 0.9; that is, 90% of symptoms reported during statin months were elicited by taking placebo tablets as well. Even more importantly, half of the participants resumed statins again after the trial!

 

SAMSON serves as a lesson to aspiring cardiovascular researchers that even a small study can have a major impact. It displays respect and empathy for the patient experience by acknowledging rather than denying that patients do experience side effects from statins. However, it also strongly suggests that these symptoms may be attributable to the act of taking a pill rather than the medication content of the pill itself. Lastly, SAMSON proves that patients who realize that statin side effects may not actually be specific to statins themselves may be willing to resume taking statins. These findings further support the foundational concept that we as physicians must respect our patients by engaging them in shared decision-making and give patients an opportunity to understand the science, rather than simply telling them what to do.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”
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Can Fish Oil Supplements Help Your Heart? Consumer Discretion is Advised

Huan Wang, PhD

The health benefits of fish oil, particularly omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) have been studied for decades. The key discoveries regarding the beneficial effects of n-3 LC-PUFAs include anti-inflammation, lowering blood lipid levels, anti-thrombotic effects, and possibly anti-arrhythmia (Mason, Libby, and Bhatt 2020). The market size of fish oil supplements expands rapidly in recent years and is estimated to reach USD 4.5 billion by 2027 (REPORTS AND DATA 2020). In many European nations, omega-3-acid ethyl esters have been prescribed to patients to reduce blood lipid levels for at least a decade and they also obtained US FDA approval in 2004 (Bays et al. 2008). However, not all news is encouraging. The findings of anti-arrhythmia effects of fish oil are mixed, with some trials demonstrating beneficial outcomes (Fig 1) and others finding no significant effects (Mozaffarian and Wu 2011; Reiffel and McDonald 2006).

Fig1. Physiological effects of n-3 PUFA that might influence cardiovascular risk.

The results of REDUCE-IT clinical trial published in 2019 promised a bright future for cardiovascular risk reduction using omega-3 fatty acids (Bhatt et al. 2019). In AHA 2020 late-breaking science session: “Fish Oil, Fancy Drugs, and Frustrations in Lipid Management”, Drs. A Michael Lincoff, Are Annesoenn Kalstad and Alberico Catapano presented compelling evidence on surprising neutral effects with omega-3 carboxylic acids supplement in two clinical trials. These controversial results provide an interesting argument on whether or not to take fish oil supplements for cardiovascular health protection.

Dr. Lincoff presented recent results about the effects of high-dose omega-3 fatty acids from the STRENGTH clinical trial (Nicholls et al. 2020). Despite moderate improvements in the blood lipid levels, patients with omega-3 supplementation have significantly increased risks of atrial fibrillation. The net outcome of omega-3 fatty acid supplementation is not beneficial. One of the possible explanations for this controversial result is using corn oil as a control condition instead of mineral oil–the control treatment in REDUCE-IT trial. Mineral oil treatment caused adverse effects, and corn oil had neutral effects on patients. Dr. Kalstad shared results from another clinical trial which showed similar findings (the OMEMI clinical trial) (Kalstad et al., n.d.). The overall effects of omega-3 fatty acids were neutral with an increased risk of atrial fibrillation. To bring together what we have learned, a summary was presented by Dr. Catapano to further evaluated the STRENGTH and OMEMI clinical trials. He thoughtfully discussed the discrepancies in REDUCE-IT, STRENGTH, and OMEMI trials, and provided several explanations such as the biochemical nature of DHA and EPA, different control conditions, and treatment dosage discrepancies.

Regardless of the discrepancies between STRENGTH and OMEMI trials, one thing is common, the increased risk of atrial fibrillation. So, if you are elderly with high cardiovascular risk, please think twice and monitor your response closely when taking fish oil as a dietary supplement. The frustrating results from STRENGTH and OMEMI trials don’t necessarily negate the beneficial effects in other aspects of the physiological benefits of fish oil (Fig 1) (Mozaffarian and Wu 2011). More research studies are needed in the future to better understand the effects and mechanisms of fish oil supplementation.

Reference

REPORTS AND DATA. 2020. Omega-3 Market To Reach USD 4.50 Billion By 2027 | CAGR: 7.2% | Reports And Data. Aug 10. https://www.prnewswire.com/news-releases/omega-3-market-to-reach-usd-4-50-billion-by-2027–cagr-7-2–reports-and-data-301109147.html.

Bays, Harold E., Ann P. Tighe, Richard Sadovsky, and Michael H. Davidson. 2008. “Prescription Omega-3 Fatty Acids and Their Lipid Effects: Physiologic Mechanisms of Action and Clinical Implications.” Expert Review of Cardiovascular Therapy. https://doi.org/10.1586/14779072.6.3.391.

Bhatt, Deepak L., P. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Steven B. Ketchum, Ralph T. Doyle, et al. 2019. “Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.” New England Journal of Medicine. https://doi.org/10.1056/nejmoa1812792.

Kalstad, Are Annesønn, Peder Langeland Myhre, Kristian Laake, Sjur Hansen Tveit, Erik Berg Schmidt, Pal Smith, Dennis Winston Trygve Nilsen, et al. n.d. “Effects of N-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial.” Circulation 0 (0). https://doi.org/10.1161/CIRCULATIONAHA.120.052209.

Mason, R. Preston, Peter Libby, and Deepak L. Bhatt. 2020. “Emerging Mechanisms of Cardiovascular Protection for the Omega-3 Fatty Acid Eicosapentaenoic Acid.” Arteriosclerosis, Thrombosis, and Vascular Biology. https://doi.org/10.1161/ATVBAHA.119.313286.

Mozaffarian, Dariush, and Jason H.Y. Wu. 2011. “Omega-3 Fatty Acids and Cardiovascular Disease: Effects on Risk Factors, Molecular Pathways, and Clinical Events.” Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2011.06.063.

Nicholls, Stephen J, A Michael Lincoff, Michelle Garcia, Dianna Bash, Christie M Ballantyne, Philip J Barter, Michael H Davidson, et al. 2020. “Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.” JAMA, November. https://doi.org/10.1001/jama.2020.22258.

Reiffel, James A., and Arline McDonald. 2006. “Antiarrhythmic Effects of Omega-3 Fatty Acids.” American Journal of Cardiology. https://doi.org/10.1016/j.amjcard.2005.12.027.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”