Omega-3 Polyunsaturated Fatty Acids for the Prevention of Cardiovascular Disease: Do Formulation, Dosage & Comparator Matter?

Abstract

Multiple trials over the past two decades testing omega-3 polyunsaturated fatty acids (PUFAs), containing eicosapentaenoic acid (EPA) and or docosahexaenoic acid (DHA), have shown substantial benefits for reducing major coronary heart disease (CHD) events, all-cause mortality, cardiovascular (CV) death, sudden cardiac death (SCD), and stroke. However, recent trials testing omega-3s have generally failed to confirm these benefits. While increased fish and fish oil intake among the general population, increased use of optimal medical therapy (including statins, aspirin, and modern antihypertensive medications) probably make it more challenging for fish oil supplementation to show additional benefits, there might be further explanations in the formulation, dosage, and comparator used in these recent omega-3 trials.

Olive oil should not be considered a placebo as it has anti-oxidative, anti-inflammatory and anti-platelet effects.

Introduction

Past trials testing omega-3 polyunsaturated fatty acids (PUFAs) have shown dramatic benefit for reducing all-cause mortality, cardiovascular (CV) mortality, sudden cardiac death (SCD), major coronary heart disease (CHD) events and even stroke.^1–4 However, recent trials have failed to confirm similar benefits. We explore several explanations that could have affected the outcomes of the recently performed omega-3 PUFAs trials.

Olive Oil

Despite the fact that prior omega-3 PUFA trials showed benefit, these past trials did not test omega-3 PUFAs against an olive oil (oleic acid) comparator, whereas at least four of the five recently published omega-3 PUFA trials have used olive oil as the “placebo”.^5–9 Indeed, omega-3 PUFAs compared to olive oil in the Risk and Prevention Study did not reduce CV mortality or morbidity (although benefit was seen in the 4,818 women).⁹ Another trial testing a similar population as the Risk and Prevention study was the Diet and Omega-3 Intervention Trial (DOIT), a three-year placebo-controlled trial in 563 elderly men at high-risk of CV disease, which showed that 2.4 grams (g) of omega-3 PUFAs (49% EPA and 35% DHA also containing 3.5 mg tocopherols/g) lead to a 47% reduction in all-cause mortality (adjusted HR 0.53, 95% confidence interval: 0.27–1.04, p = 0.063).¹⁰ However, DOIT compared omega-3s to corn oil, whereas the Risk and Prevention Study comparator was olive oil. As omega-6 PUFAs (such as corn oil) are highly prevalent in many societies, whereas monounsaturated fatty acids (MUFAs) (such as oleic acid) are not in great supply, it is unlikely that a corn oil supplement would be considered an “active-comparator.” The “placebo” used in Outcome Reduction with Initial Glargine Intervention (ORIGIN) ORIGIN, Effect of Omega 3-Fatty Acids on the Reduction of SCD After Myocardial Infarction (OMEGA) and Study of Omega-3 Fatty Acids and Coronary Mortality (Alpha Omega) was also olive oil, the primary source of fat in the Mediterranean diet, which is associated with a lower risk for CV disease and mortality.¹¹ Olive oil has been shown to improve oxidized low-density lipoprotein (LDL), inflammation, endothelial dysfunction, blood pressure, and thrombosis and to lower glucose and insulin levels in type 2 diabetic patients.¹¹ Additionally, the traditional Mediterranean diet, with olive oil being one of the daily staples, has been found in a recent large randomized trial to significantly improve long-term CV health (See Table 1).¹²

Table 1.

Reasons Why Olive Oil is Not a Suitable Placebo in Fish Oil Trials¹¹, ¹²

Inhibits oxidized LDL formation Improves Inflammation Improves endothelial dysfunction Improves blood pressure Improves thrombosis Improves glucose and insulin levels in type 2 diabetic patients Has a dose-response curve indicating a reduction in the risk of MI A recent large randomized trial has shown that olive oil (as part of the Mediterranean Diet) was found to significantly improve long-term cardio-vascular health

Thus, the broad range of anti-atherogenic effects of olive oil could easily offset any potential benefits of omega-3 PUFAs. Moreover, the California and World Olive Oil statistics estimates that the average intake of olive oil in the United States is approximately 1.6 g/day.¹³ Thus, it can be presumed that the “placebo” group in the recent fish oil trials was receiving around 2.6 g/day of olive oil vs. 1.6 g/day in the fish oil group. The dose-response curve for olive oil has indicated that from 6.1 g/day to 13.6 g/day there is a 55–61% reduction in myocardial infarction (MI) (odds ratio [OR] 0.39 [0.15–1.00] and 0.45 [0.16–1.25]).¹⁴ Thus, there is an approximate 7.3–8.1% reduction in MI for each gram increase in olive oil ingested from 6.1–13.6 g/day. However, the dose-response curve is probably steeper (more benefit derived) when the intake is closer to zero. This has been shown with fish oil in the primary prevention of CHD death and SCD.¹⁵ Mozaffarian et al. indicated that the steepest dose-response curve for omega-3 PUFAs was from 0 to 250 mg/day of EPA + DHA, with a smaller additional benefit from 250 mg/day to 500 mg/day and virtually no additional benefit beyond 500 mg/day of omega-3 intake.¹⁵ Thus, considering that the intake of olive oil in past “placebo” groups probably increased from 1.6 g to 2.6 g, a much steeper dose response is expected compared to the benefit/g of increased olive oil from 6.1 g/day to 13.6 g/day. Thus, at a minimum, the olive oil group (“placebo” group) in recent omega-3 PUFAs trials could easily have derived an additional 8% reduction in MI (this being the lowest estimation of benefit), although habitual intake of oleic acid in men from the United Kingdom has been estimated to average around 30 g/day.¹⁶

By definition, a placebo is a substance with no therapeutic effect. It is obvious that the use of olive oil as a placebo in fish oil trials may carry a therapeutic benefit that could nullify any benefit of omega-3 PUFAs. Considering that just 250 mg of omega-3 PUFAs has been shown to reduce SCD, it is no stretch of the imagination that 1 gram of oleic acid may confer cardio protection. Thus, the use of olive oil as a “placebo” in omega-3 PUFAs trials could be a contributor to the recent neutrality seen. It is our belief that olive oil should no longer be incorporated into “placebo-controlled trials” but should be thought of as an “active-comparator.” Indeed, just 12.5 mg of a hydroxytyrosol-rich extract from water obtained from freshly ground olives has been shown to cause a significant 46% decrease in serum thromboxaneB₂ (TXB₂) production after blood clotting (P < 0.02).¹⁷ Thus, even at low doses, olive oil seems to possess antiplatelet properties. Additionally, olive oil has been shown to reduce LDL susceptibility to oxidation in humans, a process critical in the development of atherosclerosis.¹⁸ While these effects may be partially be explained by the substitution of olive oil for other types of fats (such as PUFAs, saturated fats, and transfats) they may also be derived from the plethora of active compounds found within olive oil (polyphenol constituents, i.e. hydroxytirosol and oleuropein) providing an antioxidant effect.

Formulation

Omega-3 PUFAs in nature are bound to triglycerides or phospholipids when obtained from natural sources such as fish or krill, respectively, whereas prescription omega-3 PUFAs (such as Lovaza^® formerly known as Omacor^®) provide omega-3s in the ethyl-ester form. Unlike free fatty acid forms of omega-3s, which are bound to triglycerides or phospholipids, ethyl-ester omega-3s require a high fat meal in order to be absorbed appropriately.^19–21 Thus, if patients are not ingesting ethyl-ester omega-3 PUFA supplements with a meal containing fat, they may not be adequately absorbing their omega-3 PUFA supplement. This certainly may have occurred in the recent omega-3 PUFA trials. Moving for ward, it seems of utmost importance for trials testing omega-3 PUFAs to measure omega-3 status in red blood cells (not in serum) at baseline and during follow-up, to ascertain chronic omega-3 status in the participants.²² A potential strategy for future omega-3 PUFA trials would be to ensure that patients are:

1. Not already omega-3 replete at baseline-and thus the participants may not derive benefit from additional omega-3 PUFA supplementation;

2. Ascertain if patients who obtain higher omega-3 levels in their red blood cells derive a larger benefit;

3. Determine if a particular omega-3 red blood cell level (overall percentage but also ratios of different PUFAs contained within phospholipids) correlates with a reduction in a particular endpoint (i.e. lower levels with a reduction in SCD versus higher levels showing a reduction in stroke or MI).

Importantly, omega-3 PUFA trials have not been keen to measure omega-3 status in red blood cells of their participants. Thus, it is possible that the “placebo” group in these trials were already omega-3 replete.

Dose

As indicated above, ingestion of 250–500 mg of EPA/DHA seems to derive most of the benefits of omega-3 PUFAs in regards to a reduction in SCD.¹⁵ Importantly, omega-3 PUFA intake seems to have increased from past years, around 0–46 mg/day, and have now increased to approximately 210 mg/day of baseline EPA/DHA intake seen in the ORIGIN trial.^7,23 Thus, it would not be expected for omega-3 PUFA supplementation to reduce the risk of SCD in recent trials with such a high baseline omega-3 PUFA intake. Additionally, the reduction in SCD may be driving a reduction in CV/all-cause mortality with omega-3 PUFAs. Thus, these latter endpoints would also not be expected to be reduced in trials with such a high baseline intake of omega-3s.

Lifelong intakes of high omega-3 PUFAs, as seen in the traditional Inuit and the Japanese, may confer protection against CV events. Moreover, 1.8 g of EPA in The Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS) trial did reduce major CHD events and stroke (even on top of a high baseline intake of fish and concomitant statin therapy). However, recent trials have generally only tested 1 g of EPA/DHA or less.^5–9 Importantly, higher doses of omega-3 PUFAs (> 1 g/day) may be required to derive a reduction in MI and stroke. Moreover, 1.20–1.85 g/day of EPA/DHA has been shown to reduce infarct size²⁴ and 3.3 g of EPA/DHA/day for 3 months followed by 1.65 g/day of EPA/DHA for 21 months has shown anti-atherosclerotic effects (i.e. less progression and more regression of coronary atherosclerosis).²⁵ Indeed, Japanese type 2 diabetic patients given 1.8 g of EPA showed a significant improvement in carotid intima-media thickness and brachial-ankle pulse wave velocity. Thus, doses in the range of 1.5–3.0 g/day of omega-3 PUFAs may be required to obtain a reduction in atherosclerosis and arterial stiffening. Additionally, 1.485 g/day of EPA/DHA has been shown to reduce the inflammatory burden of atherosclerotic plaques even when compared to 1.55 g of oleic acid/day, which might be expected to increase plaque stability.¹⁶ Lastly, compared to sunflower oil (3.6 g/day of linoleic acid), 1.4 g of long-chain omega-3 PUFAs led to stabilization of atherosclerotic plaques.²⁶ This was shown by reductions in macrophages in plaques, fewer thin fibrous caps and signs of inflammation, and more plaques with thick fibrous caps and no signs of inflammation in the omega-3 vs. the omega-6 group. Thus, doses above 1 gram of omega-3 PUFAs may be required to prevent an acute MI caused by rupture of an unstable plaque and future omega-3 PUFA trials may need to test higher doses of omega-3 PUFAs to prove the concept.

Conclusions

In summary, recent omega-3 PUFAs trials have included patients with higher baseline intakes of omega-3 PUFAs, which may prevent the benefit of additional supplemental omega-3 PUFAs for reducing SCD, CV death and all-cause mortality. Moreover, recent trials have included oleic acid (olive oil) as a comparator, which may derive cardioprotection, and thus, should not be considered a “placebo.” Lastly, omega-3 PUFA doses given in recent trials may not be high enough to achieve plaque regression/stabilization, and thus, the possible benefit of omega-3 PUFAs on reducing MIs and strokes may not be able to be obtained with such low doses. Further trials should include true placebo comparators, higher doses of omega-3 PUFAs (in the 1.5–3 g range), should measure red blood cell omega-3 content, and ensure that supplementation of omega-3 ethyl-ester dosage forms are being ingested concomitantly with a meal containing fat to provide proper absorption.

Biography

James J. DiNicolantonio, PharmD, (above) is with the Mid America Heart Institute at Saint Luke’s Hospital, Kansas City. Pascal Meier, MD, is at the Heart Hospital, University College London Hospitals UCLH, London-UK and at Yale Medical School, New Haven, Ct. James H. O’Keefe, MD, MSMA member since 2003, is with the Mid America Heart Institute at Saint Luke’s Hospital and University of Missouri-Kansas City, Kansas City.

Contact: jjdinicol@gmail.com