REDUCE-IT, VITAL and ASCEND
are the studies that keep on giving. All published about a year ago, new findings generated from these studies continue to lift omega-3s, especially with regard to heart health.
First let’s start with the most recent paper published in late October in Nutrients. In this study, researchers set out to determine if high-dose omega-3 is anti-atherosclerotic. To do this, they conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of high-dose omega-3 on atherosclerosis.
The review looked at studies such as REDUCE-IT, which used high dose omega-3 (>3 grams/day) in Western populations OR moderate dose (1.8 grams/day) in Japan. The rationale for settling on the different doses between the two groups was that it would lead to similar final Omega-3 Index levels.
The goal was to find out if in these settings people had less coronary (or carotid) artery disease. Six studies met the criteria, and when the results were pooled, high dose omega-3 (always meaning EPA+DHA) was significantly associated with slower progression of atherosclerosis vs placebo.
In this vein, researchers concluded that slowing the disease process in the artery wall is likely one of the mechanisms by which EPA and DHA lower risk for coronary heart disease (CHD) events.
According to William S. Harris, who was an author on this paper, Dr. Sekikawa (the study’s lead author) has long been interested in the difference between US Whites and Japanese living in Japan when it comes to heart disease risk, especially with respect to omega-3 fatty acids. “He is convinced – and now more than ever with REDUCE-IT published – that lower risk is all about achieving higher blood omega-3 levels; it’s about DOSE,” he said.
Other possible mechanisms include decreased risk for blood clots or decreased risk for arrhythmia (due to changes in cell membrane omega-3 levels or to slowed heart rate secondary to a shift in autonomic nervous system activity). All of these can of course work together with lower triglyceride levels and lower blood pressure to reduce risk for CHD.
Another study Dr. Harris co-authored was published on October 15th in the Mayo Clinic Proceedings. This study evaluated the largest and most recent clinical trials on omega-3s and cardiovascular disease (CVD) (i.e., REDUCE-IT, VITAL and ASCEND).
The study also focused very much on dose. “The results of REDUCE IT, in particular, suggest that optimal omega-3 benefits require a high-enough dose. It is an axiom in medicine that if the dose of any agent is too low, the agent will be ineffective. Why would the same not be true for omega-3 fatty acids?” the authors asked. “Hence, the goal in future omega-3 RCTs should be to achieve a target blood/tissue level of EPA and DHA (i.e., Omega-3 Index), regardless of what dose is required to accomplish this.
To review, the Omega-3 Index is a quantitative measurement of EPA + DHA content of red blood cell (RBC) membranes that was proposed in 2004 to be a risk factor for CVD death. This metric is highly correlated with omega-3 levels of human cardiac tissue and is preferred to more volatile plasma-based measurements of omega-3. Hence, just as hemoglobin A1C is the clinical standard for assessing glycemic status, the Omega-3 Index is the superior method for evaluating long-term omega-3 status.
Further, a large meta-analysis published in 2017 reported that a 1 standard deviation (SD) increase (2.1%) in the Omega-3 Index, above the mean, was associated with a 15% relative risk reduction for fatal CHD. Thus, the study authors say compared with an Omega-3 Index of 4%, which is the current American approximate average, an Omega-3 Index of approximately 8% would translate into predicted risk reduction in fatal CHD by approximately 30%.
So how does this translate to how much omega-3 someone needs? The researchers in this study believe that for people who do not routinely consume at least two fish meals per week, an omega-3 product is a reasonable option. More specifically, they believe taking an omega-3 product that supplies between 500 to 4000 mg per day of EPA+DHA appears to be an effective, safe, and affordable strategy for improving long-term cardiovascular health, particularly for high-risk persons who have elevated triglyceride levels and for people who do not consume fish regularly.
In other developments this month, the October 1st edition of the Journal of the American Heart Association published a study that analyzed data from 13 trials, including REDUCE-IT, VITAL and ASCEND. Importantly, according to the study’s authors, including these three trials increased the sample size by 64%, swelling the total population size to almost 130,000 subjects.
The outcomes researchers were most interested in were the rates of myocardial infarction, CHD death, total CHD, total stroke, CVD death, total CVD, and major vascular events.
During five years of treatment, 3838 myocardial infarctions occurred, along with 3008 CHD deaths, 8435 total CHD events, 2683 strokes, 5017 CVD deaths, 15,759 total CVD events, and 16,478 major vascular events.
In the analysis excluding REDUCE‐IT (Reduction of Cardiovascular Events with Icosapent Ethyl‐Intervention Trial), omega‐3 supplementation vs. placebo was associated with significantly lower risk of myocardial infarction, CHD death, total CHD, CVD death, and total CVD.
Inverse associations for all outcomes were strengthened after including REDUCE‐IT while introducing statistically significant heterogeneity. Statistically significant linear dose–response relationships were also found for total CVD and major vascular events in the analyses with and without including REDUCE‐IT. However, there was no impact with or without REDUCE-IT on the incidence of stroke.
All of these associations, the authors concluded, seem linearly related to omega-3 dose. This means greater cardiovascular benefits may be achieved at higher doses. They also suggest conducting additional large trials testing high doses of omega‐3 supplementation to confirm and extend these findings.
Measuring Omega-3 Index Levels in the REDUCE-IT Study
REDUCE-IT, which is regarded as one of the most successful omega-3 trials in 20 years (since GISSI-Prevenzione), gave 4 grams of EPA and reduced risk for CVD by 25% on top of statins.
The question that arose was, “What Omega-3 Index was achieved in REDUCE-IT?”
Researchers answered that question using existing data to estimate the effects of EPA on the Omega-3 Index and published their findings in the Journal of Clinical Lipidology in July.
According to Dr. Bill Harris, the lead author of this study, they took two completely independent approaches to address the question.
- They extrapolated from the plasma EPA concentrations provided in the REDUCE IT publication to the Omega-3 Index using an equation derived from internal data that correlated plasma EPA with RBC EPA. They also estimated the effects of EPA on RBC DHA using other published studies.
- They used published data on RBC fatty acid composition from other, short-term Vascepa studies.
So what did they find? Baseline Omega-3 Index levels were estimated to be in the low 5% range (which fits with other population studies). They also found that both approaches detailed above predicted a final Omega-3 Index of about 7%.
“If you’re taking full strength Vascepa at 4 grams per day, then your Omega-3 Index will be about 7% and that is known to reduce your risk for CVD by 25%. Whether getting a higher Omega-3 Index would have been even more effective we don’t know… yet,” Dr. Harris said. “People taking this dose could also be identified by measuring their RBC EPA level, and if it hits 3%, then they can be confident that they are in a protective zone.”
In late 2020, the results of another study that is also giving 4 grams of omega-3s (EPA+DHA) will be released. Referred to as the STRENGTH study, it’s sponsored by AstraZeneca and the product being used is “Epanova.”
The STRENGTH study is 50% larger than REDUCE IT and the Omega-3 Index achieved will be considerably higher (because DHA is included and it boosts the Index more than EPA does).
“If that study shows even greater CVD benefit than REDUCE-IT, we’ll know that a higher Omega-3 Index is even more beneficial. If it shows the same benefit, then we conclude that it’s the total omega-3 dose that is important, and perhaps not what Omega-3 Index level (as long as it’s >7%) was achieved,” Dr. Harris said. “If it’s LESS successful than REDUCE-IT, then we might conclude that DHA is not helpful (extremely unlikely)… We just have to wait and see.”