Omega-3 for patients with hypertriglyceridemia
For many years, an omega-3 dietary supplement was the recognised treatment for patients with high triglyceride levels because such supplements had generally been proved to lower triglyceride levels by 20–30 % (11). Since hypertriglyceridemia is a cardiovascular risk factor independent of other established risk factors (including LDL cholesterol) (12), the belief was that the triglyceride reduction caused by omega-3 would translate into a beneficial effect on clinical endpoints. International guidelines have therefore been recommending a high-dose omega-3 supplement (2–4 g/day) for patients with hypertriglyceridemia. Consequently, medications that contain EPA and DHA have in Norway been pre-approved for subsidised prescription if dietary adjustments alone fail to have the desired effect in hypertriglyceridemia patients (11). It was not until recently that results were forthcoming from trials that were large enough to test if omega-3 supplements actually reduce adverse cardiovascular events in this group. In November 2020, the long-awaited results were published of a study that was both large enough to consider clinical endpoints and involved a sufficiently high dose of omega-3 (4). These results showed that for patients with hypertriglyceridemia and an elevated cardiovascular risk, the incidence of myocardial infarction, unstable angina, coronary revascularisation or cardiovascular death was similar whether they were in the placebo group or in the group that received 4 g/day of an omega-3 supplement (EPA/DHA).
It appears that a very high dose of the ethyl-EPA drug may have a cardioprotective effect which has not been proved for standard omega-3 dietary supplements
The trial that has turned the whole field on its head is REDUCE-IT, which has attracted enormous attention since it was published in 2019 (3). REDUCE-IT tested the effect of administering a high dose of pure EPA (with an ethyl group, i.e. ethyl-EPA) to hypertriglyceridemia patients with and without established cardiovascular disease. The results showed a considerably lower incidence of adverse cardiovascular events on receiving 4 g/day ethyl-EPA compared to placebo. After following up more than 8,000 patients for an average period of 5 years, the incidence of myocardial infarction, coronary revascularisation, stroke or cardiovascular death was 25 % lower among patients who received omega-3. The effect was present for all primary endpoint components and across important subgroups. Based on these results, ethyl-EPA was recently approved as a prescription drug for the treatment of hypertriglyceridemia in the United States. However, the use of mineral oil as a placebo in REDUCE-IT has attracted criticism because the placebo group experienced a rise in LDL-cholesterol and CRP, which has not been found to be the case for the corn oil used in most other trials.
Based on new knowledge, Norway, where people are enthusiastic consumers of omega-3, should also hold back on recommending and marketing omega-3 dietary supplements as a preventive treatment for heart disease
How should we interpret the highly positive REDUCE-IT results in light of the other neutral studies? It appears that a very high dose of the ethyl-EPA prescription drug may have a cardioprotective effect which has not been proved for standard omega-3 dietary supplements. It is uncertain whether this difference is due to adverse effects of DHA and/or mineral oil, differences in dose or differences in the quality of the omega-3 fatty acids. This requires more research, and ideally a large-scale randomised controlled trial that tests the efficacy of ethyl-EPA in comparison with a corn oil placebo on cardiovascular endpoints.