Do Omega-3 Fatty Acids Reduce the Risk of Heart Disease?
Do Omega-3 Fatty Acids Reduce the Risk of Heart Disease?
Omega-3 fatty acids are polyunsaturated fatty acids of which 3 types are involved in human physiology:
- Alpha-linolenic acid (ALA) – derived from plants
- Eicosapentaenoic acid (EPA) – derived from fish oils
- Docosahexaenoic acid (DHA) – derived from fish oils
The cardiovascular benefits of omega-3 fatty acids are derived only from EPA and DHA
ALA is an essential fatty acid, which means that the body can’t produce it, so ALA must be consumed in the diet. The body can convert some ALA into EPA and then to DHA, but only in very small quantities. Therefore, dietary intake of EPA and DHA is the only practical way to increase the levels of these omega-3 fatty acids in the body.
Effects on triglycerides
Omega-3 fatty acids mainly lower triglyceride levels in the body and have minimal effects on other lipoproteins. Importantly, EPA lowers triglycerides and has no effect on low density lipoprotein cholesterol (LDL-C), whereas DHA lowers triglycerides but increases LDL-C levels.1
Triglyceride levels >2.3mmol/L in the blood may be associated with an increased risk of cardiovascular disease.1
Triglyceride levels greater than 5.7mmol/L are considered severe and increases the risk of acute pancreatitis, especially if greater than 22.6mmol/L.1
About 30% of the US population have triglyceride levels between 2.3 and 5.7mmol/L and 1.7% have triglyceride levels >5.7mmol/L.2
Types of omega-3 fatty acids
Omega-3 fatty acids come in both “over the counter” and prescription formulations.
There are 3 types of prescription omega-3 fatty acids:
- Omacor (omega-3 acid ethyl esters) (available in Ireland)
- Vascepa (icosapent ethyl) (not available in Ireland)
- Epanova (omega-3 carboxylic acids) (not available in Ireland)
Omacor and epanova contain both EPA and DHA, whereas vascepa (icosapent ethyl) contains EPA only.
The “over the counter” preparations are available only as combined EPA/DHA formulas and at lower dosages than the prescription formulations.
Randomised controlled trials of “over the counter” omega-3 fatty acids:
The ASCEND trial, which randomly assigned 15,480 patients with diabetes mellitus but without cardiovascular disease to “over the counter” omega-3 fatty acids or placebo, showed no significant difference in the risk of serious vascular events after a mean follow-up of 7.4 years.3 The results of this study do not support routine dietary supplementation with omega-3 fatty acids to prevent vascular events.3
The VITAL trial was a randomized, placebo-controlled trial of “over the counter” omega-3 fatty acids (at a dose of 1g per day) in the primary prevention of cardiovascular disease and cancer among men >50 years and women >55 years.4
A total of 25,871 patients, including 5,106 black participants, underwent randomization. During a median follow-up of 5.3 years, supplementation with omega-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. However, there was a suggestion that individuals with low fish consumption (<1.5 servings/week) may derive some cardiovascular benefit from omega-3 fatty acid supplementation. In addition a 28% reduction in myocardial infarction, a secondary endpoint, was reported. However, the clinical implications of these findings are uncertain.4
Randomised controlled trials of high dose prescription omega-3 fatty acids:
Clinical trials of higher doses of prescription omega-3 fatty acids have had more promising results with regards to prevention of cardiovascular events.
The JELIS study of EPA (icosapent ethyl) 1.8 g daily in 18,645 Japanese patients with statin-treated hypercholesterolaemia found a 19% reduction in coronary events, despite minimal triglyceride lowering.5 The lowest event rate was observed in patients with the highest plasma EPA concentrations.5 This result has led to increased use of EPA for cardiovascular prevention in Japan.
A subsequent multinational trial (REDUCE-IT) in patients with high cardiovascular risk and modest hypertriglyceridaemia found that the administration of pure EPA (icosapent ethyl) 4g daily reduced cardiovascular events by 25% with no evidence of an association between triglyceride lowering and clinical benefit.6 There was a higher incidence of atrial fibrillation (3.1% vs 2.1%, p=0.004) and serious bleeding events (2.7% vs 2.1%, p=0.06) in patients taking icosapent ethyl.6 Up until recently, icosapent ethyl (vascepa) was only indicated for US patients with severe hypertriglyceridaemia (triglycerides >5.7mmol/L). However, based on the results of the REDUCE-IT trial the Food and Drug Administration recently unanimously voted to expand the indication of vascepa to patients with less severe forms of hypertriglyceridaemia. At the time of writing it is unclear when icosapent ethyl will be available in Ireland.
The ongoing STRENGTH study is comparing the effects of the carboxylic acid form of EPA and DHA (Epanova 4g) and corn oil placebo daily in patients with high cardiovascular risk with both moderate hypertriglyceridaemia and low concentrations of HDL cholesterol.7 This form of omega-3 fatty acid does not require hepatic conversion and thus produces similar tissue EPA levels as found with EPA. The STRENGTH study will help determine whether administration of high doses of combinations of EPA and DHA produces a similar cardiovascular benefit to that observed with administration of EPA alone.7
Take home message
The results of 2 large randomised controlled trials (VITAL and ASCEND) do not support the routine use of “over the counter” omega-3 fatty acids to reduce cardiovascular events. However, millions of people around the world continue to consume “over the counter” omega-3 fatty acids for little proven cardiovascular benefit and the environmental consequences of this on depleting fish stocks are unknown.
Conversely, high dose prescription omega-3 fatty acids, in particular high dose EPA, does appear to reduce cardiovascular events, but the mechanism remains unclear.
The use of prescription high dose omega-3 fatty acids in patients with baseline hypertriglyceridaemia is likely to be incorporated into future clinical guidelines.
- Evans MC, Stalam T, Miller M. Cardiovascular risk assessment in patients with hypertriglyceridemia. Curr Cardiol Rep. 2018;20:71.
- Christian JB, Bourgeois N, Snipes R, Lowe KA. Prevalence of severe (500 to 2,000 mg/dl) hypertriglyceridemia in United States adults. Am J Cardiol. 2011:107:891-7.
- The ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-50.
- Manson JE, Cook NR, Lee IM et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2019;380:23-32.
- Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098.
- Bhatt DL, Steg PG, Miller M et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Eng J Med 2019;380:11-22.
- Nicholls SJ, Lincoff AM, Bash D et al. 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;41:1281-1288.