Long-Chain Omega-3 Fatty Acids for Triglyceride-Lowering and Cardioprotection By Dr Bruce Holub, PhD

It is well established that subjects with elevated levels of blood cholesterol as well as fasting triglyceride levels (ie, as measured in the morning before breakfast) are at a significantly increased risk for adverse cardiovascular events including cardiovascular death, myocardial infarction (‘heart attack’), and stroke.⁽¹⁾ In general, the health care system has focused on the treatment of key risk factors such as elevated cholesterol levels and blood pressures with much lesser attention being given to lowering triglyceride levels. At least one-third and likely more of the adult population have risk levels of triglyceride in the circulation. Hypertriglyceridemia (elevated triglyceride levels) can be a serious risk factor for CVD (cardiovascular disease) even if the total blood cholesterol or LDL-cholesterol levels are deemed to be in the safe range. Knowing your triglyceride levels by regular blood testing can help one to take steps as needed for triglyceride-lowering. This should include a healthier lifestyle (healthier eating, less sugar and refined carbohydrate, regular exercising, reducing body weight, limiting alcohol intake) plus increased intakes of long-chain omega-3 fatty acids as EPA (eicosapentaenoic acid) plus DHA (docosahexaenoic acid) via diet (including fish) and EPA/DHA supplementation. Elevated triglyceride levels are a risk for a heart attack and stroke and, if more severe, can be associated with liver disease and pancreatitis.

Human trials have revealed the potent ability of long-chain polyunsaturated omega-3 fatty acids (namely EPA and DHA) as found in fish/seafood or supplements derived from fish oils to significantly lower circulating levels of blood triglyceride and triglyceride-rich lipoproteins.⁽²⁾ For those who cannot or do not consume sufficient amounts of fatty fish to reach the targets for EPA/DHA intakes, fish oil supplements enriched in EPA/DHA represent a viable option.

It is noteworthy that even moderate elevations in triglyceride levels (approaching 1.33 mmol/L (118 mg/dL) or above) have been associated with a progressively increased risk of ischemic heart disease. Within 2-3 weeks of daily EPA plus DHA supplementation, significantly-reduced blood triglyceride levels with an approximate reduction of 6 – 8% or more per gram (per 1000 mg) of EPA and DHA consumed are routinely observed. In a placebo-controlled, double-blinded trial from our lab, a 26% lowering in fasting triglyceride levels in post-menopausal women receiving 4 grams of omega-3 fatty acids (EPA plus DHA) daily over 28 days was demonstrated.⁽³⁾ In most clinical trials which evaluated the blood triglyceride-lowering efficacy of supplemental EPA/DHA, the supplement was ingested at or close to meal time.

Male subjects with average fasting triglyceride levels of 2.34 mmol/L at entry exhibited a 30-40% lowering at 6-8 weeks following daily supplementation with 3.6 grams of EPA plus DHA.⁽⁴⁾ Based on published relationships between fasting triglyceride levels and the prevalence of myocardial infarction, such a lowering would be calculated to provide an estimated 22-25% reduction. An inhibition of fatty acid synthesis (lipogenesis) in the liver (from glucose and fructose) by EPA and DHA and the impairment of triglyceride synthesis and release into the circulation along with the increased clearance of the lipoprotein carriers of triglyceride out of the blood are considered to account for the profound triglyceride-lowering effect of supplemental EPA/DHA.

Blood lipid/triglyceride levels are typically measured in the fasting state in the early morning after an overnight fast and before breakfast. Treatment strategies for the prevention of adverse cardiovascular events are based on such measurements despite the fact that most of our lives are spent in the non-fasted state between the consumption of regular meals. It is now recognized that the magnitude of the surge in blood triglyceride levels (referred to as postprandial lipemia) as seen after the consumption of a meal is a risk factor for serious cardiovascular events. There is evidence also that the circulating levels of non-fasting triglyceride may be even better at predicting future serious cardiovascular events. Thus, reducing the circulating levels of ‘remnant’ lipoproteins enriched in triglyceride following meals is becoming a target for the prevention of atherosclerosis.⁽⁵⁾ In human trials from our centre on adult males, after 21 days of daily supplementation with 3 grams of EPA plus DHA, we found an average lowering of both fasting and non-fasting triglyceride levels of approximately 30% which was maintained throughout a 24-hour interval indicating 24-hour triglyceride control.

Very recently, results from the REDUCE-IT clinical trial have been published.⁽⁶⁾ This extensive randomized trial was designed to evaluate the effect of an EPA omega-3 concentrate on blood triglyceride levels and cardiovascular disease outcomes in patients with hypertriglyceridemia (elevated triglyceride levels). For this study, over 8000 subjects who were on statin medication (for blood cholesterol-lowering) and who had elevated fasting triglyceride levels ranging from 1.52 to 5.63 mmol/L (135 to 499 mg/dL) were assigned to receive either a daily placebo supplement (devoid of EPA) or EPA omega-3 fatty acid (4 grams/day as 2 grams twice daily) as the ethyl ester of EPA. The subjects had either established cardiovascular disease (CVD) or diabetes plus other cardiovascular risk factors. Within one year of beginning EPA omega-3 supplementation, the overall median triglyceride levels were decreased by 18% with no decrease in the placebo (control) group. After a median follow-up period of 4.9 years, EPA supplementation was found to reduce the risk of the combined CVD endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, the need for coronary revascularization surgery, or unstable angina by 25% relative to the placebo group. The authors indicated that, in addition to the cardiovascular benefit of blood triglyceride-lowering with EPA, other mechanisms likely accounted for the magnitude of the overall effect of the EPA omega-3 fatty acid supplementation. In this regard, long-chain omega-3 fatty acid supplementation with EPA/DHA has been found to exhibit cardioprotective anti-inflammatory effects, anti-thrombotic effects (reducing blood platelet reactivity), lower blood viscosity, and improve vascular relaxation along with other effects.⁽⁷⁾

In conclusion, elevated fasting triglyceride levels is a very common risk factor for cardiovascular disease and adverse events in both the ‘healthy’ population and in those with some pre-existing form of a cardiovascular disorder who may be on pharmaceutical treatment (such as cholesterol-lowering statin medication as in the recent REDUCE-IT trial). Supplementation with long-chain omega-3 fatty acids as either EPA or DHA or mixtures thereof is well established as a nutraceutical-based approach for blood triglyceride-lowering with such a benefit being realized within a short time period of 2-3 weeks. In addition to triglyceride-lowering, other cardiovascular benefits of long-chain omega-3 supplementation can contribute to a significant reduction in serious cardiac events.

References

1. Nordestgaard, B. G. Circ. Res. 2016: 118(4): 547-563. 
2. Backes, J. et al. Lipids Health Dis. 2016: 15(1): 118-130. 
3. Stark, K. D. et al. Am. J. Clin. Nutr. 2000: 72(2): 389-394. 
4. Adler, A. J. and B. J. Holub. Am. J. Clin. Nutr. 1997: 65(2): 445-450. 
5. Nakajima, K. and A. Tanaka. Curr. Opin. Endocrinol. Diabetes Obes. 2018: 25(2): 108-117. 
6. Bhatt, D. L. New Engl. J. Med. 2019: 380(1):11-22. 
7. Holub, B. J. Can. Med. Assoc. J. 2002: 166(5): 608-615.