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Summary
Cardiovascular health is negatively affected by hypertriglyceridemia, a condition wherein circulating levels of triglycerides are too high. Triglycerides are a form of lipids, these bind to lipoproteins in the blood and carry out important functions in energy generation and storage. Excessive circulating levels of circulating triglycerides are a significant risk factor for atherosclerosis and pancreatitis. The omega-3 fatty acids EPA and DHA have beneficial cardiovascular effects in hypertriglyceridemic patients by reducing circulating triglyceride levels. Introduction Our lipid (fat) metabolism involves many players, including triglycerides, cholesterol, and lipoproteins. Lipids are not soluble in water themselves; they are carried around in the bloodstream bound to lipoproteins that are soluble in water. Two classes of lipoproteins are chylomicrons (originating from the intestine) and very-low-density-lipoprotein (originating from the liver). These lipoproteins can carry lipids such as triglycerides through the blood. Triglycerides comprise of three fatty acids bound to a glycerol backbone. In normal health conditions, normal levels of circulating lipoproteins carry triglycerides to tissues such as the heart for energy generation, or to fatty tissue for energy storage. When these circulating (lipoprotein-bound) triglyceride levels become excessive, we refer to it as hypertriglyceridemia. This condition is often accompanied by insulin resistance, obesity and type 2 diabetes; it is a significant risk factor for atherosclerosis and pancreatitis as well. Atherosclerosis refers to plaque buildup against the walls of blood vessels, a cardiovascular health condition that reduces tissue blood flow and can lead to cardiovascular events such as heart attacks. Pancreatitis refers to inflammation of the pancreas. As this organ plays an important role in regulating blood sugar levels and lipid metabolism, pancreatitis can lead to severe impairments in our digestive system. Hypertriglyceridemia can have several causing factors, genetic and dietary causing factors are often present simultaneously in patients. Accordingly, many hypertriglyceridemic patients suffer from obesity and insulin resistance, such as seen in type 2 diabetes. Common treatment methods include switching to a low-fat diet, and statin administration. Statins are cholesterol-lowering drugs, their effect on lowering tri-glyceride levels is minimal but dose-dependent. Though a plasma triglyceride reduction of 25% can be realized with high doses of statins, this effect strength compared with side effect burden may not make them viable treatment options in patients with severe hypertriglyceridemia. Cholesterol binds to lipoproteins when it circulates through our blood vessels. Low-density-lipoprotein-cholesterol is sometimes referred to as the ‘bad cholesterol’, whereas high-density-lipoprotein-cholesterol is referred to as the ‘good cholesterol’. While both low-density-lipoprotein-cholesterol and high-density-lipoprotein-cholesterol are important for normal health, excessive levels of low-density-lipoprotein-cholesterol are associated with an increased risk of cardiovascular disease. In hypertriglyceridemia, high-density-lipoprotein-cholesterol levels are often reduced, together with an increase in levels of non-high-density-lipoprotein-cholesterol types such as very-low-density-lipoprotein or small-dense-low-density-lipoprotein. Trials investigating the effects of DHA + EPA supplementation in patients with hypertriglyceridemia have shown that these omega-3 fatty acids induce changes in lipid metabolism, such as lowering levels of triglycerides. Research findings Investigating the effects of omega-3 fatty acids EPA and DHA on hypertriglyceridemia, Peña-de-la-Sancha and collaborators set up a placebo-controlled clinical crossover trial with 18 adult patients suffering from hypertriglyceridemia (Peña-de-la-Sancha et al. 2023). Patients received either a placebo or 920mg EPA + 760mg DHA per day for a period of five weeks. Then, following a washout period of 4 weeks where no supplementation was given, each patient received the opposing supplementation of their first five weeks for another five weeks. Blood plasma samples were taken at the beginning and end of every supplementation period, together with measurements of body weight and composition, and vascular function. Regarding body weight and composition, the authors found that the omega-3 fatty acid supplementation caused a decrease in body mass index and waist circumference. Furthermore, this supplementation resulted in a decrease in levels of (high-density-lipoprotein-) triglycerides and an increase in levels of high-density-lipoprotein-cholesterol. Vascular function was also improved by DHA + EPA supplementation, as measured by a flow-mediated vasodilatation test. The authors concluded that DHA + EPA supplementation improved vascular function and markers of lipid metabolism in hypertriglyceridemic men. Allaire and colleagues set out to compare the specific effects of DHA and EPA in 48 men and 106 women with abdominal obesity and low-grade systemic inflammation (Allaire et al. 2016). They designed a double-blind randomized controlled crossover trial where participants received supplementation with 2.7g EPA, 2.7g DHA and corn oil (control), each for a period of 10 weeks with a washout period of 9 weeks in between. At the beginning and end of every supplementation period, markers of inflammation as well as lipid metabolism such as triglycerides, cholesterol and lipoproteins, were measured. When comparing the effects of DHA with EPA, the authors found that DHA caused a greater reduction in inflammatory marker IL-18, whereas no significant differences were found for other inflammatory markers. Moreover, DHA caused a greater increase in levels of adiponectin, a protein that regulates fatty acid breakdown. Finally, DHA lead to a greater reduction in triglycerides, the ratio of cholesterol : high-density-lipoprotein-cholesterol, total levels of high-density-lipoprotein-cholesterol and total levels of low-density-lipoprotein-cholesterol. A sub-group analysis found that the latter effect was only significant in men, not women. The authors concluded that DHA is more effective than EPA in modulating markers of inflammation and inducing changes in lipid metabolism in people with abdominal obesity and systemic inflammation. A follow-up study was conducted by this group, where they examined the effects of EPA and DHA supplementation on lipoprotein size in samples from their previous study (Allaire et al. 2018). Here, they found that DHA supplementation increases the low-density-lipoprotein size, whereas levels of very-low-density-lipoprotein levels decreased. The size of low-density-lipoproteins is clinically relevant, as individuals with a greater ratio of small-dense-low-density-lipoprotein : large low-density-lipoprotein particles have a higher risk of cardiovascular health events such as heart attacks. The authors concluded that the increase in particle size and levels of low-density-lipoprotein following high-dose DHA supplementation warrants further investigation, to determine what the exact cardiovascular consequences of these findings are. The results of the study by Allaire and colleagues mentioned above may couple well with a publication by Jacobson and collaborators (Jacobson et al. 2012). In this review, the researchers mention that the decrease in triglyceride levels and increase in low-density-lipoprotein-cholesterol caused by DHA likely results from a conversion of very- low-density-lipoprotein to low-density-lipoprotein, which correlates with the reduction in triglycerides. Kelley and colleagues examined the effects of high-dose DHA supplementation on markers of glucose and lipid metabolism in hypertriglyceridemia men aged 39-66 (Kelley et al. 2012). A total of 34 men received either placebo (olive oil, 17 participants) or 3 grams of algae-derived DHA (17 participants) once a day for a period of 90 days. Blood samples were taken a week before the study, on the start day, twice halfway through, one week before the last day and on the last day. These were then analyzed for markers of glucose and lipid metabolism such as insulin, cholesterol and lipoproteins. They found that DHA supplementation caused a decrease in markers of lipid metabolism and insulin resistance, such as plasma levels of small-dense-low-density-lipoprotein and ratio of triglycerides to high-density-lipoprotein-cholesterol. These did not change in the group receiving the placebo. The authors concluded that high-dose DHA supplementation had a positive effect on select markers of insulin resistance and lipid metabolism in men with hypertriglyceridemia. Attempting to resolve conflicting findings regarding omega-3 fatty acid supplementation and changes in lipid metabolism, Yang and colleagues performed a meta-analysis of 32 studies with a total of 15,903 subjects (Yang et al. 2022). In these studies, omega-3 supplementation was given either as monotherapy, or in combination with statins. Yang and colleagues then analyzed the reported supplementation-induced differences in levels of triglycerides, total cholesterol, low-density-lipoprotein-cholesterol, very-low-density-lipoprotein-cholesterol and high-density-lipoprotein-cholesterol, comparing these to the in-study control groups. They found that when omega-3 fatty acids are given as monotherapy, reductions in levels of triglycerides, total cholesterol and very-low-density-lipoprotein-cholesterol are achieved, whereas levels of low-density-lipoprotein-cholesterol increase. However, when omega-3 fatty acids were given in combination with statins, the same reductions in levels of triglycerides, total cholesterol and very-low-density-lipoprotein-cholesterol are achieved without increasing levels of low-density-lipoprotein-cholesterol. The authors mention that because of significant differences in study design, results regarding the effect of omega-3 fatty acids on lipid metabolism should be approached with caution; further research is required to resolve this. Nevertheless, robust evidence supports the triglyceride-lowering effect of omega-3 fatty acids. Conclusion The studies mentioned above have aided in providing robust evidence for the triglyceride-lowering effects of omega-3 fatty acids. The complexity of lipid metabolism, as well as varying results from publications using different study designs, have made it difficult to determine the precise effects of specific omega-3 fatty acids such as DHA and EPA. While triglyceride levels generally go down following omega-3 fatty acid supplementation, some studies report a subsequent increase in low-density-lipoprotein-cholesterol, though this might be gender-specific. The consequences of this effect, not measured in all studies, are unclear. The increase in low-density-lipoprotein-cholesterol coupled with a decrease in very-low-density-cholesterol following DHA supplementation, as reported by Jacobson (2012), might be beneficial if the decrease of the latter offsets the increase in low-density-lipoprotein-cholesterol. Moreover, the increase in low-density-lipoprotein particle size as reported by Allaire and colleagues might be beneficial in cardiovascular context. In summation, further research is required to determine the exact effects and consequences of omega-3 fatty acid supplementation on triglycerides and lipid metabolism in general. Omega-3 fatty acids such as DHA may be beneficial for patients with hypertriglyceridemia, by (amongst others) lowering levels of triglycerides. A medical professional should always be consulted for advice regarding cardiovascular health, such as lowering triglyceride levels. Sources Allaire, Janie, Patrick Couture, Myriam Leclerc, Amélie Charest, Johanne Marin, Marie-Claude Lépine, Denis Talbot, André Tchernof, and Benoît Lamarche. 2016. ‘A Randomized, Crossover, Head-to-Head Comparison of Eicosapentaenoic Acid and Docosahexaenoic Acid Supplementation to Reduce Inflammation Markers in Men and Women: The Comparing EPA to DHA (ComparED) Study, ’,. The American Journal of Clinical Nutrition 104 (2): 280–87. https://doi.org/10.3945/ajcn.116.131896. Allaire, Janie, Cécile Vors, André J Tremblay, Johanne Marin, Amélie Charest, André Tchernof, Patrick Couture, and Benoît Lamarche. 2018. ‘High-Dose DHA Has More Profound Effects on LDL-Related Features Than High-Dose EPA: The ComparED Study’. The Journal of Clinical Endocrinology & Metabolism 103 (8): 2909–17. https://doi.org/10.1210/jc.2017-02745. Jacobson, Terry A., Sara B. Glickstein, Jonathan D. Rowe, and Paresh N. Soni. 2012. ‘Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Low-Density Lipoprotein Cholesterol and Other Lipids: A Review’. Journal of Clinical Lipidology 6 (1): 5–18. https://doi.org/10.1016/j.jacl.2011.10.018. Kelley, Darshan S., Yuriko Adkins, Leslie R. Woodhouse, Arthur Swislocki, Bruce E. Mackey, and David Siegel. 2012. ‘Docosahexaenoic Acid Supplementation Improved Lipocentric but Not Glucocentric Markers of Insulin Sensitivity in Hypertriglyceridemic Men’. Metabolic Syndrome and Related Disorders 10 (1): 32–38. https://doi.org/10.1089/met.2011.0081. Peña-de-la-Sancha, Paola, Adolfo Muñoz-García, Nilda Espínola-Zavaleta, Rocío Bautista-Pérez, Ana María Mejía, María Luna-Luna, Victoria López-Olmos, et al. 2023. ‘Eicosapentaenoic and Docosahexaenoic Acid Supplementation Increases HDL Content in N-3 Fatty Acids and Improves Endothelial Function in Hypertriglyceridemic Patients’. International Journal of Molecular Sciences 24 (6): 5390. https://doi.org/10.3390/ijms24065390. Yang, Yunjiao, Wen Deng, Yanmei Wang, Tongyi Li, Yiding Chen, Cong Long, Qing Wen, Yue Wu, and Qiu Chen. 2022. ‘The Effect of Omega-3 Fatty Acids and Its Combination with Statins on Lipid Profile in Patients with Hypertriglyceridemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials’. Frontiers in Nutrition 9 (October). https://doi.org/10.3389/fnut.2022.1039056. |
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