Omega-3s for cardiometabolic wellness

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Omega-3 fatty acids from fish, specifically the crucial fatty acids DHA and EPA, suffered negative news headlines this summer as the Cochrane Collaboration published its latest meta-analysis looking at the effects of omega-3 DHA and EPA on reducing the risk of heart disease, stroke, and death.¹ The authors of the review concluded that omega-3 supplements had little or no effect on these parameters.

The review assessed 79 randomized trials involving more than 112,000 people. While the review acknowledged benefits of omega-3 supplements for reducing some blood fats and triglycerides, the authors suggest that omega-3 supplements’ net benefits are negligible for the reduction of heart risk.

However, researchers in the field of omega-3 science have roundly criticized the findings of this review as being highly flawed. Bill Harris, PhD, the founder of OmegaQuant (Sioux Falls, SD) and a researcher who has studied omega-3s for decades, outlines several basic criticisms of the Cochrane review for Nutritional Outlook readers. According to Harris, the Cochrane reviewers ignored a large body of evidence showing beneficial effects of omega-3 intake on cardiovascular risk by eliminating some of the larger studies conducted to date. Additionally, Harris states that the Cochrane review essentially rehashes the same old studies that have been included in earlier unfavorable reviews and presents nothing new. Harris also adds that, while such negative reviews are quick to be publicized in the mainstream press, other favorable omega-3 meta-analyses that have been published have not generated the same level of media interest.

Several studies on the benefits of omega-3s for heart risk are underway and should add to our understanding of how significant the effects of these fatty acids ultimately are.

It is well known that EPA and DHA support cardiovascular and metabolic health through several mechanisms. While their ability to impact blood lipids, and specifically triglycerides, are documented, a recent review looking at evidence from human and animal studies highlights several potential areas in which omega-3 fatty acids act to influence metabolic function.² These include: influencing the plasma concentrations of adiponectin and leptin, resulting in increased thermogenesis; altering the expression of genes that regulate fat metabolism by upregulating fatty acid oxidation and downregulating lipogenesis in fat tissue; reducing inflammatory processes by impairing the activation of a key inflammatory regulator, NF-Kβ; and improving endothelial health and circulation.

Moreover, several current clinical trials reviewed here have found that omega-3 fatty acids favorably impact metabolic health in diabetics, while others indicate that omega-3s, when administered to those on statin therapy, provide additional cardiovascular benefits.

As the prevalence of diabetes and metabolic syndrome in the U.S. exceeds 100 million individuals³, and the number of those using statin drugs approaches 40 million⁴ and continues to grow, adding omega-3s in both of these groups may be well-indicated.

Omega-3s for Diabetes and Metabolic Health

Omega-3 fatty acids have been demonstrated to have beneficial effects on metabolic health and in those with diabetes. Due to their broad mechanism of action, these benefits extend to several different metabolic pathways.

A recent study led by Mohammad Golzari from Tehran University of Medical Sciences (Tehran, Iran) investigated the effects of supplementation with the omega-3 fatty acid EPA (from Mino Pharmaceutical Co.; Iran) on the activity of the enzyme paraoxonase-1 (PON1) in type 2 diabetics.⁵ PON1 is an enzyme involved in antioxidant and anti-inflammatory processes in the body, including in supporting the detoxification of free radicals and drug metabolites, while also showing the ability to inhibit the production of Monocyte Chemoattractant Peptide 1 (MCP-1) in endothelial cells incubated with oxidized LDL, an important step in atherogenesis associated with atherosclerosis. PON1 further has been found to support the integrity of HDL cholesterol molecules by displaying antioxidant effects.

In the double-blind, randomized, placebo-controlled study, 36 individuals with type 2 diabetes were asked to supplement with 2 g of EPA daily, or a placebo, for eight weeks. PON1 activity as well as blood lipids were monitored over the course of the study. At the end of the study, researchers found that EPA supplementation led to significant increases versus placebo in PON1 serum levels and activity, as well as an increase in the serum ratio of PON1 to HDL cholesterol. Furthermore, significant increases in HDL cholesterol levels were also noted versus placebo. These results indicate that EPA supplementation may confer some protection against atherogenesis in individuals with type 2 diabetes.

A second trial in type 2 diabetics sought to look at the ability of omega-3 supplements to enhance metabolic health and reduce inflammatory biomarkers. Led by M. Gorety Jacobo-Cejudo of Universidad Autónoma del Estado de México (Toluca, Mexico), the placebo-controlled pilot study included 54 Mexican individuals on metformin who were asked to supplement with fish oil containing daily amounts of 320 mg EPA and 200 mg DHA (from General Nutrition Centers), or a placebo, for six months.⁶ The investigators aimed to assess the effects of supplementation on the metabolic markers adiponectin, resistin, and leptin, as well as lipid profiles. They also looked at the effects on blood glucose markers and anthropometric measures.

While no significant changes in body weight, BMI, or body fat were evident in either group, the fish oil group had significant reductions in waist circumference following supplementation. In addition, fish oil decreased fasting blood glucose levels. Decreases in both groups were seen in glycosylated hemoglobin and leptin, while adiponectin levels did not show significant changes. Interestingly, both groups showed a significant increase in HOMA-IR, a measure of insulin resistance, which the authors attribute to the lack of weight loss seen in the study. It is also likely that concomitant use of metformin impacted the results seen in both groups. However, fish oil supplementation significantly decreased triglyceride levels and the atherogenic index whereas the placebo group showed significant increases in total and non-HDL cholesterol levels as well as in the atherogenic index.

While the results of this pilot study are preliminary in nature, it is likely that fish oil supplementation in type 2 diabetics on metformin leads to several beneficial metabolic effects. Further studies on similar individuals across different ethnic groups are needed to tease out any differences due to genetics, dietary, and cultural factors.

Metabolic abnormalities are also evident in women with gestational diabetes, a common complication of pregnancy, which is further associated with development of diabetes, insulin resistance, and poorly regulated blood lipids after delivery. A study led by Mehri Jamilian from Arak University of Medical Sciences (Arak, Iran) aimed to determine whether fish oil supplementation could benefit gene expression to favorably alter insulin action, inflammatory response, and blood lipids in women with gestational diabetes.⁷

In the double-blind, placebo-controlled study, 40 women aged 18-40 were supplemented with fish oil containing 180 mg EPA and 120 mg DHA (from Barij Essence Pharmaceutical Company; Kashan, Iran) twice daily, or a placebo, for six weeks. Gene expression was assessed using peripheral blood mononuclear cells (PBMCs) at baseline and after six weeks. Blood measures for fasting blood sugar, C-reactive protein (CRP; a marker of inflammation), and blood lipids were also evaluated in both groups.

Omega-3 supplementation led to a significant reduction of fasting blood sugar and serum triglycerides, as well as a significant reduction in CRP levels. HDL cholesterol levels increased, while LDL levels also increased in the fish oil group compared to placebo (an effect seen in other studies with fish oil as well). Gene expression was significantly upregulated for peroxisome proliferator-activated receptor gamma (PPAR-γ) and downregulated for the LDL receptor in the fish oil group versus placebo. PPAR-γ is thought to be intimately involved in the regulation of glucose, insulin, and lipid metabolism. Furthermore, omega-3 supplementation led to significant downregulation of gene expression markers of inflammation, including IL-1 and tumor necrosis factor alpha (TNF-α). These results suggest that fish oil may beneficially impact several important parameters of metabolic health in women with gestational diabetes.

Omega-3s as Statin Companions

Several recent studies have investigated the effects of adding fish oil therapy in individuals on statin drugs to confer potential additive or additional benefits for reducing cardiovascular risk.

Abdulhamied Alfaddagh and colleagues from Beth Israel Deaconess Medical Center (Boston, MA) conducted a randomized trial in which 285 subjects aged 63 years old on average with stable coronary artery disease already taking statins were given a pharmaceutical product containing 1.86 g of EPA and 1.5 g of DHA as ethyl esters daily (as Lovaza; GlaxoSmithKline; Research Triangle Park, NC) for 30 months or were maintained on statin therapy alone (control group).⁸ The researchers assessed coronary plaque volume via computed tomographic angiography.

While non-calcified plaque volume was not significantly different between groups, when researchers stratified the results by age, they found that younger individuals in the omega-3 group had significantly slower progression to non-calcified plaque, indicating a preventive effect of omega-3s in this demographic. Furthermore, fibrous, calcified, and total plaque were all lower in this group.

Looking at plaque subtypes in the overall study group, those in the control group had significant progression to fibrous plaque whereas those in the omega-3 group showed no progression over the study period. When looking at differences between statin dose in the groups at baseline, omega-3s led to significant reductions in progression to fibrous plaque in those on lower-dose statin therapy compared to control subjects. No significant changes were evident in those taking higher doses of statins. These findings suggest significant additive benefits of omega-3s for preventing the progression of coronary plaque in younger individuals on statin therapy as well as those taking lower doses of statins.

A second trial led by Tetsu Watanabe and colleagues from Yamagata University School of Medicine (Yamagata, Japan) looked at whether the addition of EPA to high-dose pitavastatin therapy enhanced its benefits for coronary arterial plaque stabilization.⁹ In the study, 193 coronary heart disease patients were randomly assigned to pitavastatin (4 mg/day) or pitavastatin plus EPA (4 mg/day pivastatin plus 1,800 mg/day EPA) and followed for six to eight months. Ultrasound analysis of coronary plaque volume and composition was performed.

The results of the study indicated that the group consuming EPA had a greater reduction in total atheroma volume compared to the group on the statin alone, with significant reductions in coronary plaque lipid volume in the fish oil group. The study suggests that adding EPA omega-3 fatty acid supplementation to intensive statin therapy is a promising option to further reduce aspects of cardiovascular risk in patients with coronary heart disease.

A more recent study led by Chee Hae Kim from Seoul National University Hospital Cardiovascular Centre (Seoul, Korea) sought to assess the additive triglyceride-lowering potential of omega-3 fish oil administration in those individuals with elevated triglycerides despite being on rosuvastatin therapy.¹⁰

In the randomized, double-blind trial, 201 individuals with an average age of 58 on statin therapy underwent a four-week run-in period prior to being randomized to rosuvastatin alone (20 mg/day) or a combination of rosuvastatin and omega-3 fatty acids (20 mg/day rosuvastatin plus 4 g/day omega-3 fatty acids) for eight weeks.

The investigators found that triglycerides decreased significantly more in the fish oil/statin combination group than with the statin alone. Average reductions in triglycerides in the combination group were 26.3%, while they were only 11.4% with the statin alone. Furthermore, non-HDL cholesterol was also reduced to a greater extent in the combination group (-10.7%) than with the statin alone (-2.2%). Thus, the addition of omega-3s to statin therapy resulted in significant additional benefits for the reduction of blood lipid levels than singular therapy with rosuvastatin.

Omega-3: Building Positive Evidence

A plethora of research has shown that omega-3 fatty acids have several important benefits for cardiovascular and metabolic health. However, perhaps the jury is still out on whether these benefits translate into preventive effects above and beyond those seen with drug therapy in more chronic conditions.

It is clear that omega-3s from fish have a strong scientific basis for being a healthy nutritional option that is likely to lead to significant heart health support. With recent studies indicating positive effects in two growing groups of individuals-those with diabetes and those on statin drugs-the inclusion of omega-3s in an overall health regimen may be a key consideration for cardiometabolic support.

References:

1. Abdelhamid AS et al. “Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease.” Cochrane Database of Systematic Reviews. Published online July 18, 2018.
2. Howe P et al. “Metabolic health benefits of long-chain omega-3 polyunsaturated fatty acids.” Military Medicine, vol. 179, 11 suppl. (November 2014): 138-143
3. Centers for Disease Control and Prevention Press Release. “New CDC report: More than 100 million Americans have diabetes or prediabetes.” July 18, 2017. Retrieved September 3, 2018. www.cdc.gov/media/releases/2017/p0718-diabetes-report.html
4. Adedinsewo D et al. “Prevalence and factors associated with statin use among a nationally representative sample of U.S. adults: National Health and Nutrition Examination Survey, 2011-2012.” Clinical Cardiology, vol. 39, no. 9 (September 2016): 491-496
5. Golzari MH et al. “The effect of eicosapentaenoic acid on the serum levels and enzymatic activity of paraoxonase 1 in the patients with type 2 diabetes mellitus.” Acta Medica Iranica, vol. 55, no. 8 (August 2017): 486-495
6. Jacobo-Cejudo MG et al. “Effect of n-3 polyunsaturated fatty acid supplementation on metabolic and inflammatory biomarkers in type 2 diabetes mellitus patients.” Nutrients, vol. 9, no. 6 (June 3, 2017)
7. Jamilian M et al. “A randomized double-blinded, placebo-controlled trial investigating the effect of fish oil supplementation on gene expression related to insulin action, blood lipids, and inflammation in gestational diabetes mellitus-fish oil supplementation and gestational diabetes.” Nutrients, vol. 10, no. 2 (January 31, 2018)
8. Alfaddagh A et al. “Effect of eicosapentaenoic and docosahexaenoic acids added to statin therapy on coronary artery plaque in patients with coronary artery disease: a randomized clinical trial.” Journal of the American Heart Association, vol. 6, no. 12 (December 15, 2017)
9. Watanabe T et al. “A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins.” Journal of Cardiology, vol. 70, no. 6 (December 2017): 537-54
10. Kim CH et al. “Efficacy and safety of adding omega-3 fatty acids in statin-treated patients with residual hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a randomized, double-blind, and placebo-controlled trial.” Clinical Therapeutics, vol. 40, no. 1 (January 2018): 83-94