Do patients benefit from omega-3 fatty acids?

Abstract

Omega-3 fatty acids (O3FAs) possess beneficial properties for cardiovascular (CV) health and elevated O3FA levels are associated with lower incident risk for CV disease (CVD.) Yet, treatment of at-risk patients with various O3FA formulations has produced disparate results in large, well-controlled and well-conducted clinical trials. Prescription formulations and fish oil supplements containing low-dose mixtures of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have routinely failed to prevent CV events in primary and secondary prevention settings when added to contemporary care, as shown most recently in the STRENGTH and OMEMI trials. However, as observed in JELIS, REDUCE-IT, and RESPECT-EPA, EPA-only formulations significantly reduce CVD events in high-risk patients. The CV mechanism of action of EPA, while certainly multifaceted, does not depend solely on reductions of circulating lipids, including triglycerides (TG) and LDL, and event reduction appears related to achieved EPA levels suggesting that the particular chemical and biological properties of EPA, as compared to DHA and other O3FAs, may contribute to its distinct clinical efficacy. In vitro and in vivo studies have shown different effects of EPA compared with DHA alone or EPA/DHA combination treatments, on atherosclerotic plaque morphology, LDL and membrane oxidation, cholesterol distribution, membrane lipid dynamics, glucose homeostasis, endothelial function, and downstream lipid metabolite function. These findings indicate that prescription-grade, EPA-only formulations provide greater benefit than other O3FAs formulations tested. This review summarizes the clinical findings associated with various O3FA formulations, their efficacy in treating CV disease, and their underlying mechanisms of action.

Keywords: Atherosclerosis; Cardiovascular outcome trials; Cholesterol; Docosahexaenoic acid; Eicosapentaenoic acid; Endothelial function; Lipid oxidation; Omega-3 fatty acids.

Figure 1

EPA and DHA can be synthesized from ALA, and adopt distinct orientations in the lipid bilayer. Production of EPA and DHA from ALA is an inefficient process, thus the most effective route to obtaining these O3FAs is often through the diet or pharmaceutical formulations. Within the membrane, EPA and DHA adopt distinct orientations and have contrasting effects on membrane fluidity. EPA has an extended, stable conformation and maintains normal cholesterol distribution and overall membrane fluidity, while DHA rapidly isomerizes on a nanosecond time scale, increases fluidity, and displace cholesterol into distinct domains, often rich in sphingolipids. DHA is known to often concentrate in retina and neuronal cell membranes, while EPA may concentrate in the membranes of endothelial cells and other vascular cells. FADS1, Δ⁵-desaturase; FADS2, Δ⁶-desaturase; ELOVL1, elongase of very long chain fatty acids protein 1; ELOVL2, elongase of very long chain fatty acids protein 2; ACOX1, peroxisomal acyl-coenzyme A oxidase 1; HSD1784, peroxisomal multifunctional enzyme type 2.

Figure 2

Omega-3 fatty acids EPA, DPA, and DHA give rise to various specialized pro-resolving mediators (SPMs) following release from membrane phospholipids. The O3FAs in the membrane are released enzymatically by PLA₂ before conversion to bioactive, anti-inflammatory downstream metabolites by P450, 12/15-LOX, COX-2, and acetylated COX-2. These metabolites mediate various anti-inflammatory effects and modulate the transcriptome in resolving inflammation and reducing cytokine activity. 5-NGT, 5-nitrosoglutathione; COX, Cyclooxygenase; EH, epoxide hydrolase; LOX, lipoxygenase; Mar, Maresin; PD, Protectin; PLA₂, phospholipase A₂; RvE, E-series resolvins; RvD, D-series resolvins.

Figure 3

EPA interrupts multiple atherosclerotic and diabetes-related mechanisms caused by glucose. In the subpopulation of REDUCE-IT that had diabetes at baseline, treatment with IPE, which is converted to EPA by lipases in the intestinal lumen, experienced a 23% relative risk reduction in the primary endpoint. Elevated levels of glucose have been shown to increase the rate of oxidation in model membranes and induce formation of cholesterol liquid-crystalline domains. Due to its favourable orientation within the membrane and highly conjugated structure, EPA interrupts free radical propagation and cholesterol domain formation, thereby maintaining cholesterol distribution and preventing further acyl chain degradation. EPA-derived resolvin E1 has also been shown to reduce plasma glucose and insulin levels, a mechanism dependent on its receptor ERV1/ChemR23. Finally, EPA can bind to the free fatty acid receptor GPR120, which can increase GLUT4 translocation to the membrane and increase glucose uptake in adipocytes, as well as interrupt inflammatory signalling to NF-κB. COX2, cyclooxygenase-2; EPA, eicosapentaenoic acid; IPE, icosapent ethyl; RRR, relative risk reduction; RvE1, resolvin E1.

Figure 4

EPA improving endothelial nitric oxide bioavailability depends on eNOS coupling efficiency. Endothelial dysfunction is one of the early stages of atherosclerosis, characterized by the loss of NO bioavailability and adhesion/transendothelial migration (diapedesis) of circulating monocytes. NO is crucial for regulating vascular tone, as it binds gyanalyl guanylyl cyclase in vascular smooth muscle cells which in turn generates cGMP for further downstream signalling pathways leading to vasodilation and reduced inflammatory changes. Under disease conditions, the dimeric eNOS can become uncoupled to favour production of superoxide and peroxynitrite. EPA has been shown to reverse endothelial dysfunction by decreasing adhesion molecule expression, monocyte adhesion, and increasing eNOS coupling efficiency. This constitutes a key atheroprotective mechanism of EPA. Arg, arginine; cGMP, cyclic guanosine monophosphate; CV, cardiovascular; eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate; HO-1, heme oxygenase-1; NO, nitric oxide; ONOO−, peroxynitrite; oxLDL, oxidized LDL; PM, particulate matter; SOD-1, superoxide dismutase-1.

Figure 5

EPA interrupts the cardiovascular disease continuum at multiple points. There are multiple mechanisms associated with the cardiovascular disease continuum, starting with endothelial dysfunction and dyslipidaemia and culminating in ischaemic events, organ damage and death. Clinical trials, most notably REDUCE-IT, showed treatment with icosapent ethyl (IPE) reduced risk of major adverse cardiovascular events by 25%. The active ingredient of IPE, EPA, has shown beneficial activity at several points along the continuum, all of which contribute to the overall risk reduction.