Prescription Omega-3 Fatty Acids for the Treatment of Hypertriglyceridemia

James M. McKenney; Domenic Sica

Disclosures

Am J Health Syst Pharm. 2007;64(6):595-605. 

In This Article

Pharmacology

There are two classes of essential fatty acids, the omega-6 (linoleic acid, γ-linolenic acid, and arachidonic acid) and the omega-3 (α-linolenic acid, EPA, and DHA) fatty acids, collectively referred to as polyunsaturated fatty acids (Figure 1).[4,5,6,7] Whereas the nonessential fatty acids can be synthesized by mammalian cells de novo, essential fatty acids cannot because the enzymes required for adding double bonds onto these molecules are not present in mammalian cells.[6,7] Although α-linolenic acid, which is derived from plants (the main sources are canola and soybean oils, flaxseed, and walnuts), can undergo conversion to EPA in vivo, this conversion is quite modest (<1%), and further transformation to DHA is very low.[8,9,10] Thus, for the most part, EPA and DHA must be obtained through dietary sources or dietary supplementation. Omega-6 fatty acids are converted into 2-series prostanoids and 4-series leukotrienes that are associated with proinflammatory and prothrombotic activity, while omega-3 fatty acids are converted into 3-series prostanoids and 5-series leukotrienes that are associated with antiinflammatory and antithrombotic properties.

The beneficial effects of omega-3 fatty acids on cardiovascular health have long been recognized, beginning with the observation that indigenous populations that consumed large amounts of foods such as seal, whale, and fatty fish, which contain high concentrations of omega-3 fatty acids, have low rates of CHD, despite the high-fat content of their diets.[4,11,12,13] Fatty fish and marine mammals are rich in EPA and DHA, and a wide body of research has established these fatty acids as the active agents in fish oil.[14] Among the many effects of omega-3 fatty acids that are believed to contribute to their cardiovascular benefits are (1) small reductions in blood pressure, (2) decreases in platelet aggregation, (3) modest increases in bleeding time, (4) reductions in heart rate, and (5) potential antiarrhythmic effects.[9,12,15,16,17] The growing database on the benefits of omega-3 fatty acids has even led to a proposal that blood levels of EPA and DHA should be evaluated as a new, modifiable, and clinically relevant risk factor for CHD mortality.[18]

The triglyceride-reducing effects of EPA and DHA have been detailed in numerous studies among a wide range of patient types.[8,14] A dose-response relationship between EPA or DHA and triglyceride lowering has been demonstrated, with doses between 2 and 4 g/day lowering serum triglycerides by approximately 20-50%.[4,9,11] As with fibric acid derivatives (fibrates) and nicotinic acid (niacin), reductions in triglycerides and very-low-density-lipoprotein (VLDL) cholesterol are generally greater in patients with higher baseline triglyceride levels.[8,19] An increase in low-density-lipoprotein (LDL) and high-density-lipoprotein (HDL) cholesterol can accompany a reduction in triglycerides; the higher the baseline triglyceride level, the greater these lipids may be increased. In most cases, the rise in LDL cholesterol is less than the reduction in VLDL cholesterol, resulting in a net decrease in non-HDL cholesterol (VLDL cholesterol plus LDL cholesterol). In addition, the LDL cholesterol in patients with very high triglycerides is usually very low; so if LDL cholesterol is increased with omega-3 fatty acid therapy, it is still in a relatively low range.

Although the mechanism of action of omega-3 fatty acids is not completely understood, two main actions are believed to cause the reduction of serum triglycerides (Figure 2).[20] First, triglyceride synthesis in the liver may be reduced by omega-3 fatty acids due to the inhibition of acyl coenzyme A (CoA): 1,2-diacylglycerol-O-acyltransferase.[21] Because omega-3 fatty acids such as EPA and DHA have substantial affinity to, but are poor substrates for, the enzymes responsible for triglyceride synthesis, the esterification and release of other fatty acids are inhibited.[21,22] Second, omega-3 fatty acids appear to induce peroxisomal ß-oxidation in the liver.[5] Hepatic nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), are thought to mediate the hypolipidemic effect of polyunsaturated fatty acids.[6] Because of a high affinity for PPAR-α and PPAR subclasses, omega-3 fatty acids may also upregulate the metabolism of fatty acids in the liver.[23]

Figure 2.

The mechanism of action of omega-3 fatty acids. Omega-3 fatty acids have been reported to inhibit (-) lipogenesis and the activities of diacylglycerol acyltransferase (DGAT), phosphatidic acid (PA), and hormone-sensitive lipase, and to stimulate (+) ß-oxidation, phospholipid synthesis, and apo-B degradation. The end result is a reduced rate of secretion of very-low-density-lipoprotein (VLDL) triglyceride. [20] DAG = diacylglycerol, TG = triglyceride, PAP = phosphohydrolase, FA = fatty acids, NEFA = nonesterified fatty acids. Reproduced, with permission, from reference[20].

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