18 June 2014

Epanova for the treatment of adults with severe Hyper Triglyceridemia

The US Food and Drug Administration (FDA) has approved Epanova  as an adjunct with diet to reduce triglyceride levels in adults suffering from severe hyper-triglyceridemia (patients with triglyceride levels greater than or equal to 500 mg/dL).

Triglycerides are types of lipid found in blood which are essential energy source for the body. Some people develop very high triglyceride levels (severe hyper-triglyceridemia), which referred to a condition in which the patients have high level of fat accumulation in their blood which could lead to serious health complications. Triglycerides are the most abundant fatty molecules available in human system. Elevated levels of triglycerides are associated with atherosclerosis, even in the absence of  hypercholesterolemia (high cholesterol levels), and predispose to cardiovascular disease. Very high triglyceride levels also increase the risk of acute pancreatitis. The disease itself is usually symptomless, although high levels of triglycerides could be linked with skin lesions known as xanthomas.

Three classes of medications are generally used for the treatment of elevated level of triglyceride are (i) Fibric acid derivatives, (ii) Niacin, and (iii) Omega-3 fatty acids. Doses of Fibrate ( Fibric acid derivatives)  such as Gemfibrozil, Fenofibrate used to increase the level HDL (High Density Lipoprotein) , LDL(Low Density Lipoprotein) and reduce triglycerides (TG) when the  level is greater than 400 mg/dL. If left untreated  hypertriglyceridemia ( TG over 500 mg/dL may lead to pancreatitis .

High doses of a strong Statins (Simvastatin, Atorvastatin, Rosuvastatin, Lovastatin) also lower triglyceride approximately half of the initial level. If triglycerides remain high despite Statin therapy, then niacin is introduced to lower them to normal range (less than 150 mg/dL, or 1.7 mmol/L).Patients with niacin treatment has a risk of stroke and other cardiovascular disorder .

Omega-3-fatty acids are used as  treatment for improving the condition by 3 ways: i) They reduce substrate (i.e. fatty acids) availability, which could be secondary to increase in beta-oxidation, decreased free fatty acids delivery to the liver, (ii) decreased hepatic fatty acids synthesis; (iii) increased phospholipid synthesis; or decreased activity of triglyceride-synthesizing enzymes (diacylgylcerol acyltranferase or phosphatidic acid phosphohydrolase). Prolonged bleeding time has been reported with omega- 3 fatty acids if co-administered with anticoagulants or antiplatelet agents. Hypertriglyceridemia is associated with 1–4% of all cases of pancreatitis. The symptoms are similar to pancreatitis secondary to other causes, although the presence of xanthomas or risk factors for hypertriglyceridemia. This drug is supplied as a capsule for oral administration. The recommended dose is 2 grams (2 capsules) or 4 grams (4 capsules) once daily. The dosage should be individualized according to the patient’s response and tolerability.

The FDA approval of Epanova was based on a 12-week randomized, placebo controlled, double-blinded trial. Patients whose TG levels were between 500 and 2,000 mg/dL were randomly assigned to placebo or Epanova 2, 3, or 4 grams per day. Overall, the median baseline triglyceride level was 694 mg/dL. Median baseline non-HDL, LDL, and HDL levels were 217 mg/dL, 81 mg/dL, and 28 mg/dL, respectively. Treatment with Epanova led to statistically significant reductions in fasting triglyceride levels and statistically significant reductions in non-HDL levels compared with placebo, but increased LDL levels.    
Epanova (omega-3-carboxylic acids) is a lipid-regulating agent containing fish oil-derived free fatty acids known as omega-3-carboxylic acids composed of Eicosa Pentaenoic Acid (EPA) and Docosa Hexaenoic Acid (DHA). Potential mechanisms of action of Epanova include inhibition of Acyl-CoA 1,2-diacylglycerol acyltransferase. Inhibition of this enzyme in turn increased mitochondrial and peroxisomal ß-oxidation of fat in the liver, decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity. As a cumulative effect triglyceride levels are reduced. Epanova may reduce the synthesis of triglycerides in the liver because EPA and DHA present in the drug are poor substrates for the enzymes which are responsible for TG synthesis, and EPA and DHA also inhibit esterification of other fatty acids. Thus for patients suffering from hyper triglyceridemia Epanova opens a new horizon towards better and effective treatment.

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