Pharmacy & Therapeutics - May 2008 - (Page 272) DRUG FORECAST This amount of fish provides approximately 250 to 300 mg/day of EPA and DHA. For patients with CHD, the AHA recommends 1,000 mg/day of EPA and DHA. In the U.S., the current DHA/EPA intake ranges from 130 to 150 mg/day, which is well below the recommended amount.12 In 2004, the Food and Drug Administration (FDA) approved Lovaza, a highly purified and concentrated omega-3 polyunsaturated fatty acid preparation, as the first prescription omega-3 product.8 Originally called Omacor, Lovaza was developed by Reliant Pharmaceuticals, which was acquired by GlaxoSmithKline in December 2007. fits of omega-3 fatty acids are a decrease in platelet aggregation, a slight reduction in blood pressure and heart rate, and fewer arrhythmias. Omega-3 fatty acids (specifically, DHA and EPA) have been found to reduce sudden cardiac death in patients with or without a history of CHD. The efficacy of these esters in reducing ventricular fibrillation or tachycardia in patients with implantable cardioverter defibrillators and atrial and ventricular premature complexes in patients with a history of cardiac arrhythmias have also been studied. So far, however, the results have been inconsistent.15–18 Because Lovaza is a fatty acid, it is incorporated into cell membranes; as a result, plasma levels are not detectable. Clinically significant drug interactions with this agent are not expected in humans.9 placebo increased them by an average of 6.7%. The higher the baseline TG level before therapy began, the greater the percentage reduction achieved after therapeutic drug levels were attained. These trials also demonstrated a 10% to 46% increase in LDL-C levels and an increase of 11% to 14% in HDL-C levels with the active drug versus a 4.8% decrease in LDL-C levels and no change in HDL-C concentrations with placebo. Lovaza appeared to be well tolerated with few complications reported. Table 1 presents two pivotal trials that support the use of omega-3-acid ethyl esters for severe hypertriglyceridemia.20,21 When compared with gemfibrozil 1,200 mg daily for the treatment of very high TG levels in two small, double-blind, randomized trials, Lovaza 4 g daily showed the following results. A study by Stalenhoef et al. included 30 patients with baseline TG levels between 354 and 2,480 mg/dL.22 No significant difference in TG reduction was noted between the two groups. Gemfibrozil decreased TG levels by 40.4%, whereas Lovaza decreased them by 37.1%. Gemfibrozil increased HDL-C levels by 17.1%, and Lovaza increased them by 11%. In the second study,23 gemfibrozil decreased TG levels more than Lovaza did (51.2% vs. 28.9%, respectively). Gem fibrozil increased HDL-C levels by 27.9%, but Lovaza increased them by only 1.2%. Lovaza has also been studied in combination with statins.24,25 In a study by Durrington et al., a dose of 4 g daily decreased TG levels by 23% at 24 weeks in patients whose levels remained elevated (above 200 mg/dL) despite taking simvastatin (Zocor, Merck) 10 to 40 mg daily. The results were sustained in patients who continued therapy for an additional 24 weeks of open-label treatment.24 In a study by Nordoy et al., 4 g daily decreased TG concentrations by an additional 27.9% in patients with elevated TG levels (177–1,327 mg/dL) who were taking simvastatin 20 mg daily.25 The effects of Lovaza on other biomarkers or risk factors for CVD have been studied as well. Calabresi et al. discovered that Lovaza 4 g daily for eight weeks both decreased VLDL-C and changed LDL-C into more buoyant and cholesterol-rich particles.26 In two trials, Lovaza did not significantly cause a change in lipoprotein A (LpA) levels.15,27 PHARMACOLOGY Each 1-g capsule of omega-3-acid ethyl esters (Lovaza) contains at least 900 mg (90% or more) of the ethyl esters of omega-3 fatty acids. The product is predominantly a combination of ethyl esters of EPA (465 mg) and DHA (375 mg). Each capsule contains 60 mg of other omega-3 fatty acids, and the remaining 10% comprises mostly omega-6 fatty acids. Lovaza reduces hepatic production of TG, but the mechanism of action is complex and not completely understood.9 In the liver, EPA and DHA inhibit acylCoA: 1,2-diacylglycerol acyltransferase (resulting in decreased TG synthesis) and they increase peroxismal beta-oxidation, resulting in up-regulation of fatty acid metabolism. They also inhibit the esterification and release of other fatty acids, because they have a high affinity for, but are poor substrates of, the enzymes responsible for TG synthesis. In addition, EPA and DHA increase lipoprotein lipase activity, resulting in increased TG clearance.8–10,13 Omega-3 fatty acids also decrease hepatic production of ver y-low-density lipoprotein-cholesterol (VLDL-C). The ef fects on HDL-C are minimal. Lowdensity lipoprotein-cholesterol (LDL-C) levels may increase, but LDL-C changes from small, dense atherogenic particles to larger, more buoyant and less atherogenic particles. Clinically, this latter cholesterol change could offset the increase in LDL-C that may occur. Also, the rise in LDL-C is usually less than the decrease in VLDL-C.8–10,13,14 Other potential cardiovascular bene- INDICATIONS AND USAGE Lovaza is approved as an adjunct to diet to reduce very high TG levels of 500 mg/dL or greater in adults.9 Reliant received an approval letter for Lovaza for use in patients with TG levels of 200 to 499 mg/dL. This agent is also being evaluated for preventing CHD and for treating immunoglobulin A (IgA) nephropathy, inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus er ythematosus, and osteoporosis.8–10 The clinical data are promising for CHD, but the evidence is insufficient to support its use in the other medical conditions listed. Lovaza is approved in most European countries for the treatment of high TG levels or the secondary prevention of CVD.19 Lovaza can be used as monotherapy or in combination with a statin. The manufacturer is currently working on a combination product of Lovaza and a statin.19 CLINICAL EFFICACY Triglycerides and Cholesterol Some small, prospective, randomized, placebo-controlled trials have been conducted to study the effect of omega-3acid ethyl esters on very high TG levels. The trials lasted from 6 to 24 weeks. In most of the trials, the placebo was corn oil. The baseline TG levels for study subjects ranged from 500 to 2,000 mg/dL. In these studies, Lovaza decreased TG levels by 26% to 47%, whereas corn oil 272 P&T® • May 2008 • Vol. 33 No. 5
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