The prevalence of hypertriglyceridemia has increased several-fold over the past few decades, mostly as a result of the concomitant obesity epidemic.1,2 The categorization of hypertriglyceridemia as endorsed by the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guidelines3 and the AHA scientific statement on triglycerides (TG) and cardiovascular disease4 is summarized in Table 1. Approximately 40 million adults in the United States have hypertriglyceridemia, and ~4 million have very high triglycerides (VHTG; TG ≥ 500 mg/dL).5 Indeed, VHTG is more common than numerically analogous increases in total cholesterol levels.6

Table 1: Categorization of Hypertriglyceridemia

Triglyceride Range (mg/dL) NCEP ATP III (2004) AHA Statement (2011) < 100 Desirable Optimal < 150 Normal 150-199 Borderline high Borderline 200-499 High High > 500 Very high Very high

AHA = American Heart Association; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III

The most alarming untoward effect of VHTG is hypertriglyceridemia-associated pancreatitis.7 Risk of hypertriglyceridemia-associated pancreatitis is more clearly defined at higher TG levels, and is approximately 5 percent with TG > 1,000 mg/dL and 10 to 20 percent with TG > 2,000 m/dL. TG-lowering therapy is recommended in patients with VHTG based on the observation that hypertriglyceridemia-associated pancreatitis tends to be more severe than other etiologies of pancreatitis.8-10 At least three different studies have demonstrated the cost effectiveness of such an approach.11-13

Pharmacologic options for VHTG include fibrates, niacin, and omega-3 polyunsaturated fatty acids, the latter of which will be the focus of this analysis. Omega-3 fatty acids are composed primarily of eicosapentaenoic acid and docosahexaenoic acid. Omega-3 fatty acids reduce TGs through a variety of interactions with hepatic nuclear receptors that subsequently lead to reduced substrate for hepatic lipogenesis and enhanced beta-oxidation of fatty acids.14 It is noteworthy that omega-3 fatty acids facilitate rapid conversion of very low density lipoprotein (VLDL) to low-density lipoprotein cholesterol (LDL-C), a phenomenon that has borne out in both in vitro15 and clinical observations.16 However, an increase in LDL-C levels appears to be a manifestation of increased LDL-C size rather than increased particle number.16,17

Because the majority of generic fish oil supplements have an omega-3 composition of only 30-50%, several commercial preparations with higher compositions have been developed. Pharmacologic dosages of at least 2 g/day of omega-3 fatty acids are needed to enact significant reductions in serum TG levels. The three FDA-approved formulations of prescription omega-3 fatty acids are summarized in Table 2. All 3 products are FDA approved; however OM-3-FFA is not yet available in the U.S. Each has been evaluated for the management of VHTG through a variety of clinical trials. Of importance are the differential lipid-lowering effects of icosapentaenoic acid and docosahexaenoic acid.

Table 2: Prescription Omega-3 Fatty Acid Formulations

Formulation Description EPA/DHA content OM3-A-EE Contains EPA and DHA ethyl esters 47% EPA, 38% DHA IPE Contains EPA ethyl ester (icosapent ethyl) > 96% EPA OM3-FFA Contains EPA and DHA free fatty acids 55% EPA, 20% DHA

In the late 1990s, OM3-A-EE, 4 g/day for 16 weeks was studied in patients with VHTG and significantly reduced TG concentrations by 45%.18 Significant reductions were also observed in VLDL (32%), total cholesterol (15%), and the total cholesterol:high-density lipoprotein cholesterol (HDL-C) ratio (20%). Concomitant significant increases in HDL-C (13%) and LDL-C (31%) were also observed. Importantly, despite this increase, mean LDL-C concentrations among patients treated with OM3-A-EE were 104 mg/dL and, thus, not markedly elevated.18 Similar results were also obtained in another study of OM3-A-EE for VHTG, with significant reductions observed in all of the same parameters following just 6 weeks of therapy at the same dose: TG by 39%, VLDL by 29%, and total cholesterol by 10%. A significant increase in LDL-C (16.7%) was again observed, although the concomitant rise in HDL-C did not achieve statistical significance.19

In 2011, the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension (MARINE) study investigated the effect of IPE 2 g/day or 4 g/day versus placebo in 229 patients with VHTG treated over 12 weeks.20 At the end of the study, the 2 g/day and 4 g/day treatment arms rendered significant declines in TG (20% and 33%), VLDL (15% and 29%), total cholesterol (7% and 16%), and non-HDL-C (8% and 18%), respectively. Subgroup analyses of patients on background statin therapy and those with hypertriglyceridemia levels > 750 mg/dL demonstrated even more marked declines in serum TG levels. Importantly, no significant increase in LDL-C was observed in either the overall study population or any of the subgroup analyses.20

In 2012, the multi-center, placebo-controlled, randomized, double-blind, 12-week (ANCHOR) study investigated the effect of IPE 2g/day or 4g/day versus placebo in 663 high-risk statin-treated patients with residual HTG despite adequate LDL-C control. The results confirmed the findings of the subgroup analysis of statin-treated patients seen in MARINE. IPE at 2g/day and 4g/day achieved significant reductions in TG (10% and 22%) and non-HDL-C (6% and 14%). The 4g/day achieved further reductions in LDL-C, VLDL, total cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A2 and high-sensitivity-C-reactive protein. The most pronounced reductions in TG and non-HDL-C were observed in those patients treated with higher intensity statin regimens.21

The theoretical advantage of omega-3 free fatty acids stems from the fact that their absorption is not contingent upon pancreatic lipase mediated hydrolysis, as are the ethyl ester formulations. Two studies have investigated the pharmacokinetics of OM3-FFA. The Epanova Compared to Lovaza In a Pharmacokinetic, Single-dose, Evaluation (ECLIPSE) study compared single 4 g/day doses of OM3-FFA and OM3-A-EE in overweight adults during periods of low and high fat consumption. OM3-FFA demonstrated a near four-fold increased bioavailability compared to ethyl ester, but only during periods of low fat consumption.21

The ECLIPSE II study compared the pharmacokinetics and bioavailability of the two omega-3 forms following repeat dosing and yielded similar conclusions.22 ECLIPSE II also reported a significantly greater reduction in TG levels (21% vs. 8%, p = 0.013), although no differences in the percentage change from baseline were seen in terms of LDL-C, HDL-C and non-HDL-C. In 2014, the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial investigated the utility OM3-FFA for patients with VHTG at three dosages (2, 3, and 4 g/day) versus placebo.23 After 12 weeks of treatment, during which patients also adhered to a low-fat diet, significant reductions of 26%, 26%, and 31% were observed in serum TG at dosages of 2, 3 and 4 g/day, respectively. Total cholesterol, non-HDL-C, VLDL and remnant-like lipoprotein particle cholesterol (RLP-C) were all significantly reduced across all dosage groups.

Secondary analyses further demonstrated significant reductions in arachidonic acid and lipoprotein-associated phospholipase A2 levels, both important mediators of inflammation and atherogenesis, following treatment with all dosages of OM3-FFA. However, significant increases in LDL-C (by 19%, 14%, and 19%, p < 0.05) versus placebo were also observed. Subgroup analyses among patients with diabetes, those with baseline TG ≥ 750 mg/dL, and those with the highest tertile of baseline apolipoprotein C-III or RLP-C demonstrated the most significant reductions in TG levels and non-HDL-C, therein demonstrating the efficacy of OM3-FFA in particularly high-risk patients.23

Combination therapy with OM3-FFA (at 2 or 4 g/day) and statins among high cardiovascular risk patients with persistent HTG was evaluated against a control of statin and 4 g/day olive oil in the ESPIRIT trial.24 At both 2 and 4 g/day, OM3-FFA plus statin significantly reduced TG (by 15% and 21%, respectively), total cholesterol (by 2% and 4%), VLDL (by 14% and 22%), non-HDL-C (by 4% and 7%). Reductions in both TG and non-HDL-C were greatest among those on higher-intensity statins. A significant 5% increase in LDL-C was only observed in the 2 g/day group. Secondary endpoints demonstrated increased serum concentrations of both eicosapentaenoic acid and docosahexaenoic acid compared to other studies of OM3-A-EE as well as significant reductions in arachidonic acid levels.24

In conclusion, in patients with VHTG, OM3-A-EE, IPE, and OM3-FFAs may all be important components to therapy, especially when combined with other lifestyle and therapeutic measures aimed at weight loss and improved glycemic control.

References

Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH. Hypertriglyceridemia and its pharmacologic treatment among US adults. Arch Intern Med 2009;169:572-8. Christian JB, Bourgeois N, Snipes R, Lowe KA. Prevalence of severe (500 to 2,000 mg/dl) hypertriglyceridemia in United States adults. Am J Cardiol 2011;107:891-7. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1-45. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333. Maki KC, Bays HE, Dicklin MR. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J Clin Lipidol 2012;6:413-26. Brinton EA. Management of hypertriglyceridemia for prevention of atherosclerotic cardiovascular disease. Cardiol Clin 2015;33:309-23. Ewald N, Hardt PD, Kloer HU. Severe hypertriglyceridemia and pancreatitis: presentation and management. Curr Opin Lipidol 2009;20:497-504. Anderson F, Thomson SR, Clarke DL, Buccimazza I. Dyslipidaemic pancreatitis clinical assessment and analysis of disease severity and outcomes. Pancreatology 2009;9:252-7. Lloret Linares C, Pelletier AL, Czernichow S, et al. Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia. Pancreas 2008;37:13-2. Deng LH, Xue P, Xia Q, Yang XN, Wan MH. Effect of admission hypertriglyceridemia on the episodes of severe acute pancreatitis. World J Gastroenterol 2008;14:4558-61. Christian JB, Arondekar B, Buysman EK, Johnson SL, Seeger JD, Jacobson TA. Clinical and economic benefits observed when follow-up triglyceride levels are less than 500 mg/dL in patients with severe hypertriglyceridemia. J Clin Lipidol 2012;6:450-61. Nichols GA, Arondekar B, Garrison LP, Jr. Patient characteristics and medical care costs associated with hypertriglyceridemia. Am J Cardiol 2011;107:225-9. Nichols GA, Arondekar B, Jacobson TA. Hospital use and medical care costs up to 5 years after triglyceride lowering among patients with severe hypertriglyceridemia. J Clin Lipidol 2012;6:443-9. Pirillo A, Catapano AL. Update on the management of severe hypertriglyceridemia--focus on free fatty acid forms of omega-3. Drug Des Devel Ther 2015;9:2129-37. Lu G, Windsor SL, Harris WS. Omega-3 fatty acids alter lipoprotein subfraction distributions and the in vitro conversion of very low density lipoproteins to low density lipoproteins. J Nutr Biochem 1999;10:151-8. Jacobson TA. Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr 2008;87:1981S-90S. Satoh N, Shimatsu A, Kotani K, et al. Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in metabolic syndrome. Diabetes Care 2007;30:144-6. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk 1997;4:385-91. Pownall HJ, Brauchi D, Kilinc C, et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 1999;143:285-97. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol 2011;108:682-90. Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova((R)) compared to Lovaza((R)) in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol 2012;6:573-84. Offman E, Marenco T, Ferber S, et al. Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study. Vasc Health Risk Manag 2013;9:563-73. Kastelein JJ, Maki KC, Susekov A, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. J Clin Lipidol 2014;8:94-106. Maki KC, Orloff DG, Nicholls SJ, et al. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clin Ther 2013;35:1400-11.e1-3.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Diet

Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase, Adenosine Triphosphate, Apolipoprotein C-III, Arachidonic Acid, Atherosclerosis, Biological Availability, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cholesterol, HDL, Cost-Benefit Analysis, Diabetes Mellitus, Diet, Fat-Restricted, Docosahexaenoic Acids, Double-Blind Method, Drug Combinations, Eicosapentaenoic Acid, Esters, Fatty Acids, Fatty Acids, Omega-3, Fatty Acids, Nonesterified, Fibric Acids, Fish Oils, Hydrolysis, Hypertriglyceridemia, Inflammation Mediators, Life Style, Lipase, Lipogenesis, Lipoproteins, Lipoproteins, HDL, Lipoproteins, VLDL, Niacin, Obesity, Overweight, Pancreatitis, Prevalence, Receptors, Cytoplasmic and Nuclear, Risk Factors, Triglycerides, Weight Loss