Patients with severe hypertriglyceridemia benefit from omega-3 carboxylic acids 2 g/day

Omega-3 carboxylic acids in patients with severe hypertriglyceridemia: EVOLVE II, a randomized, placebo-controlled trial

Literature - Stroes ESG, Susekov AV, de Bruin TWA, et al. - J of Clin Lipidol 2017; printed online ahead of print

Background

Severe hypertriglyceridemia (SHTG) is characterized by a serum TG concentration ≥ 500 mg/dL (5.65 mmol/L), and is associated with a high risk of acute pancreatitis and CVD [1,2]. International guidelines state that the treatment goal is to minimize TG concentration in this condition, for example by administration of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [3,4]. A new formulation of omega-3 carboxylic acids (OM3-CA), derived from fish oils and containing EPA and DHA, provides improved bioavailability compared with ethyl ester formulations, and is approved for treatment of SHTG with a daily dose of 2 g or 4 g as an adjunct to diet [5,6].

In this randomized, double-blind, phase 3 trial, the primary objectives were to assess the efficacy and safety of OM3-CA 2 g daily compared with olive oil 2 g daily in reducing serum TG and lipid concentrations over a 12-week treatment period. This study enrolled 162 patients with SHTG, including patients with qualifying TG concentrations > 885 mg/dL (10 mmol/L) and patients with Fredrickson Type V hyperlipidemia, a condition which is biochemically defined as TG:VLDL-c ratio ≥ 6.

The secondary objectives of the study were to determine the effects of OM3-CA 2 g daily, compared with olive oil 2 g daily, on non-HDL-c and HDL-c concentrations over a 12-week treatment period, whereas the effects of the study medication on LDL-c and LVDL-c comprised the exploratory objectives of this investigation.

Eligible participants had a BMI ≥ 20 kg/m2, untreated dyslipidemia or dyslipidemia treated with lipid-lowering therapy, and qualifying serum TG concentrations of ≥ 500 mg/dL and < 2500 mg/dL (< 2000 mg/dL in Canada).

Main results

  • In the overall study population, the median percentage change from baseline in TG concentrations in the OM3-CA treatment group was –28.1% (interquartile range [IQR]: –42.1% to –5.5%) versus –10.2% (IQR: –36.4% to 23.0%) in the olive oil treatment group.
  • For patients with qualifying TG concentrations > 885 mg/dL, the median percentage change in TG concentrations for the OM3-CA treatment group was –37.5% (IQR: –46.1% to –18.1%) versus –9.3% (IQR: –36.3% to 27.0%) in the olive oil treatment group.
  • The median of differences in TG concentrations between the two treatment groups was –14.2% (95%CI: –26.2% to –2.8%; P=0.017) in the overall study population and –26.3% (95%CI: –40.5% to –11.5%; P=0.001) in patients with qualifying TG concentrations > 885 mg/dL.
  • The median of differences in non-HDL-c concentrations between the two treatments was statistically significant in both the overall study population (–9.0%; 95%CI: –14.8% to –2.8%; adjusted P=0.018), as well as in patients with qualifying TG concentrations > 885 mg/dL (–15.9%; 95%CI: -24.0% to –7.8%; unadjusted P=0.001).
  • The median of differences between the two treatments was not statistically significant with respect to HDL-c concentrations in the overall study population and in patients with qualifying TG concentrations > 885 mg/dL.
  • In 112 patients with Fredrickson type V hyperlipidemia, the median of differences between the two treatment groups was not statistically significant in the overall study population (–10.3%; 95%CI: –23.9% to 3.5%; adjusted P=0.303), but it was statistically significant in those with qualifying TG concentrations > 885 mg/dL (–24.3%; 95%CI: –40.9% to –7.3%; unadjusted P=0.007).
  • Treatment with either OM3-CA or olive oil resulted in a non-significant difference in LDL-c concentrations in the overall study population, as well as in patients with qualifying TG concentrations > 885 mg/dL.
  • In the overall study population, the median percentage change from baseline to week 12 in VLDL-c concentrations in the OM3-CA treatment group was –19.0% (IQR: –34.7% to –3.6%) versus –0.8% (IQR: –29.2% to 24.2%) in the olive oil treatment group with a median difference of -14.5%; 95%CI: -24.9% to -4.0%; unadjusted P=0.006). For patients with qualifying TG concentrations > 885 mg/dL, the median percentage change in VLDL-c concentrations was –28.2% (IQR: –37.9% to –12.9%) in the OM3-CA treatment group and –0.2% (IQR: –28.8% to 28.8%) in the olive oil treatment group with a median difference of -25.0%; 95%CI: -36.7% to -11.0%, unadjusted P=0.001).
  • In general, treatment with OM3-CA was well tolerated. There were 13 reported treatment-emergent adverse events (TEAEs) that were considered to be related to the study drug, seven in the OM3-CA treatment group and six in the olive oil treatment group, of which diarrhea, dysgeusia, and eructation were the most commonly reported.

Conclusion

Patients with SHTG treated with OM3-CA 2 g daily had a statistically significant reduction in TG and non-HDL-c concentrations compared with those treated with olive oil 2 g daily. Patients with qualifying TG concentrations > 885 mg/dL (> 10 mmol/L) showed a larger TG reduction than those in the overall study population. These findings suggest that OM3-CA may be useful for the prevention of acute pancreatitis and CVD in these patients.

References

1. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–2381.

2. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37(39):2999–3058.

3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res.2016;118(4):547–563.

4. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1–full report. J Clin Lipidol.2015;9(2):129–169.

5. Davidson MH, Johnson J, Rooney MW, et al. 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®) compared to Lovaza®) in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol.2012;6(6):573–584.

6. Lawson LD, Hughes BG. Human absorption of fish oil fatty acids as triacylglycerols, free acids, or ethyl esters. Biochem Biophys Res Commun. 1988;152(1):328–335.

Find this article online at J Clin Lipidol 2017

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