Efficacy of phospholipid-bound omega-3 versus standard omega-3 in patients with hypertriglyceridemia: a randomized clinical trial

Abstract Background Hypertriglyceridemia is a modifiable risk factor for cardiovascular disease, and while omega-3 fatty acids (omega-3 FAs) are known to lower triglyceride (TG) concentrations, their effectiveness is influenced by formulation and bioavailability. Phospholipid-bound (PL) omega-3 FAs—such as those found in krill oil—demonstrate superior intestinal absorption and membrane integration compared with TG- and ethyl ester omega-3 FAs based forms. Preclinical studies have shown that PL omega-3 FAs exhibit anti-inflammatory, antithrombotic, and TG-lowering properties; however, clinical data remain limited. This pilot randomized clinical trial compared the efficacy of PL omega-3 FAs with standard omega-3 FAs in patients with mild to moderate hypertriglyceridemia. Methods We performed a randomized, controlled, double-blind, parallel-group pilot trial involving patients aged 18–65 years with fasting TG between 150 and 499 mg/dL. Patients were randomized to receive PL omega-3 FAs (eicosapentaenoic acid [EPA) + docosahexaenoic acid [DHA), 825 mg/day) or standard omega-3 FAs (EPA + DHA, 903 mg/day). Primary outcomes were changes in fasting TG and omega-3 index (O3I) after 12 weeks. Secondary outcomes included changes in lipid profile, glycemic markers, inflammatory markers, anthropometric measures, hemodynamic variables, and safety parameters. Results Of the 47 randomized participants, 44 (22 per group) completed the study and were included in the analysis. Mean TG levels decreased slightly in the PL group (-9.1 mg/dL) and increased in the standard group (+ 15.2 mg/dL), with no statistically significant difference between-groups ( p  = 0.416). Although the O3I increased significantly in both groups, the between-group difference was not statistically significant, despite a greater rise in the PL group (+ 1.78% vs. +1.50%, p  = 0.446). At week 12, 36.4% of participants in the PL group achieved TG ≤ 150 mg/dL, compared with 13.6% in the standard group ( p  = 0.041). No serious adverse events were reported, and treatment adherence exceeded 95%. Conclusions In summary, this pilot randomized trial did not demonstrate statistically significant differences between the PL and TG formulations in triglyceride or Omega-3 Index reduction. However, the numerically higher responder rate and favorable biochemical trends observed with the PL formulation warrant further investigation in larger, adequately powered studies. Trial registration NCT06749028 (retrospectively registered on December 19, 2024, after enrollment of the first participant). Available at: https://clinicaltrials.gov/study/NCT06749028 . European Food Safety Authority (EFSA) EFSA-2024-00030369.