Background/rationale: Treatment of severe hypertriglyceridemia is indicated to reduce the risk of pancreatitis in patients with triglyceride (TG) levels > or =500 mg/dL. Hypertriglyceridemia is also a risk factor for atherosclerotic coronary heart disease. Prescription omega-3 fatty acids (P-OM3) and fenofibrate (FENO) are among the most effective lipid-altering agents that reduce TG levels. Given that some patients may not achieve optimal TG levels with a single agent, we hypothesized that concomitant use of P-OM3 or addition of P-OM3 to FENO would result in a TG reduction greater than that with FENO alone.
Methods: This randomized, 8-week, double-blind, placebo-controlled study was designed to compare the safety and efficacy of P-OM3 4 g QD plus concomitant FENO 130 mg with FENO 130 mg QD plus placebo in subjects with very high TG levels (> or =500 mg/dL). Subjects who completed the double-blind study were given the option to continue into an open-label, 8-week extension study, wherein they all received P-OM3 4 g plus FENO 130 mg QD. On completion of the first extension study, subjects were eligible to continue into an open-label 24-month extension of the treatment with P-OM3 4 g plus FENO 130 mg QD.
Results: Concomitant P-OM3 + FENO (n = 81) and FENO monotherapy (n = 82) reduced median TG values from 649.5 to 267.5 mg/dL (60.8%) and from 669.3 to 310 mg/dL (53.8%), respectively (P = 0.059). When subjects who had received 8 weeks of stable FENO monotherapy were given P-OM3 during the 8-week, open-label extension study (n = 58), TG levels were reduced 17.5% (P = 0.003) over the course of the extension. The second extension phase was terminated early (n = 93)-not because of a safety signal but because of the lack of a substantial incremental change in the primary endpoint lipid values above that reached in either the original study or the first extension in subjects receiving the combination of fenofibrate and P-OM3.
Conclusions: Both FENO monotherapy and P-OM3 + FENO significantly reduced TGs in subjects with very high TGs, with a trend to greater reduction in the P-OM3 + FENO group. The addition of P-OM3 to stable FENO therapy in the same subjects in an open-label extension study resulted in a statistically significant reduction in TG levels. Subjects who received P-OM3 + FENO for 16 weeks and subjects in which P-OM3 was added to FENO monotherapy during the open-label phase of the study did not differ in their final lipid responses. In the second open-label extension, within the combined group taking P-OM3 and FENO, analysis of change from the second extension baseline to end of treatment revealed no clinically important change.
Trial registration: ClinicalTrials.gov NCT00246636 NCT00891293.