Omega-3–tocotrienol–vitamin D3 combination versus fenofibrate in mixed dyslipidemia: a multicenter, randomized, controlled trial

Introduction: Mixed dyslipidemia is highly prevalent in the Indian population and is a major contributor to residual cardiovascular risk despite statin therapy. Fenofibrate remains a commonly used triglyceride-lowering agent; however, its long-term use is limited by safety concerns. Nutraceutical combinations containing omega-3 fatty acids, tocotrienols, and vitamin D3 have shown potential synergistic effects on lipid metabolism, inflammation, and insulin resistance, but robust comparative clinical evidence against fibrates is lacking. This study aimed to evaluate the superiority of a fixed-dose combination of omega-3 fatty acids (EPA, DHA, ALA), tocotrienol, and vitamin D3 compared with fenofibrate, when used in combination with rosuvastatin, in reducing serum triglyceride levels in patients with mixed dyslipidemia. Material and methods: A multicenter, open-label, randomized, active-controlled, parallel-group study was conducted across five tertiary care centers in India, including KPC Medical College and Hospital, Kolkata, following institutional ethics committee approval. A total of 312 patients aged 18–70 years with mixed dyslipidemia were randomized in a 1:1 ratio to receive either rosuvastatin 10 mg plus a nutraceutical fixed-dose combination (EPA 525 mg, DHA 375 mg, ALA 500 mg, tocotrienol 60 mg, and vitamin D3 1000 IU) or rosuvastatin 10 mg plus fenofibrate 160 mg once daily for 180 days. The primary endpoint was percentage change in fasting serum triglyceride levels from baseline to end of study. Secondary endpoints included changes in HDL-C, LDL-C, hs-CRP, insulin resistance (HOMA-IR), and safety parameters. Statistical analysis was performed using intention-to-treat principle, with ANCOVA adjustment, mixed-effects modeling, and multivariate regression. Results: The nutraceutical combination demonstrated significantly a greater reduction in triglyceride levels compared with fenofibrate (−48.2% ± 12.4 vs. −36.5% ± 11.1), with a mean difference of −11.7% (95% CI −14.5 to −8.9; p < 0.001). Significant improvements wer also observed in HDL-C (+12.6% vs. +7.8%, p = 0.003), LDL-C reduction (−22.4% vs. −18.2%, p = 0.04), hs-CRP reduction (−38.4% vs. −21.6%, p < 0.001), and HOMA-IR (−21.3% vs. −12.5%, p = 0.002). ANCOVA-adjusted analysis confirmed independent treatment superiority (p < 0.001), with a large effect size (Cohen’s d = 1.12). The incidence of adverse events was significantly lower in the nutraceutical group (8.3% vs. 18.6%, p = 0.01). Conclusions: The combination of omega-3 fatty acids, tocotrienol, and vitamin D3 is significantly superior to fenofibrate in reducing serum triglyceride levels and improving cardiometabolic parameters when used alongside statin therapy, with a more favorable safety profile. This combination represents a promising alternative therapeutic strategy for managing mixed dyslipidemia in Indian patients.