Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events (STRENGTH)

The STRENGTH (A Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial randomized 13,078 high-cardiovascular-risk patients with hypertriglyceridemia to high-dose omega-3 carboxylic acid (4 g/day, combined EPA+DHA) or corn oil and followed them for cardiovascular events.

The trial was stopped early for futility: the omega-3 CA group showed no reduction in major adverse cardiovascular events compared with the corn oil control. Triglycerides were reduced and HDL modestly increased, confirming pharmacological activity, but these lipid changes did not translate to clinical benefit. Notably, the corn oil comparator itself may have had modest cardiovascular effects, complicating interpretation.

The STRENGTH result stands in direct contrast to REDUCE-IT (icosapentaenoic acid, EPA only, 4 g/day), which showed a 25% relative risk reduction in MACE. The critical difference is the formulation: REDUCE-IT used pure EPA, while STRENGTH used EPA+DHA combined. The most discussed hypothesis is that DHA attenuates EPA’s anti-inflammatory and plaque-stabilizing effects — though the debate about mineral oil as a control in REDUCE-IT remains unresolved.

Together, STRENGTH and REDUCE-IT define the central controversy in omega-3 cardiology: the same lipid-lowering effect without clinical benefit (DHA+EPA) versus clinical benefit without an obvious lipid mechanism (EPA alone). The divergence argues strongly that the EPA effect, if real, is not mediated by triglyceride lowering.

We rate the evidence strong. A well-powered, rigorously executed null trial that reshapes how we interpret the omega-3 literature and narrows the question to EPA-specific versus combination formulations.