Efficacy of Omega-3 Fatty Acid Supplements in the Management of CDE

Key Takeaways:

• Evidence is conflicting. Research findings on omega-3s for dry eye disease are mixed; the 2018 DREAM study found no benefit over a placebo, but a 2023 meta-analysis of 19 trials showed significant improvements in symptoms.
• Efficacy is likely formulation-dependent. The 2023 meta-analysis identified a significant positive correlation between DED symptom reduction and 3 factors: higher daily dose, longer duration of intake, and especially a higher percentage of EPA.
• The DREAM extension study found that patients who stopped taking omega-3 supplements after 12 months did not have significantly worse outcomes than those who continued the supplement for an additional year.

Chronic dry eye is a multifactorial disorder characterized by ocular discomfort, visual disturbance, and tear film instability, often driven by underlying ocular surface inflammation.^1-4

While standard first-line treatments include artificial tears, lubricating ointments, and topical anti-inflammatory agents, both patients and clinicians have shown significant interest in systemic interventions, particularly omega-3 fatty acid supplementation.^1-4

The rationale for using omega-3s stems from their established anti-inflammatory properties. However, the clinical evidence regarding their efficacy in managing dry eye disease has been complex and, at times, contradictory. For clinicians navigating patient questions, understanding the nuances of this research, including the major trials and subsequent meta-analyses, can be helpful.^1,2,5

The scientific rationale for omega-3 in dry eye

Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are long-chain polyunsaturated fatty acids. Their therapeutic potential in inflammatory conditions is linked to their role in lipid mediator pathways. Omega-3s serve as competitive substrates against arachidonic acid (an omega-6 fatty acid), shifting eicosanoid production toward a less inflammatory state.^1,2,5

Furthermore, EPA and DHA are precursors to specialized pro-resolving mediators (SPMs), such as resolvins and protectins, which actively help resolve inflammation rather than just blocking it. In the context of CDE, researchers have suggested that omega-3s may also improve the lipid composition of the meibomian glands, enhancing tear film quality and reducing evaporation.^1,2,5

The DREAM study findings

A significant portion of the clinical debate regarding omega-3s is dominated by the Dry Eye Assessment and Management (DREAM) study, a large-scale, multicenter, randomized controlled trial funded by the National Eye Institute.²

The primary DREAM trial, published in 2018, compared the effects of 3000 mg of omega-3 (2000 mg EPA and 1000 mg DHA) against a refined olive oil placebo in patients with moderate to severe DED. After 12 months, the study found that while both groups showed improvement in symptoms, there was no statistically significant difference between the omega-3 group and the placebo group for the primary outcome, the Ocular Surface Disease Index (OSDI) score, or for secondary outcomes of clinical signs (e.g., conjunctival staining, corneal staining, Tear Break-Up Time [TBUT], and Schirmer test).^2,5

A 2019 follow-up, the DREAM extension study, evaluated the effects of withdrawing supplementation. Patients from the primary trial who had received active omega-3 for 12 months were randomized to either continue the supplement or switch to the olive oil placebo for an additional 12 months.⁶

The results were consistent: Discontinuing omega-3 supplementation did not lead to significantly worse outcomes compared to continuing it. The authors of the DREAM studies concluded that their results, taken together, do not support a beneficial effect of omega-3 supplementation on DED.^5,6

A comprehensive meta-analysis

While the DREAM study results were definitive in their cohort, they stand in contrast to a large body of other research. A 2023 systematic review and meta-analysis aggregated data from 19 randomized clinical trials conducted between 2013 and 2023, encompassing 4,246 dry eye disease patients.¹

This comprehensive analysis, which included the DREAM studies in its pooled data, found that omega-3 supplementation provided statistically significant improvements compared to placebo across multiple metrics:¹

• Dry eye symptoms – Patients receiving omega-3s showed a significant reduction in symptom scores.
• TBUT – Omega-3 intake resulted in a significant improvement in tear break-up time.
• Schirmer test – Supplementation was associated with a significant increase in tear production.
• Osmolarity – A significant decrease in tear osmolarity was noted in the omega-3 group.

Reconciling the data: Dose, duration, and EPA

The critical question for clinicians is how to reconcile the negative findings of the large-scale DREAM trial with the overwhelmingly positive results of the 2023 meta-analysis. The meta-analysis itself offers a potential answer through its meta-regression analysis.¹

The researchers found a significant positive correlation between the efficacy of omega-3s and 3 specific factors:¹

• Daily dose – Higher doses were associated with greater symptom reduction.
• Duration of intake – Longer treatment periods were linked to better outcomes.
• EPA percentage – A higher percentage of EPA in the supplement correlated significantly with a reduction in dry eye symptom scores.

This suggests that not all omega-3 supplements are created equal, and formulation may be paramount. The DREAM study used a high-quality supplement, but its specific 2:1 EPA-to-DHA ratio was just 1 formulation.^1,2

The meta-analysis included studies with EPA percentages as high as 80 percent. This finding implies that the type of omega-3, particularly one with a very high concentration of EPA, may be more critical than the total omega-3 dose alone.¹

Clinical considerations

While the DREAM trial provided high-quality evidence that 1 specific formulation was not superior to placebo, it does not close the door on omega-3s as a therapeutic category. The broader 2023 meta-analysis of 19 trials strongly suggests that omega-3 fatty acids are effective in reducing and improving DED signs and symptoms.^1,2

For clinicians, the key takeaway is that efficacy is likely dependent on regimen details. Based on the current evidence, supplementation with high-dose, high-EPA-concentration omega-3 fatty acids for a duration of 3 months or more may offer a significant benefit to patients with chronic dry eye.¹