The effects of different forms of omega-3 polyunsaturated fatty acids on dry eye disease resulting from various etiologies: a meta-analysis and systematic review

BACKGROUND: To compare the therapeutic effects of omega-3 polyunsaturated fatty acids (PUFAs) supplements across different formulations and dry eye disease (DED) etiologies. METHODS: Studies were systematically searched in six databases without language restrictions. Dry eye symptom scores, tear break-up time (TBUT), Schirmer test, corneal fluorescein staining (CFS), and meibomian gland dysfunction (MGD) scores were extracted as outcomes. Meta-regression, sensitivity and subgroup analyses were implemented to investigate significant heterogeneity. RESULTS: Twenty-seven randomized controlled trials (RCTs) were included. Systemic omega-3 supplementation appeared to improve all assessed outcomes in the overall pooled analysis; however, subgroup analyses revealed formulation- and etiology-dependent effects. Among systemic long-chain omega-3 formulations, efficacy was etiology-dependent: no significant benefits were observed in MGD-associated dry eye or in cases of unspecified etiology, whereas significant improvements were found in video display terminal-related dry eye and contact lens-associated dry eye. Given the limited evidence, findings were synthesized qualitatively: omega-3 supplements demonstrated beneficial effects in rosacea-associated and Sjögren's syndrome-related dry eye, whereas no clinically meaningful improvement was observed in LASIK-induced dry eye. In contrast, neither systemic short-chain fatty acids nor the combination of long- and short-chain omega-3 PUFAs achieved statistical significance. Furthermore, topical omega-3 delivery failed to demonstrate significant benefits compared with artificial tears. Meta-regression analysis revealed a significant association between omega-3 supplementation and several external factors, including mean age, geographic location, assessment methodologies, omega-3 dose, and publication year. CONCLUSIONS: Our research suggests that omega-3 supplements in different forms fail to demonstrate consistent effectiveness for DED of various etiological origins. Therefore, personalized guidance from healthcare providers regarding the application of omega-3 PUFAs for the management of ocular surface disorders is warranted. PROSPERO REGISTRATION: CRD42024623916.