Efficacy of rebamipide for the treatment of dry eye disease: An updated meta-analysis of randomized and non-randomized controlled trials

BACKGROUND: Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by tear film instability and inflammation. Rebamipide 2% ophthalmic suspension, a mucin secretagogue, has been investigated as a potential treatment due to its unique mechanism targeting mucin deficiency and ocular surface repair. METHODS: A systematic search of PubMed, Embase, and Cochrane Library was conducted for studies published between January 2013 and March 2025. Non-randomized and randomized controlled trials evaluating topical 2% rebamipide in patients with DED were included. Outcomes assessed included tear breakup time, Schirmer I test, fluorescein staining scores, ocular surface disease index, and adverse events. Data were synthesized using standard meta-analytic techniques and subgroup analyses. RESULTS: Thirteen studies, including both randomized and non-randomized trials, were analyzed, comprising a total of 575 participants. Meta-analysis showed that rebamipide nonsignificantly increased tear breakup time at 2 weeks (standardized mean difference [SMD] = 1.04; 95% confidence interval (CI):-0.94 to 3.03; P = .30; I2 = 89.3%), significant at 4 weeks (SMD = 1.19; 95% CI: 0.74-1.64; P < .0001; I2 = 85%) and nonsignificant at 12 weeks (SMD = 0.97; 95% CI:-0.15 to 2.08; P = .09; I2 = 80.1%) indicating enhanced tear film stability. Schirmer I test values showed no significant improvement (SMD = 0.04; 95% CI: -0.35-0.43; P = .83), suggesting limited effect on aqueous tear production. Fluorescein staining scores showed a reduction approaching statistical significance (SMD = -0.68; P = .051), while symptom scores measured by ocular surface disease index trended toward improvement, also approaching significance (SMD = -1.17; P = .055). Subgroup analyses revealed greater efficacy in contact lens wearers and postsurgical patients. Safety analysis indicated excellent tolerability, with a high adherence rate (96.8%) and only mild adverse effects such as dysgeusia and nasopharyngitis. CONCLUSION: Rebamipide 2% ophthalmic suspension improves tear stability and ocular surface health in mucin-deficient DED with a favorable safety profile. Further high-quality trials in diverse populations are warranted to confirm its role in global clinical practice.