Omega-3 and omega-6 polyunsaturated fatty acids for dry eye disease (Review)

Background Polyunsaturated fatty acid (PUFA) supplements, involving omega-3 and/or omega-6 components, have been proposed as a therapy for dry eye. Omega-3 PUFAs exist in both short- (alpha-linolenic acid [ALA]) and long-chain (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHAD forms, which largely derive from certain plant-and marine-based foods respectively. Omega-6 PUFAs are present in some vegetable oils, meats, and other animal products. Objectives To assess the effects of omega-3 and omega-6 polyunsaturated fatty acid (PUFA) supplements on dry eye signs and symptoms. Search methods CENTRAL, Medline, Embase, two other databases and three trial registries were searched in February 2018, together with reference checking. A top-up search was conducted in October 2019, but the results have not yet been incorporated. Selection criteria We included randomized controlled trials (RCTs) involving dry eye participants, in which omega-3 and/or omega-6 supplements were compared with a placebo/control supplement, artificial tears, or no treatment. We included head-to-head trials comparing different forms or doses of PUFAs. Data collection and analysis We followed standard Cochrane methods and assessed the certainty of the evidence using GRADE. Main results We included 34 RCTs, involving 4314 adult participants from 13 countries with dry eye of variable severity and etiology. Follow-up ranged from one to 12 months. Nine (26.5%) studies had published protocols and/or were registered. Over half of studies had high risk of bias in one or more domains. Long-chain omega-3 (EPA and DNA) versus placebo or no treatment (10 RCTs) We found low certainty evidence that there may be little to no reduction in dry eye symptoms with long-chain omega-3 versus placebo (four studies, 677 participants; mean difference [MD]-2.47, 95% confidence interval [CI]-5.14 to 0.19 units). We found moderate certainty evidence for a probable benefit of long-chain omega-3 supplements in increasing aqueous tear production relative to placebo (six studies, 1704 participants; MD 0.68, 95% CI 0.26 to 1.09 mm/5 min using the Schirmer test), although we did not judge this difference to be clinically meaningful. We found low certainty evidence fora possible reduction in tear osmolarity (one study, 54 participants; MD-17.71, 95% Cl -28.07 to -7.35 mOsmol/L). Heterogeneity was too substantial to pool data on tear break-up time (TBUT) and adverse effects. Combined omega-3 and omega-C versus placebo (four RCTs) For symptoms (low certainty) and ocular surface staining (moderate certainty), data from the four included trials could not be meta-analyzed, and thus effects on these outcomes were unclear. For the Schirmer test, we found moderate certainty evidence that there was no intergroup difference (four studies, 455 participants; MD: 0.66, 95% CI -0.45 to 1.77 mm/5 min). There was moderate certainty fora probable improvement in TBUT with the PUFA intervention relative to placebo (four studies, 455 participants; MD 0.55, 95% CI 0.04 to 1.07 seconds). Effects on tear osmolarity and adverse events were unclear, with data only available from a single small study for each outcome. Omega-3 plus conventional therapy versus conventional therapy alone (two RCTs) For omega-3 plus conventional therapy versus conventional therapy alone, we found low certainty evidence suggesting an intergroup difference in symptoms favoring the omega-3 group (two studies, 70 participants; MD-7.16, 95% CI-13.97 to -0.34 OSDI units). Data could not be combined for all other outcomes. Long-chain omega-3 (EPA and DNA) versus omega-C (five RCTs) For long-chain omega-3 versus omega-6 supplementation, we found moderate certainty evidence for a probable improvement in dry eye symptoms (two studies, 130 participants; MD -11.88, 95% CI-18.85 to -4.92 OSDI units). Meta-analysis was not possible for outcomes relating to ocular surface staining. Schirmer test or TBUT. We found low certainty evidence for a potential improvement in tear osmolarity (one study, 105 participants; MD -11.10, 95% CI -12.15 to -10.05 mOsmol/L). There was low level certainty regarding any potential effect on gastrointestinal side effects (two studies, 91 participants; RR 2.34, 95% CI 0.35 to 15.54). Authors' conclusions Overall, the findings in this review suggest a possible role for long-chain omega-3 supplementation in managing dry eye disease, although the evidence is uncertain and inconsistent. A core outcome set would work toward improving the consistency of reporting and the capacity to synthesize evidence. PLAIN LANGUAGE SUMMARY Omega-3 and omega-6 polyunsaturated fatty acid supplements for dry eye disease What is the aim of this review? Dry eye is a long-term eye condition that can lead to eye discomfort and changes to vision. Omega-3 and omega-6 supplements, including the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been studied as a treatment for dry eye. This Cochrane Review summarizes the best available research evidence. Key messages More research is needed to gain a full understanding of the role of omega-3 and omega-6 supplements in treating dry eye disease, particularly with how to use this therapy to treat dry eye due to different causes and severities. There is also a need for more research to provide information about how the supplement characteristics (eg, dose, form, composition) affect clinical outcomes. What was studied in the review? The main outcome was improvement in dry eye symptoms, measured after at least one month of follow-up. Secondary outcomes considered a range of clinical measures and side effects. What are the main results of the review? We included 34 randomized controlled trials (RCTs) involving more than 4314 adult participants from 13 countries. Although much of the evidence was uncertain, long-chain omega-3 supplements may have little to no benefit, relative to placebo, on dry eye symptoms, but did improve some clinical signs. There was a beneficial effect on dry eye symptoms when omega-3 supplements were combined with standard dry eye treatments (eg, artificial tears, eyelid warm compresses, corticosteroid eye drops) compared to standard treatment alone, and when long-chain omega-3 supplements were compared with omega-6 supplements. The most common side effect was temporary gastrointestinal problems. For combined omega-3 and omega-6 supplements, relative to placebo, there was no benefit for tear production, and a small amount of improvement in the stability of the tears. Effects on other clinical measures, including dry eye symptoms and side effects, could not be clearly determined. It is also unclear whether other types of supplement combinations are effective for treating dry eye. We have low to moderate confidence in the evidence for ail outcomes. These findings suggest that long-chain omega-3 supplements may have a role in managing dry eye, however the evidence is currently inconsistent and more research is needed. How up-to-date is this review? The Cochrane review authors searched for studiesthat had been published up to February 2018. A top-up search was conducted in October 2019, but the results have not yet been incorporated.