We employed a comprehensive and structured literature search aligned with the PRISMA framework (Figure 1) to enhance the transparency and rigor of our study selection. The protocol initiated with the retrieval of 146 candidate research articles, pinpointed through meticulous database queries that leveraged precisely formulated keywords and search operators. A preliminary relevance screening of titles and abstracts, coupled with the deduplication of results, yielded 47 articles for a more comprehensive appraisal. This in-depth analysis assessed both abstracts and complete manuscripts to ascertain a precise alignment with our focus on the safety and therapeutic potential of topical insulin treatments within the realm of ophthalmology. The stringent application of our eligibility criteria culminated in the selection of 10 pivotal articles [11-20] for further data extraction and synthesis.
Our systematic literature review investigated the safety profile and clinical effectiveness of topical insulin for the management of various eye diseases. The ten selected studies represented a methodological spectrum, including case-control (n=1), randomized prospective (n=3), retrospective (n=3), and double-blind (n=3) study designs. This research originated from diverse geographical contexts and incorporated sample populations of 3 to 160 individuals.
A combined total of 10 clinical trials met the criteria for inclusion in the systematic review for quantitative analysis.
Delineating the key characteristics of the selected studies
- Study 1: Wang AL, et al.11; Objective: “To report the clinical course of 6 patients with refractory neurotrophic corneal ulcers that were treated with topical insulin drops”; Method: Retrospective study; Conclusion: “Topical insulin may be a simple and effective treatment for refractory neurotrophic corneal ulcers”.
- Study 2: Diaz-Valle D, et al.12; Objective: “To investigate the effect of topical insulin on epithelization in persistent epithelial defects refractory to usual treatment compared to autologous serum”; Method: Retrospective, consecutive case-control series; Conclusion: “Topical insulin is an effective treatment and safely promotes healing of persistent epithelial defects”.
- Study 3: Diaz-Valle D, et al.13; Objective: “To evaluate insulin eye drops for persistent epithelial defects that are refractory to usual treatment in clinical practice and to analyze how it may improve epithelization”; Method: Prospective non-randomized; Conclusion: “Topical insulin can promote and accelerate corneal reepithelization of refractory persistent epithelial defects”.
- Study 4: Esmail A, et al.14; Objective: “To evaluate the effect of topical insulin in treatment of recurrent epithelial corneal erosion”; Method: Prospective non-randomized; Conclusion: “Topical insulin can promote corneal reepithelization in recurrent epithelial erosion and decreases recurrence in these cases”.
- Study 5: Burgos-Blasco B, et al.15; Objective: “To evaluate the efficacy of insulin eye drops for dry eye disease in reducing corneal staining and improving symptoms”; Method: Retrospective case series; Conclusion: “The excellent results presented in these case series illustrate topical insulin as a promising treatment in dry eye disease with refractory epithelial damage”.
- Study 6: Soares RJDSM, et al.16; Objective: “To evaluate the clinical outcome of patients with refractory neurotrophic keratopathy in stages 2 and 3 treated with topical insulin”; Method: Retrospective study; Conclusion: “Our results suggest that topical insulin drops may be an effective therapeutic in refractory neurotrophic keratopathy”.
- Study 7: Balal S, et al.17; Objective: “To evaluate the effectiveness of insulin eye drops for treating refractory persistent epithelial defects”; Method: Prospective case series; Conclusion: “The use of topical insulin eye drops led to a successful resolution of persistent epithelial defects”.
- Study 8: Dasrilsyah AM, et al.18; Objective: “To measure and compare the effect of topical insulin (0.5 units, 4 times per day) versus artificial tears (Vismed, sodium hyaluronate 0.18%, 4 times per day) for the healing of postoperative corneal epithelial defects induced during vitreoretinal surgery in diabetic patients”; Method: Double-blind randomized controlled; Conclusion: “Topical insulin is more effective compared with artificial tears for the healing of postoperative corneal epithelial defects induced during vitreoretinal surgery in diabetic patients, without any adverse events”.
- Study 9: Fai S, et al.19; Objective: “To determine the effect of topical insulin of 3 concentrations on postoperative corneal epithelial wound healing in diabetic patients”; Method: Double blind randomized controlled; Conclusion: “Topical insulin 0.5 units 0.5, 1, and 2 units per drop 4 times per day is most effective for healing corneal epithelial defect in diabetic patients after vitrectomy surgery compared with placebo and higher concentrations”.
- Study 10: Aniah Azmi N, Bastion MC.20; Objective: “To assess the short-term effects of topical insulin 1 unit/drop 4 times per day for 4 weeks on the symptoms and signs of diabetic with dry eye disease”; Method: Randomized, double-blind interventional study; Conclusion: “The study has shown a significant and similar improvement in the Ocular Surface Disease Index score for topical insulin 1 unit/drop four times daily and standard artificial tears in treating diabetics with dry eye disease”.
Methodological Evaluation and Risk of Bias
This systematic review rigorously assessed the quality and potential biases within the ten included studies. Employing a multifaceted approach, we categorized the studies based on methodological strength. Three studies demonstrated robust methodologies, meriting designation as "high quality." An additional three exhibited moderate methodological rigor, falling under the "medium quality" category. The remaining four studies presented limitations in methodology, resulting in a "low quality" classification.
Furthermore, a risk of bias assessment was conducted utilizing the QUADAS-2 tool, revealing a concerning distribution of potential biases that could potentially influence the study findings. Four studies exhibited a high risk of bias, necessitating cautious interpretation of their results. Three studies demonstrated a moderate risk of bias, requiring careful consideration when drawing conclusions. Fortunately, three studies displayed a low risk of bias, offering a more robust foundation for their findings. A comprehensive overview of the included studies and their respective quality and risk of bias assessments is presented in Table 1.
Potential of Topical Ocular Insulin for Ocular Disease Management
The ten studies meticulously evaluated in this review unveil the promising potential of topical ocular insulin as a simple, safe, and cost-effective therapeutic approach for diverse ocular conditions. These conditions encompass neurotrophic corneal ulcers, corneal re-epithelialization in persistent epithelial defects, dry eye disease, recurrent epithelial erosion, and corneal epithelial defects induced during vitreoretinal surgery in diabetic patients. Notably, none of the studies reported any adverse events associated with topical ocular insulin administration.
These findings collectively suggest that topical ocular insulin could emerge as a promising first-line treatment modality for a range of ocular disorders. Its favorable attributes, including excellent tolerability, readily available formulation, and cost-effectiveness, position it as a potential alternative to conventional therapeutic strategies. Further research is warranted to confirm these initial findings and establish the optimal therapeutic role of topical ocular insulin in the management of various ocular diseases.
Table 1. The synthesis of the research and corresponding results.
Safety and Efficacy of Topical Insulin for Ocular Disease
A total of four studies (299 subjects) compared the healing time between topical insulin and placebo, and the synthesized result turned out to favor topical insulin (Q = 26.81, df = 3, P = 0,000, I2 = 96%) (Figure 2).
The majority of the points are above the zero line, indicating that, overall, the studies observed an increased risk of the observed outcome in the group exposed to the risk factor. The 95% confidence intervals for the majority of the studies do not include the zero line, confirming that the increased risk is statistically significant. The fixed effect line indicates that, on average, the relative risk is 7.67 (95% CI: 2.66-12.69). There is a large heterogeneity between studies, as indicated by the width of the confidence intervals and the dispersion of the points.