Supplementary Material for: Early vs late switch to an intravitreal Dexamethasone implant after failed Anti-VEGF therapy for diabetic macular edema: A systematic review and meta-analysis

Introduction: Monthly anti-vascular endothelial growth factors (VEGF) are the primary line of management of diabetic macular edema (DME). However, a large number of patients do not respond to anti-VEGF and require Dexamethasone implants (DEXI) as a second line of therapy. There remains a clinical conundrum on the optimal timing of the switch to DEXI. We systematically reviewed the literature to assess outcomes after an early vs late switch to DEXI after failed anti-VEGF therapy in DME.
Methods: Relevant studies were identified by searching PubMed, CENTRAL, Scopus, Web of Science, and Embase till 25th December 2024. We assessed changes in central retinal thickness (CRT), best-corrected visual acuity (BCVA), and risk of ocular hypertension between early vs late switch groups.
Results: Six studies were included. Pooled analysis of all six studies showed that there was a tendency of improved CRT (MD: 19.01 95% CI: -27.29, 65.31 I2=85%) and BCVA (MD: 0.05 95% CI: -0.04, 0.14 I2=72%) with early switch as compared to late switch group but without statistical significance. Removing one outlier study showed statistically significant improvement in CRT (MD: 36.84 95% CI: 7.54, 66.14 I2=48%) and BCVA with early switch (MD: 0.09 95% CI: 0.08, 0.11 I2=0%). Subgroup analysis based on the definition of late switch indicated better outcomes with an early switch when the late switch was defined as after >6 anti-VEGF injections. No difference was noted in the risk of ocular hypertension between the two groups (OR: 0.81 95% CI: 0.38, 1.73 I2=30%).
Conclusions: An early switch to DEXI may tend towards better outcomes as compared to a late switch in treatment-resistant DME patients. High heterogeneity of the meta-analysis and outlier studies are important limitations of present evidence which can only be resolved with high-quality randomized controlled trials.

引言：每月一次的抗血管内皮生长因子（Vascular Endothelial Growth Factor, VEGF）疗法是糖尿病性黄斑水肿（Diabetic Macular Edema, DME）的一线治疗方案。然而，大量患者对抗VEGF疗法应答不佳，需采用地塞米松植入剂（Dexamethasone Implants, DEXI）作为二线治疗方案。目前临床仍存在一个亟待解决的难题：转换至DEXI治疗的最佳时机尚未明确。本研究对现有文献进行系统综述，旨在评估糖尿病性黄斑水肿患者在抗VEGF治疗失败后，早期与晚期转换为DEXI治疗的预后情况。

方法：本研究通过检索PubMed、CENTRAL、Scopus、Web of Science及Embase数据库，检索时限截至2024年12月25日，以筛选相关研究。本研究对比分析了早期转换组与晚期转换组患者的中心视网膜厚度（Central Retinal Thickness, CRT）、最佳矫正视力（Best-Corrected Visual Acuity, BCVA）变化情况，以及高眼压发生风险。

结果：最终纳入6项研究。对全部6项研究的合并分析结果显示，相较于晚期转换组，早期转换组患者的CRT（均数差Mean Difference, MD=19.01，95%置信区间Confidence Interval, CI：-27.29~65.31，I²=85%）与BCVA（MD=0.05，95%CI：-0.04~0.14，I²=72%）均呈现改善趋势，但差异无统计学意义。剔除1项异常值研究后，早期转换组患者的CRT（MD=36.84，95%CI：7.54~66.14，I²=48%）与BCVA（MD=0.09，95%CI：0.08~0.11，I²=0%）的改善均具有统计学意义。基于晚期转换定义的亚组分析显示，当晚期转换被定义为抗VEGF注射次数＞6次后再转换时，早期转换可获得更优预后。两组患者的高眼压发生风险无显著差异（比值比Odds Ratio, OR=0.81，95%CI：0.38~1.73，I²=30%）。

结论：对于抗VEGF治疗耐药的糖尿病性黄斑水肿患者，早期转换为DEXI治疗或可获得更优预后。本研究证据存在的主要局限性为Meta分析异质性较高且存在异常值研究，该问题需通过高质量随机对照试验加以解决。