The role of interleukin-6 in diabetic retinal disease: pathophysiology and therapeutic targeting

Therapeutic strategies in the management of diabetic retinal diseases have typically employed anti-vascular endothelial growth factor A (anti-VEGF-A) therapies. While generally effective, clinical trials and real-world analyses demonstrate that a substantial proportion of patients do not show adequate response to this drug class, with retinal edema persisting in upwards of 60% of cases after one to two years of therapy, exhibiting suboptimal visual outcomes and insufficient disease control, with VEGF independent pathways remaining unaddressed. Inflammation is increasingly recognized as a pivotal pathogenic driver in diabetic eye disease, with Interleukin-6 (IL-6) identified as a central mediator of acute and chronic inflammatory responses. This review discusses the role of inflammation in diabetic retinal disease and synthesizes emerging evidence regarding the therapeutic targeting of IL-6. We highlight the differences between cis-, trans-, and cluster signaling, and describe the IL-6 buffer system. We review preclinical evidence demonstrating how IL-6 signaling disrupts the blood-retinal barrier, both directly and synergistically with VEGF. Finally, we describe the emerging clinical evidence for selective IL-6 and bispecific IL-6/VEGF monoclonal antibodies currently in drug development. These novel approaches aim to address the multiple pathogenic pathways that drive Diabetic Macular Edema (DME), with potential to show superior efficacy.