Diabetes is a growing worldwide epidemic and a leading cause of blindness in working-age people around the world. Diabetic retinopathy (DR) and diabetic macular edema (DME) are common causes of visual impairment in people with diabetes and often indicate the presence of diabetes-associated preclinical micro- and macrovascular complications. As such, patients with DR and DME often display complex, highly comorbid profiles. Several treatments are currently available for the treatment of DME, including anti-vascular endothelial growth factor (VEGF) agents, which are administered via intravitreal injection. While the safety profiles of approved ocular anti-VEGF therapies have been reassuring, the high-risk nature of the DME patient population means that treatment must be carefully considered and a holistic approach to disease management should be taken. This requires multidisciplinary, collaborative care involving all relevant specialties to ensure that patients not only receive prompt treatment for DME but also appropriate consideration is taken of any systemic comorbidities to evaluate and minimize potentially serious safety issues.