Eye screening is mandatory in diabetes, but treatment is only indicated at the sight-threatening stages of diabetic retinopathy (DR). Treatments include intravitreal injections, laser photocoagulation and vitrectomy, which are all invasive options. In order to prevent or delay DR, it is important to investigate earlier, non-invasive managements prior to sight-threatening DR. The aim of this study is to evaluate the effect of systemic treatment on incident and progressive DR. The search in this systematic review was performed in PubMed and Embase using the keywords 'diabetic retinopathy' AND 'systemic therapy'. Two independent researchers identified 619 studies; 26 duplicates were removed, 579 articles were excluded based on title and abstract, and six were removed after full-text assessment. Five articles were added from reference screening, resolving in a total of 13 eligible articles. These were quality-assessed using the Cochrane Risk of Bias tool. Twelve randomized control trials and one follow-up study were included. Intensive glycaemic control (IGC), antihypertensive and lipid-lowering treatments were some of the main interventions tested in the studies. Three studies found statistically significant reduction of progression of DR by IGC, three by antihypertensive, and two by the lipid-lowering drug fenofibrate. Systemic intervention appears important in different stages of DR. While IGC seems effective in relation to incident and progressive DR, antihypertensive treatments may be valuable in the early stages of DR, as opposed to fenofibrate, which could benefit at a later stage.