To identify optical coherence tomography angiography (OCTA)-derived vessel metrics of the macula and optic nerve head (ONH) that predict diabetic retinopathy (DR) disease progression. Secondary analysis of clinical trial data. This was a sub-analysis of prospectively collected data from 73 subjects that participated in the TIME-2b study (Aerpio Pharmaceuticals), a multicenter clinical trial for patients with moderate-to-severe DR treated with AKB-9778 and followed over a 12-month period. Eligible subjects were tested every 3months with color fundus photography, spectral-domain OCT, and slit-lamp biomicroscopy. OCTA of the macula and ONH was obtained for a subset of patients enrolled at participating sites. En face, full-depth retinal projections centered at the macula were analyzed for multiple metrics including foveal avascular zone (FAZ) area and perimeter, nonperfusion area, vessel density (VD), and presence of intraretinal microvascular abnormalities (IRMA). VD of the radial peripapillary capillaries was evaluated in 4 quadrants surrounding the optic disc for ONH images. Progression was defined as a ≥2-step increase in DR severity scale score or development of diabetic macular edema. Over a follow-up period of 12months, 15 of 73 (20.5%) subjects progressed. At pretreatment baseline, larger FAZ area, presence of IRMA, and reduced peripapillary VD in the superior temporal and inferior temporal regions were significantly associated with increased odds of progression. FAZ area and temporal peripapillary VD are predictors of DR progression. OCTA metrics may improve progression risk assessment in DR when compared to established risk factors alone.