Glycated hemoglobin and retinal microvascular changes in type 2 diabetic retinopathy patients treated with metformin and/or insulin: A retrospective study

Abstract: Background: Diabetes retinopathy (DR) is the main blinding complication of type 2 diabetes (T2DM). Glycated hemoglobin (HbA1c) can reflect long-term blood glucose control and optical coherence tomography (OCT) can evaluate retinal microvessels. The effects of metformin and insulin regimens on microvascular structure are not yet clear. Objectives: To explore the relationship between HbA1c levels and retinal microvascular changes in T2DM patients receiving metformin and/or insulin and to evaluate the impact of different hypoglycemic regimens on DR progression. Methods: This retrospective study included T2DM patients with non proliferative DR treated between January 2023 and December 2024. After propensity score matching (PSM), 31 patients per group received metformin monotherapy (M), insulin based therapy (Ins), or combined therapy (M Ins). HbA1c, HbA1c variability (HbA1c SD), DR grade, central macular thickness (CMT), retinal nerve fiber layer (RNFL) thickness and superficial/deep capillary plexus (SCP/DCP) density were recorded at baseline, 1 and 2 year follow up. Multiple linear regression and Cox regression were used. Results: After 2 years, HbA1c and HbA1c SD decreased significantly in all groups (p<0.05), with greater reduction in the M Ins group. DR progression was documented in 23 patients (24.7%), with rates of 16.1%, 38.7% and 19.4% in the M, Ins and M-Ins groups, respectively (p>0.05). OCT showed reduced CMT/RNFL and increased SCP/DCP density in all groups (p<0.05), with better improvement in M Ins group (p<0.05). HbA1c correlated positively with CMT/RNFL and negatively with SCP/DCP (p<0.05). Cox regression indicated that higher HbA1c-SD was an independent risk factor for DR progression (HR = 3.216, 95% CI: 1.011–10.230, p= 0.048), while metformin use was an independent protective factor (HR=0.694, 95% CI: 0.451–0.840, p=0.001). Conclusion: Metformin plus insulin was associated with greater HbA1c reduction, decreased glycemic variability and increased retinal vessel density and may thus slow DR progression. Both HbA1c-SD and SCP density were correlated with DR progression risk, supporting the combined use of glycemic variability and OCT parameters for clinical evaluation and treatment guidance.