An exploratory study of the effect of metformin on the whole blood transcriptome of nondiabetic older adults with age-related macular degeneration

Metformin has received increasing attention for benefits beyond blood glucose lowering. The purpose of this study was to identify changes in whole blood transcriptome from a course of metformin in a randomized trial (NCT02684578) of nondiabetic older adults with age-related macular degeneration (AMD). We included patients who were ≥ 55 years of age, nondiabetic, and had geographic atrophy due to AMD. We excluded patients with metformin use for another reason, reduced renal or liver function, or other vitreoretinal diseases. Participants were randomized to metformin or control. The metformin group was prescribed 1000 mg metformin twice daily for 18 months. All eligible patients were approached for consent to blood sample collection. We performed metagenomic sequencing on whole blood samples and conducted differential expression analysis. Fifteen patients underwent blood collection, with eight in the metformin group and seven in the control group. No individual gene achieved statistical significance of difference between groups after correction for multiple comparisons. As a secondary, hypothesis-generating analysis, canonical pathway analysis found downregulation of interferon α/β signaling (P = 0.003, z score = -2.4), cell junction organization (P = 0.03, z score = -2.2), and epithelial mesenchymal transition pathways in the metformin group (P = 0.02, z score = -2.2). There was possible inhibition of upstream proinflammatory molecules and activation of anti-inflammatory molecules by metformin. In this small sub-study of a randomized trial, no gene was significantly changed after metformin exposure. Pathway enrichment analysis identified signals potentially consistent with metformin-associated modulation of "inflammaging(definition)" and other biological pathways which require validation in larger cohorts.