Hemoglobin Trajectories After Metformin Initiation Compared With Dipeptidyl Peptidase-4 Inhibitors: A Real-World Cohort Study.

Background Metformin is associated with vitamin B12 deficiency, and we recently reported latent iron and copper deficiency among metformin users, suggesting a potential contribution to anemia risk. However, real-world evidence on hemoglobin trajectories after metformin initiation remains limited. We evaluated short- and long-term hemoglobin changes after metformin initiation compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in Japanese patients with type 2 diabetes. Methods This single-center retrospective cohort study used electronic medical record data from Kobe University Hospital from January 2014 to June 2025. Short-term hemoglobin changes were defined as changes from Day 0 to Day 180, and long-term trajectories were evaluated from Day 0 to Day 1,826 (five years). Patients initiating metformin or a DPP-4 inhibitor were selected using predefined eligibility and exclusion criteria and matched by propensity scores. Hemoglobin changes over 180 days and up to five years were analyzed using multiple regression and mixed-effects models. Results The short-term cohort included 72 matched pairs, and the long-term cohort included 182 matched pairs. Hemoglobin decreased from 14.74 ± 0.22 to 14.39 ± 0.23 g/dL (mean ± SEM) from Day 0 to Day 180 in the metformin group, whereas no significant change was observed in the DPP-4 inhibitor group. Pre-initiation hemoglobin change, but not metformin dose, was independently associated with subsequent hemoglobin change. Over five years, annual hemoglobin slopes did not differ significantly between groups (-0.0572 vs. -0.0725 g/dL/year, p = 0.31). Older patients showed more negative annual hemoglobin slopes in both groups. Conclusions Metformin initiation was associated with a short-term hemoglobin decrease, whereas excess long-term decline was not observed in this cohort. Long-term changes were modest and age-related, supporting continued monitoring in older patients.