Iron Deficiency Anemia and Oxidative Stress in Type 2 Diabetic Patients on Metformin: A Meta-Analysis

Iron deficiency anemia (IDA), one of the most prevalent nutritional disorders globally, is increasingly recognized among patients with type 2 diabetes mellitus (T2DM). Metformin, the first-line antidiabetic drug, is widely used in T2DM management and known for its favorable metabolic effects. However, growing evidence suggests that long-term metformin use may contribute to micronutrient deficiencies, including vitamin B12 and potentially iron, which could impair hematological status and exacerbate oxidative stress in diabetic individuals. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) and antioxidant defenses, plays a crucial role in the pathogenesis of diabetic complications. The interconnection between metformin-associated IDA and oxidative stress remains inadequately explored. This meta-analysis aimed to assess the association between IDA and oxidative stress in patients with T2DM receiving metformin therapy. A systematic search was conducted in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, ProQuest, and Google Scholar for studies published between January 2000 and March 2024. Studies were included if they reported both iron-related hematological indices and oxidative stress markers in adult patients with T2DM on metformin. Data were extracted and analyzed using the Comprehensive Meta-Analysis software, applying a random-effects model. Three studies meeting the inclusion criteria were identified, encompassing 521 participants from Egypt, China, and Pakistan. Pooled analysis revealed significantly lower hemoglobin levels in metformin-treated patients with IDA (mean 11.6 ± 1.2 g/dL) compared to non-IDA controls (13.8 ± 1.4 g/dL; P < 0.001). Markers of oxidative stress were also significantly altered, with higher malondialdehyde (MDA: 3.9 ± 0.7 µmol/L vs. 2.4 ± 0.5 µmol/L) and lower antioxidant levels (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GPx]). Meta-regression indicated that higher HbA1c and longer diabetes duration were associated with worsened oxidative parameters. Sensitivity analysis confirmed the robustness of these findings. In conclusion, IDA in patients with T2DM receiving metformin therapy is significantly associated with elevated oxidative stress and compromised antioxidant defenses. These findings underscore the importance of routine screening for anemia and oxidative stress markers in metformin-treated diabetic patients, while also emphasizing the need for further research to inform long-term therapeutic strategies.