Beyond the Benefits: High-Dose Metformin and Emerging Metabolic Risks in type 2 diabetic patients

Abstract

Introduction: Metformin is well-known for its several beneficial effects on diabetic complications. However, the results regarding the dose-effect relationship remain unclear.

Objectives: This study aimed to evaluate the effects of different doses of metformin on the metabolic profile and oxidative markers in Type 2 diabetes (T2D) patients.

Methods: A total of 285 T2D patients were stratified into three groups based on their metformin dosage: 500–1000 mg/day (Dose 1, n = 58), 1000–1500 mg/day (Dose 2, n = 66), and 1500–3000 mg/day (Dose 3, n = 161). A control group of 90 non-diabetic subjects was included. Metabolic (glucose, lipid profile, renal, and hepatic function), hematological and coagulation parameters, and oxidative stress markers (malondialdehyde (MDA), carbonylated proteins (CP), nitric oxide (NO), superoxide radical (O₂), catalase (CAT), and reduced glutathione (GSH)) were analyzed.

Results: Despite metformin therapy, patients displayed persistent hyperglycemia and elevated HbA1c levels, indicating suboptimal glycemic control. A dose-dependent worsening of lipid parameters was observed, characterized by increased LDL and triglycerides and reduced HDL levels, suggesting an elevated cardiovascular risk. Hematological alterations—including reduced red blood cells and hemoglobin, along with increased bilirubin and ferritin—were more pronounced at higher doses, possibly reflecting hepatic stress. Furthermore, high-dose metformin was associated with elevated inflammatory and oxidative stress markers, potentially compromising its antioxidant and anti-inflammatory properties.

Conclusions: These findings highlight a potential risk associated with higher doses of metformin in T2D patients, emphasizing the need for personalized dosing strategies and regular monitoring of metabolic and oxidative indicators to minimize adverse effects.