Effect of Metformin on Oxidative Stress and Left Ventricular Geometry in Nondiabetic Heart Failure Patients: A Randomized Controlled Trial

Introduction: There is an increasing interest in using metformin in cardiovascular diseases and its potential new roles. Only two randomized controlled trials investigated the effect of metformin in nondiabetic heart failure (HF) patients. However, none of these studies assess the role of metformin in reducing oxidative stress. We hypothesized that metformin might improve oxidative stress and left ventricular remodeling in nondiabetic HF patients with reduced ejection fraction (HFrEF) Methods and Methods: Seventy HFrEF patients (EF 37%8%; median age 66 years) were randomized to metformin (n=35) or standard of care (SOC) for HF (n=35) for 6 months in addition to standard therapy. Outcomes included the difference in the change (Delta) in total antioxidant capacity (TAC) and malondialdehyde (MDA), both assessed colorimetrically and left ventricular mass index (LVMI) assessed through transthoracic echocardiography. Results: Compared with the SOC, metformin treatment increased TAC [Delta=0.12mmol/L, confidence intervals (95% CIs): 0.03-0.21; P=0.007]. TAC increased significantly only in the metformin group (0.900.08mmol/L at baseline vs. 1.04 +/- 0.99mmol/L at 6 months, P < 0.05). Metformin therapy preserved LVMI (Delta=-23g/m(2), 95% CI: -42.91 to -4.92; P=0.014) and reduced fasting plasma glucose (Delta=-6.16, 95% CI: -12.31 to -0.02, P=0.047) compared with the SOC. Results did not change after adjusting for baseline values. Changes in MDA left ventricular ejection fraction (LVEF) and blood pressure were not significantly different between groups. Conclusion: Metformin treatment in HF patients with reduced LVEF improved TAC and prevented the increase in LVMI compared with the SOC. These effects of metformin warrant further research in HF patients without diabetes to explore the potential benefits of metformin. Trial Registration Number: This protocol was registered in ClinicalTrials.gov under the number NCT05177588.