The Impact of Metformin on Myocardial Hypertrophy: An Updated Systematic Review, Meta-Analysis, and Meta-Regression of Randomized Controlled Trials Publisher



Azarboo A ; Jalali S ; Shaker F ; Khalaji A ; Assempoor R ; Javidan A ; Mohammadi Y ; Bahrami O ; Farahmandniya N ; Cannavo A
Source: Diabetology and Metabolic Syndrome Published:2026

Abstract

Background: Metformin is a cornerstone treatment for diabetes that has demonstrated significant cardioprotective effects. Studies in animals and humans supported metformin as an anti-remodeling drug by regulating molecular pathways involved in cardiac hypertrophy, as a strong, independent predictor of cardiovascular events and mortality. Herein, we aimed to systematically evaluate metformin’s therapeutic potential on myocardial hypertrophy, a topic that remains argued and still lacks a consensus. Methods: A systematic review and meta-analysis were conducted on randomized controlled trials (RCTs) following PRISMA guidelines (PROSPERO: CRD42024619803). PubMed, Scopus, Web of Science, and Embase databases were searched until June 2025. Primary outcomes were changes in left ventricular mass index (LVMI), left ventricular mass (LVM), and left ventricular ejection fraction (LVEF). Data were pooled and heterogeneity was assessed via I² statistics. Meta-regression explored covariates such as age, BMI, lipid profile, blood pressure, and metformin dose. Sensitivity analyses and publication bias assessments were performed. Results: After screening, only ten studies were included in our analysis. Our results revealed that metformin significantly reduced LVMI after 12 months in the overall population (SMD − 0.23, 95% CI -0.42 to -0.04, I² = 0%), with a consistent effect observed in the change data analysis (SMD − 0.29, 95% CI -0.48 to -0.10, I² = 34%). The subgroup analysis reported a reduction in LVMI that was more pronounced in non-diabetic individuals (SMD − 0.35, 95% CI -0.60 to -0.10, I² = 50%) compared to diabetic populations, where the effect was modest and not statistically significant (SMD − 0.12, 95% CI -0.35 to 0.11, I² = 45%). Next, meta-regression analysis identified total cholesterol (p = 0.0007) and male proportion (p = 0.0016) as significant sources of heterogeneity. Notably, across the included studies, we did not observe any significant impact on LVM after 6 or 12 months in diabetic or non-diabetic subgroups. Similarly, no significant effect on LVEF, E/e’, or left atrial diameter was revealed. Sensitivity analysis confirmed the robustness of our findings, and Egger’s test indicated no publication bias. Conclusions: Our data demonstrated that metformin administration results in a modest but significant effect in reducing LVMI, particularly over longer treatment durations and in non-diabetic individuals. However, its impact on other echocardiographic parameters remains uncertain. Despite the need for further research (experimental and clinical), our study supports metformin as a therapeutic strategy for optimizing cardiovascular benefits in diabetic and non-diabetic patients at risk of cardiac hypertrophy. © The Author(s) 2025.