Effect of Metformin on Progression from Prediabetes to Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Background/Objectives: Prediabetes is a highly prevalent metabolic condition associated with an increased risk of progression to type 2 diabetes mellitus (T2DM) and related cardiometabolic complications. Although lifestyle modification remains the cornerstone of diabetes prevention, long-term adherence is often challenging in routine clinical practice. This systematic review and meta-analysis aimed to evaluate the effect of metformin therapy on progression from prediabetes to T2DM and its impact on glycemic and metabolic outcomes. Methods: A systematic literature search was conducted in PubMed, MEDLINE, and Web of Science in accordance with the PRISMA 2020 guidelines. Studies involving adults with prediabetes that evaluated metformin therapy and reported diabetes-related outcomes were eligible for inclusion. Risk of bias was assessed using the RoB 2 tool and the NOS. Where appropriate, quantitative meta-analysis was performed using a random-effects model. Results: Forty-one publications were included in the systematic review, with eligible subsets contributing to the quantitative analyses. Overall, the available evidence suggested that metformin was associated with a reduced risk of progression from prediabetes to T2DM compared with placebo, usual care, or lifestyle intervention alone. Long-term follow-up studies demonstrated sustained preventive effects extending beyond 10 years. Meta-analysis demonstrated a significant reduction in BMI among metformin-treated participants (MD = −2.06, 95% CI −2.53 to −1.60; I2 = 0%; p < 0.001). Findings for glycated hemoglobin and fasting plasma glucose were variable across studies and did not consistently reach statistical significance. Some studies reported additional improvements in insulin sensitivity and other cardiometabolic outcomes, although these findings were not consistently reported across the evidence base. Conclusions: The available evidence supports metformin as an effective adjunctive pharmacological strategy for reducing progression from prediabetes to T2DM, particularly among selected high-risk adults. When used alongside lifestyle modification, metformin may provide additional benefits in body weight and metabolic health. However, lifestyle intervention should remain the first-line preventive strategy. Further high-quality studies are needed to optimize patient selection, dose, treatment duration, and long-term clinical outcomes.