Metformin as an Adjunct Treatment to Temozolomide for High-Grade Gliomas: A Systematic Review and Meta-Analysis

High-grade gliomas (HGGs) are aggressive tumors known for their poor prognosis. Despite research into its molecular and clinical aspects, current management minimally impacts survival. It is unclear whether combining temozolomide (TMZ) with metformin (MET) could enhance survival in this population.

A systematic search on PubMed, Embase, and Cochrane Library databases was conducted for studies comparing TMZ+MET versus TMZ alone for HGG. The outcomes of interest were overall survival, progression-free survival, and subgroup analysis with O6-methylguanine-DNA methyltransferase and patients with diabetes. The analysis comprised outcomes reported as hazard ratios (HRs) and odds ratios with corresponding 95% confidence intervals (CIs) as all the outcomes are continuous. A significance level of P < 0.05 was considered statistically significant. Heterogeneity was assessed using the I² statistic with P values inferior to 0.10, and I² > 25% were considered significant for heterogeneity. The random effects model was employed for all outcomes.

Ten studies were included, comprising 3623 patients, of which 346 (9.5%) were assigned for TMZ+MET. The TMZ+MET group was associated with a significant reduction in mortality rates when compared to the TMZ alone group (HR 0.74; 95% CI 0.59, 0.93; P < 0.01; I² 29%). There was no significant difference between groups for progression-free survival (HR 0.87; 95% CI 0.68-1.12; P = 0.29). In a subgroup analysis restricted to patients who received TMZ+MET, the diabetic subgroup had a significantly higher mortality rate than the normoglycemic subgroup (odds ratio 1.25; 95% CI 1.10, 1.41; P < 0.01; I² 79%).

Our results showed that patients who received TMZ+MET had a significantly higher overall survival than patients who received TMZ alone. These findings support the use of MET along with TMZ for the treatment of HGGs.