Metformin influences progression in diabetic glioblastoma patients

Sebastian Adeberg, Denise Bernhardt, Semi Ben Harrabi, Tilman Bostel, Angela Mohr, Christian Koelsche, Christian Diehl, Stefan Rieken, Juergen Debus

Changes in metabolism, including high glucose serum levels, seem to influence the initiation of malignancy as well as recurrence. Therefore, limiting the energy supply in tumor cells with the antidiabetic drug metformin might be a useful approach to inhibit glioma cell progression. However, little is known about the effects of endocrine disorders (e.g., diabetes mellitus, corticosteroid therapy, and metformin therapy) on progression and survival in primary glioblastoma patients. Between 2006 and 2013, 276 patients with primary glioblastoma underwent radiation therapy at Heidelberg University Hospital and German Cancer Research Center. Clinical records as well as pretherapeutic and follow-up magnetic resonance (MR) images were assessed. Forty patients (14.5 %) were identified with a pretherapeutic history of diabetes, and 20 (50 %) of them were treated with metformin. Survival and correlations were calculated using t-test and log-rank, univariate and multivariate Cox proportional hazards ratio analyses. Persistent mild and excessive hyperglycemia were correlated with decreased survival. Corticosteroid therapy was associated with decreased progression-free and overall survival in the multivariate analysis. No negative influence of diabetes on progression and survival could be detected. Interestingly, diabetic patients with metformin therapy demonstrated prolonged progression-free intervals. Corticosteroid therapy and hyperglycemia were strongly associated with impaired survival rates and serves as negative prognostic factors. Diabetes did not influence survival. Interestingly, our findings showed an association of metformin therapy and prolonged progression-free survival in glioblastoma patients with diabetes and therefore serve as a foundation for further preclinical and clinical investigations.