Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale

Andrea Casadei Gardini, Luca Faloppi, Serena De Matteis, Francesco Giuseppe Foschi, Nicola Silvestris, Francesco Tovoli, Vincenzo Palmieri, Giorgia Marisi, Oronzo Brunetti, Umberto Vespasiani-Gentilucci, Giuseppe Perrone, Martina Valgiusti, Anna Maria Granato, Giorgio Ercolani, Giulia Negrini, Emiliano Tamburini, Giuseppe Aprile, Alessandro Passardi, Daniele Santini, Stefano CascinuGiovanni Luca Frassineti, Mario Scartozzi

Research output: Contribution to journalArticlepeer-review


Purpose In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance. Patients and methods We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples. Results In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P <.0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P =.013). Conclusions Our findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.

Original languageEnglish
Pages (from-to)106-114
Number of pages9
JournalEuropean Journal of Cancer
Publication statusPublished - Nov 1 2017


  • Hepatocellular carcinoma
  • Insulin
  • Liver cancer
  • Metformin
  • NASH
  • SIRT-3
  • Sorafenib
  • Type II diabetes mellitus

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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