Open Access

ARTICLE

The Effect of Metformin on Atezolizumab/Bevacizumab Treatment in Patients with Hepatocellular Carcinoma and Diabetes

Andrea Dalbeni^1,2, Marco Vicardi^1,2,*, Leonardo A. Natola^1,2, Alessandra Auriemma³, Bernardo Stefanini⁴, Caterina Vivaldi⁵, Piera Federico⁶, Andrea Polloni⁷, Caterina Soldà⁸, Lorenzo Lani⁴, Ingrid Garajová⁹, Stefano Tamberi¹⁰, Stefania De Lorenzo¹¹, Fabio Piscaglia^4,12, Vincenzo Di Maria¹, Gianluca Masi⁵, Sara Lonardi⁸, Giovanni Brandi^4,7, Bruno Daniele⁶, Franco Trevisani^4,13, Gianluca Svegliati-Baroni¹⁴, Laura Schiada¹⁴, Fabio Marra¹⁵, Claudia Campani¹⁵, Ciro Celsa¹⁶, Giuseppe Cabibbo¹⁶, Mariangela Bruccoleri¹⁷, Massimo Iavarone^17,18, Leonardo Stella¹⁹, Francesca R. Ponziani¹⁹, Tiziana Pressiani²⁰, Lorenza Rimassa^20,21, Francesco Tovoli 1 Unit of General Medicine C, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
2 Liver Unit, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
3 Section of Innovation Biomedicine-Oncology Area, University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
4 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
5 Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
6 Medical Oncology Unit, Ospedale del Mare, Napoli, Italy
7 Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
8 Oncology 1 Unit, Veneto Institute of Oncology IOV—IRCCS, Padova, Italy
9 Medical Oncology Unit, University Hospital of Parma, Parma, Italy
10 Unit of Oncology, Ospedale Santa Maria Delle Croci, Ravenna AUSL Romagna, Ravenna, Italy
11 Oncology Unit, Azienda USL Bologna, Bologna, Italy
12 Unit of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
13 Unit of Semeiotics, Liver and Alcohol-Related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
14 Liver Injury and Transplant Unit, Polytechnic University of Marche, Ancona, Italy
15 Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy
16 Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo, Palermo, Italy
17 Division of Gastroenterology and Hepatology, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
18 CRC “A. M. and A. Migliavacca” Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
19 Liver Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
20 Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
21 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
* Corresponding Author: Marco Vicardi. Email:
(This article belongs to the Special Issue: Molecular Targets and Combinatorial Therapeutics of Liver Cancer)

Oncology Research https://doi.org/10.32604/or.2026.073063

Received 10 September 2025; Accepted 29 January 2026; Published online 18 February 2026

Abstract

Objectives: The combination of atezolizumab plus bevacizumab (A+B) represents one of the standards first-line treatments for unresectable hepatocellular carcinoma (HCC). Metformin has garnered attention for its potential antitumour and immunomodulatory properties beyond glycaemic control. This study aimed to assess metformin’s impact in patients with type 2 diabetes mellitus (T2DM) receiving A+B therapy. Methods: This retrospective analysis of a prospectively-maintained multicentre database included 523 patients with HCC treated with A+B from the ARTE (Atezolizumab-bevacizumab Real-life Experience for Treatment of Hepatocellular Carcinoma) dataset across 18 Italian centres (May 2020–January 2024). We evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP) using Cox regression analysis and Inverse Probability of Treatment Weighting (IPTW) to address confounding. Results: Among 523 patients, 341 (65.2%) did not have diabetes and 182 (34.8%) had T2DM. In the overall population, metformin showed no significant benefit for PFS (HR = 1.15, 95% CI [0.88–1.50], p = 0.316) or OS (HR = 1.28, 95% CI [0.94–1.74], p = 0.124). In the subgroup with T2DM (N = 180), metformin showed no significant benefit for PFS (HR = 1.41, 95% CI [0.97–2.05], p = 0.069), OS (HR = 1.23, 95% CI [0.81–1.86], p = 0.333), or TTP (HR = 0.82, 95% CI [0.53–1.26], p = 0.363). IPTW analysis confirmed these negative findings. Conclusion: This study found no evidence of improved outcomes with metformin use in patients with HCC in particular with T2DM receiving A+B therapy. Routine metformin use should not be expected to enhance A+B efficacy based on current evidence.

---

Keywords

Hepatocellular carcinoma; immune checkpoint inhibitors; type 2 diabetes mellitus; metformin; atezolizumab; bevacizumab

---