Treatment With Metformin Is Associated With a Prolonged Survival in Patients With Hepatocellular Carcinoma

Lena Schulte; Bernhard Scheiner; Torsten Voigtländer; Sandra Koch; Nora Schweitzer; Silke Marhenke; Philipp Ivanyi; Michael P. Manns; Thomas Rodt; Jan B. Hinrichs; Arndt Weinmann; Matthias Pinter; Arndt Vogel; Martha M. Kirstein

Disclosures

Liver International. 2019;39(4):714-726. 

In This Article

Abstract and Introduction

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet.

Methods: Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC.

Results: Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child-Pugh-Score A: 69.2% vs 47.4%, P < 0.001) and underwent significantly more often tumour resection (22.1% vs 16.5%, P = 0.024). Patients on metformin had a significantly longer median OS (mOS) compared to diabetic patients not treated with metformin (22 vs 15 months, P = 0.019). The prolongation of survival was most significant in patients treated with surgery. Using a propensity score match (PSM), patients were adjusted for hepatic function and initial therapy. In the matched cohorts, mOS remained significantly longer in metformin-treated patients (22 vs 16 months, P = 0.021). Co-treatment of metformin and sorafenib was associated with a survival disadvantage.

Conclusion: Treatment with metformin was associated with an improved survival in patients with T2DM and HCC. This effect was most pronounced in patients at potentially curative tumour stages.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer-related death. The prognosis is still dismal.[1–3] While the incidence of viral hepatitis-associated HCC is currently decreasing, nutrition- and life style-associated risk factors for HCC development such as obesity, type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent.[4]

The biguanide metformin is the recommended first-line treatment and one of the most frequently prescribed drugs for patients with T2DM. Metformin improves glycaemic control, supports weight loss and may slow down progression of NAFLD.[5,6] Additionally, a risk reduction for HCC development has been reported for diabetic patients who were treated with metformin based on several large, population-based, case-control studies including up to 97 430 patients with HCC.[7–10] These results were supported by two meta-analyses and have led to the acknowledgement of the metformin-associated HCC risk reduction within the current German practice guideline.[11–13]

In contrast to its effects on HCC development, the impact of metformin on clinical outcome of patients with established HCC is less well defined. However, there are several studies that have investigated the influence of metformin in specific treatment subgroups. Accordingly, treatment with metformin has been associated with reduced tumour recurrence and a prolonged survival in patients who underwent hepatic resection,[14–17] liver transplantation (LT),[18] radiotherapy[19] and radiofrequency ablation (RFA) for HCC.[20] The potential anticancer mechanisms of metformin include interference with pivotal oncogenic signalling pathways such as the mammalian target of rapamycin (mTOR) signalling pathway, activation of AMP-activated protein kinase (AMPK), p53-dependent and -independent pro-apoptotic activities and cell cycle arrest.[7,21,22] Specifically, deactivation of sirtuin-1 and -3 (SIRT1, SIRT3) – proteins involved in metabolic diseases and known tumour suppressors in HCC – has been suggested as key players in the potential metformin-related anti-HCC mechanisms.[22–24] In contrast to these antitumour effects, there are studies suggesting that metformin may confer resistance to sorafenib treatment in patients with advanced HCC potentially leading to a worse outcome.[23,25]

The aim of this multicentre study was to analyse the impact of metformin treatment on overall survival (OS) in a large cohort of 5093 patients with HCC.

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