Diabetes Impact on Hepatocellular Carcinoma Outcomes

Hepatocellular carcinoma (HCC), the most common primary liver malignancy, has emerged as a major cause of cancer mortality worldwide. The rising prevalence of type 2 diabetes mellitus (T2DM) has had a profound impact on HCC risk, progression and clinical outcomes. Chronic hyperglycaemia and compensatory hyperinsulinaemia fuel insulin-like growth factor signalling, drive hepatic steatosis and promote inflammatory mediators that facilitate tumour initiation. Insulin resistance, oxidative stress and epigenetic alterations further reinforce a pro-tumour microenvironment. Patients with diabetes exhibit increased incidence of HCC, higher rates of tumour recurrence after curative treatments and shorter overall and disease-free survival. In the era of systemic therapies, coexisting T2DM may modulate response to targeted agents and immunotherapies, while antidiabetic medications such as metformin are under investigation for repurposing as adjuncts to cancer care. Globally, populations with high burdens of metabolic syndrome and chronic hepatitis face a dual epidemic of diabetes and HCC. Recognition of the bidirectional interplay between metabolic dysregulation and liver carcinogenesis is essential to refine surveillance strategies, optimise glycaemic control and tailor therapeutic regimens for improved outcomes.

Research from Nature Portfolio

Recent studies have explored the influence of common antidiabetic agents on the efficacy of first-line systemic therapies. In a multinational cohort of patients receiving either a tyrosine kinase inhibitor or the combination of an anti-PD-L1 antibody with an anti-VEGF monoclonal antibody, chronic metformin exposure was associated with significantly shorter overall survival and progression-free survival in those treated with immunotherapy plus anti-angiogenic therapy, whereas no such effect was observed in the tyrosine kinase inhibitor cohort. These findings highlight the need to consider the interplay between concurrent medications and immune-based regimens in treatment planning.

Diabetes Impact on Hepatocellular Carcinoma Outcomes publication trend

The graph below shows the total number of articles in diabetes impact on hepatocellular carcinoma outcomes across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatocellular carcinoma: A primary malignancy of the liver arising from hepatocytes.

Type 2 diabetes mellitus (T2DM): A metabolic disorder characterised by insulin resistance and elevated blood glucose.

Insulin resistance: A diminished cellular response to insulin signalling, leading to hyperinsulinaemia.

Immune checkpoint inhibitor: A therapeutic antibody that blocks regulatory pathways in T cells to enhance antitumour immunity.

Overall survival (OS): The duration from treatment initiation to death from any cause.

Progression-free survival (PFS): The length of time during and after treatment that a patient lives without disease progression.

References

1. Insight into the impact of diabetes mellitus on the increased risk of hepatocellular carcinoma: mini-review. Journal of Diabetes & Metabolic Disorders (2014).
2. Impact of Diabetes Mellitus on the Prognosis of Patients with Hepatocellular Carcinoma after Curative Hepatectomy. PLOS ONE (2014).
3. The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?. Cancers (2023).
4. Impact of metformin, statin, aspirin and insulin on the prognosis of uHCC patients receiving first line Lenvatinib or Atezolizumab plus Bevacizumab. Scientific Reports (2024).
5. SOD1 inhibition enhances sorafenib efficacy in HBV‐related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS‐mediated cell death. Journal of Cellular and Molecular Medicine (2024).
6. Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma. International Journal of Molecular Sciences (2022).