Association of Metformin Use With Cancer-Specific Mortality in Hepatocellular Carcinoma After Curative Resection

Abstract

Many preclinical reports and retrospective population studies have shown an anticancer effect of metformin in patients with several types of cancer and comorbid type 2 diabetes mellitus (T2DM). In this work, the anticancer effect of metformin was assessed in hepatocellular carcinoma (HCC) patients with T2DM who underwent curative resection.A population-based retrospective cohort design was used. Data were obtained from the National Health Insurance Service and Korea Center Cancer Registry in the Republic of Korea, identifying 5494 patients with newly diagnosed HCC who underwent curative resection between 2005 and 2011. Crude and adjusted hazard ratios (HRs) were calculated using Cox proportional hazard models to estimate effects. In the sensitivity analysis, we excluded patients who started metformin or other oral hypoglycemic agents (OHAs) after HCC diagnosis to control for immortal time bias.From the patient cohort, 751 diabetic patients who were prescribed an OHA were analyzed for HCC-specific mortality and retreatment upon recurrence, comparing 533 patients treated with metformin to 218 patients treated without metformin. In the fully adjusted analyses, metformin users showed a significantly lower risk of HCC-specific mortality (HR 0.38, 95% confidence interval [CI] 0.30–0.49) and retreatment events (HR 0.41, 95% CI 0.33–0.52) compared with metformin nonusers. Risks for HCC-specific mortality were consistently lower among metformin-using groups, excluding patients who started metformin or OHAs after diagnosis.In this large population-based cohort of patients with comorbid HCC and T2DM, treated with curative hepatic resection, metformin use was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events.

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

“…So far, some observational studies have already suggested that metformin use might have antitumoural effects against HCC in specific subgroups. In line with our observation, metformin treatment was associated with reduced tumour recurrence and improvement of OS in patients who underwent hepatic resection for HCC . Another retrospective study in patients undergoing LT for HCC could show that OS was improved in patients receiving sirolimus and metformin .…”

“…In line with our observation, metformin treatment was associated with reduced tumour recurrence and improvement of OS in patients who underwent hepatic resection for HCC. [14][15][16][17] Another retrospective study in patients undergoing LT for HCC could show that OS was improved in patients receiving sirolimus and metformin. 18 In a small propensity score matched cohort of 76 patients receiving radiotherapy for HCC, medication with metformin was also associated with a prolonged survival.…”

“…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, liver transplantation (LT), radiotherapy and radiofrequency ablation (RFA) for HCC . 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 .…”

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

“…143 Population studies such as that of Seo et al have shown that diabetic patients treated with metformin, which inhibits ETC Complex I, present an approximately 30% reduced overall cancer incidence and mortality rate. 144 Therefore, mitochondrial-targeted therapeutics are emerging as an exciting opportunity for cancer therapy.…”

Metformin inhibited colitis and colitis-associated cancer (CAC) through protecting mitochondrial structures of colorectal epithelial cells in mice

“…Patients taking metformin display approximately 30% reduced overall cancer incidence as well as cancer mortality. 10 However, the mechanisms of metformin on cancers have still not fully understood. A number of studies suggest that the inhibition of metformin on cancer cells might associate with its activity of targeting cellular mitochondria.…”