Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma

Abstract

Antidiabetic medication may modify the incidence of hepatocellular carcinoma (HCC). We aimed to compare the use of different antidiabetic strategies and the incidence of HCC. PubMed, Embase.com and Cochrane Library databases were searched up to 31 October 2015 and randomized controlled trials (RCTs), cohort studies or case-control studies were included for our analyses. A total of thirteen studies enrolling 481358 participants with 240678 HCC cases who received at least two different strategies were retrieved in this analysis. Direct comparisons showed that use of metformin (risk ratio [RR] 0.49, 95% CI 0.25–0.97) was associated with a significant risk reduction of HCC, while insulin (RR = 2.44, 95% CI 1.10- 5.56) may significantly increase the risk. Indirect evidence also suggested that insulin (RR = 2.37, 95% CI 1.21–4.75) was associated with a significantly increased risk of HCC. Additionally, metformin was effective in reducing the risk of HCC when compared with sulphonylurea (RR = 0.45, 95% CI 0.27–0.74) and insulin (RR = 0.28, 95% CI 0.17–0.47). Notably, metformin was hierarchically the best when compared with other antidiabetic therapies for the prevention of HCC. In summary, available evidence suggests that metformin was the most effective strategy to reduce HCC risk when compared with other antidiabetic interventions.

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

“…These results have been validated in the context of HCC within several, large observational studies including up to 97 430 patients with HCC demonstrating a reduced HCC for metformin users when compared to diabetic and/or non‐diabetic controls . Finally, two meta‐analyses summarizing 10 and 13 studies reported a 50% reduction of HCC incidence among up to 481 358 participants including 240,678 patients with HCC . These convincing results have led to the acknowledgement of HCC risk reduction by metformin within the current German practice guideline …”

“…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 . 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 …”

“…[7][8][9][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][12][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.…”

Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes

“…This study by Lee et al was not selected by Singh et al or by authors of later meta‐analyses. The third meta‐analysis, by Zhou et al and published in 2016, included 13 studies (1 randomized controlled trial and 12 observational studies) and estimated a relative risk of 0.49 (95% confidence interval: 0.25‐0.97). The most recent meta‐analysis, published in 2017, included 19 studies and estimated a very similar odds ratio of 0.52 (95% confidence interval: 0.40‐0.68) …”

Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China

“…Metformin, which is an insulin sensitizer, could not only reduce the levels of circulating insulin but also the levels of glucose in patients with IR and hyperinsulinemia. [38–41] In addition, some observational studies [42] hypothesized that metformin aids in improving the responses to antiviral treatment including peg-IFN (PEG-IFN) alfa-2a plus ribavirin (RBV) in patients with naïve genotype 1 (G1) CHC. This indicated that metformin might decrease the incidence of liver cancer in patients with CHC.…”