Metformin and Risk of Hepatocellular Carcinoma in Patients With Type 2 Diabetes

Chin-Hsiao Tseng


Liver International. 2018;38(11):2018-2027. 

In This Article

Abstract and Introduction


Background: Whether metformin may reduce hepatocellular carcinoma (HCC) risk requires confirmation.

Methods: Type 2 diabetes patients newly diagnosed during 1999–2005 and with 2 or more prescriptions of antidiabetic drugs were enrolled from the Taiwan's National Health Insurance database. A total of 173 917 ever-users and 21 900 never-users of metformin were identified (unmatched cohort). A 1:1 matched-pair cohort of 21 900 ever-users and 21 900 never-users based on a propensity score (PS) was created. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the PS. In addition, interactions with aspirin and statin were evaluated.

Results: In the unmatched cohort, 619 never-users and 2642 ever-users developed HCC, with a respective incidence of 668.0 and 330.7 per 100 000 person-years and an overall hazard ratio of 0.49 (95% confidence interval: 0.45–0.54). The hazard ratios for the first (<25.7 months), second (25.7–56.9 months) and third (>56.9 months) tertile of cumulative duration of metformin therapy were 0.89 (0.81–0.98), 0.50 (0.46–0.56) and 0.23 (0.21–0.26) respectively. Analyses of the matched cohort showed an overall hazard ratio of 0.76 (0.67–0.85), and the hazard ratios for the respective tertiles were 1.39 (1.19–1.62), 0.77 (0.65–0.91) and 0.37 (0.30–0.45). Aspirin and statin were observed to have a significant interaction with metformin.

Conclusions: Metformin was associated with a reduced risk of HCC in a dose-response pattern. Users of both metformin and aspirin or metformin and statin had the lowest risk.


High incidence rates of hepatocellular carcinoma (HCC) are observed in countries in East and Southeast Asia and in Northern and Western Africa.[1] Taiwan is among the countries with a high incidence.[2] Viral hepatitis B and C are the main causes of HCC in countries with a high incidence, but alcohol, obesity and type 2 diabetes mellitus may be responsible in more developed countries.[3] Risk factors that have not yet been confirmed include Helicobacter pylori infection,[4] gallstones[5] and fibrate use.[6]

Patients with type 2 diabetes mellitus may have an increased risk of various types of cancer including HCC.[7,8] However, use of different classes of antidiabetic drugs may be associated with different risks of HCC. For example insulin and sulfonylurea are associated with a higher risk, but use of metformin has been reported to be associated with a lower risk.[9]

Two meta-analyses published in 2013 suggested a reduced risk of HCC in patients treated with metformin.[9,10] The first meta-analysis by Zhang et al,[10] which included 7 observational studies (3 cohort and 4 case-control), suggested a significant risk reduction of 76% (relative risk: 0.24%, 95% confidence interval: 0.13–0.46) in metformin users. The other meta-analysis published later in the same year by Singh et al[9] included 8 observational studies and reported an odds ratio of 0.50 (95% confidence interval: 0.34–0.73). These 2 meta-analyses were published in the same year but the magnitudes of the estimated risk reduction differed markedly. This could be because of the different studies included in the respective meta-analyses. These 2 meta-analyses shared 5 papers in common, but the meta-analysis by Zhang et al included a study by Lee et al[11] that reported an extremely low relative risk of 0.06 (95% confidence interval: 0.02–0.16). 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[12] 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).[13]

Although all meta-analyses reported a significantly lower risk of HCC associated with metformin use, not all studies reached the same conclusion. For example a study using the Clinical Practice Research Datalink did not support a role for metformin relative to HCC risk.[14] Singh et al[9] pointed out the considerable heterogeneity among the different studies in the meta-analyses, probably because of different study settings and the lack of concomitant consideration of the cancer-modifying effects of other antidiabetic drugs. The risk reduction associated with metformin use may also be because of a missing link with statins in some studies[15] and the lack of full consideration of potential confounders and biases commonly seen in pharmaco-epidemiological studies using administrative databases. Therefore, the beneficial effect of metformin on HCC should be interpreted more cautiously, and confirmation with additional studies that consider adequate confounders and avoid potential biases such as selection bias, prevalent user bias, immortal time bias and confounding by indication is needed.

This study further investigated whether the risk of HCC might differ between ever– and never-users of metformin among Taiwanese patients with type 2 diabetes mellitus, considering most confounders and addressing potential biases. Analyses of both an unmatched cohort and a cohort matched in terms of propensity score (PS) were conducted. In addition, potential interactions with aspirin and statin were also analyzed.