Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis

Am J Gastroenterol. 2013 Jun;108(6):881-91; quiz 892. doi: 10.1038/ajg.2013.5. Epub 2013 Feb 5.


Several preclinical and observational studies have shown that anti-diabetic medications (ADMs) can modify the risk of hepatocellular cancer (HCC) in patients with diabetes mellitus (DM). We performed a systematic review and meta-analyses of studies evaluating the effect of metformin, thiazolidinediones (TZDs), sulfonylureas, and/or insulin on the risk of HCC. We conducted a systematic search of Medline, EMBASE, and Web of Science up to August 2012. Studies were included if they (1) evaluated and clearly defined exposure to metformin, TZDs, sulfonylureas, and/or insulin, (2) reported HCC outcomes in patients with DM, and (3) reported relative risks or odds ratio (OR) or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model. Ten studies reporting 22,650 cases of HCC in 334,307 patients with type 2 DM were included in the analysis. Meta-analysis of observational studies showed a 50% reduction in HCC incidence with metformin use (n=8 studies; OR 0.50, 95% CI 0.34-0.73), 62% and 161% increase in HCC incidence with sulfonylurea (n=8 studies; OR 1.62, 95% CI 1.16-2.24) or insulin use (n=7; OR 2.61, 95% CI 1.46-4.65), respectively. TZDs did not modify the risk of HCC (n=4; OR 0.54, 95% CI 0.28-1.02). There was considerable heterogeneity across studies, which was partly explained by study setting, location, and whether the studies adjusted for the concomitant use of other ADMs. Post-hoc analysis of randomized controlled trials did not reveal any significant association between ADM use and risk of HCC. ADMs may modify the risk of HCC in patients with DM, especially in the Western population. However, the effect of each individual agent should be interpreted with caution owing to inherent cancer-modifying effect of the comparator group.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Carcinoma, Hepatocellular / epidemiology*
  • Confidence Intervals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / therapeutic use
  • Liver Neoplasms / epidemiology*
  • Metformin / therapeutic use
  • Odds Ratio
  • Sulfonylurea Compounds / therapeutic use
  • Thiazolidinediones / therapeutic use


  • Hypoglycemic Agents
  • Insulin
  • Sulfonylurea Compounds
  • Thiazolidinediones
  • Metformin