Anti-Diabetic Medications and the Risk of Hepatocellular Cancer: A Systematic Review and Meta-Analysis

Abstract

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.

Cancer risks of anti-hyperglycemic drugs for type 2 diabetes treatment – a clinical appraisal

“…A second meta-analysis by the same authors found that metformin use might also be associated with a 50% relative risk reduction in hepatocellular cancer, while sulfonylurea use may be associated with a 62% increase in the relative risk (Singh, et al, 2013c). Lastly, the group found that metformin, thiazolidinediones, and insulin use had no significant effect on pancreatic cancer risk, while sulfonylurea use was associated with a 70% increase in the odds of pancreatic cancer (Singh, et al, 2013b).…”

Diabetes Mellitus, Insulin, Sulfonylurea and Advanced Fibrosis in Non-Alcoholic Fatty Liver Disease

“…The use of insulin and sulfonylurea was associated with a 161% and 62% increased risk of HCC respectively, while the use of metformin was associated with 50% reduction in the incidence of HCC incidence [23]. While it is commonly postulated that insulin and insulin secretagogues have direct effects of carcinogenesis, it may also be possible that the risk of HCC development is due in part to the insulin/ insulin secretagogues stimulated progression of liver tissue to advanced fibrosis or cirrhosis, especially since HCC typically develops following the sequence of chronic hepatic inflammation to fibrosis and cirrhosis [23,24].…”

Spontaneous regression of hepatocellular carcinoma in a Caucasian male patient: A case report and review of the literature

“…Metoprolol has been associated with an inhibition of low-density lipoprotein cholesterol synthesis in a study on human cell lines, thereby reducing the risk of HCC (11). Metformin has been associated with a decreased risk of HCC in a meta-analysis of 8 observational studies (odds ratio=0.50), whereas insulin usage increased the risk on HCC (odds ratio=1.62) (12). Metformin decreases insulin resistance and inhibits the mammalian target of rapamycin pathway, thereby inhibiting cell proliferation and inducing apoptosis (13).…”