Research Article Diabetes and Insulin Therapy, but Not Metformin, Are Related to Hepatocellular Cancer Risk Luca Miele, 1,2 Cristina Bosetti, 3 Federica Turati, 3 Gianlodovico Rapaccini, 1,2 Antonio Gasbarrini, 1 Carlo La Vecchia, 4 Stefania Boccia, 5 and Antonio Grieco 1 1 Institute of Internal Medicine, Catholic University of Rome, Largo Francesco Vito 1, 00168 Rome, Italy 2 Internal Medicine and Gastroenterology Unit, Complesso Integrato Columbus, Via Giuseppe Moscati 31-33, 00168 Rome, Italy 3 Department of Epidemiology, IRCCS-“Mario Negri” Institute for Pharmacological Research, Via G. La Masa 19, 20156 Milan, Italy 4 Department of Clinical Sciences and Community Health, University of Milan, Via G. Venezian 1, 20122 Milan, Italy 5 Institute of Public Health Section of Hygiene, Catholic University of Rome, Largo Francesco Vito 1, 00168 Rome, Italy Correspondence should be addressed to Federica Turati; federica.turati@marionegri.it Received 21 January 2015; Revised 24 April 2015; Accepted 27 April 2015 Academic Editor: Roberto C´ esar P. Lima-J´ unior Copyright © 2015 Luca Miele et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Metabolic conditions, including type 2 diabetes, have been related to hepatocellular carcinoma (HCC) risk. We have further analyzed the role of diabetes and antidiabetic treatments on HCC. Methods. Data derived from a hospital-based case-control study (Italy, 2005–2012) on 224 HCC patients and 389 controls. Odds ratios (ORs) were estimated using multiple logistic regression models. Results. Sixty-nine (30.9%) cases versus 52 (13.5%) controls reported a diabetes diagnosis, corresponding to a multivariate OR of 2.25 (95% conidence interval, CI = 1.42–3.56). A stronger excess risk emerged for a longer time since diabetes diagnosis (OR = 2.96 for <10 years and 5.33 for ≥10 years). Oral therapies were inversely, though not signiicantly, related to HCC risk, OR being 0.44 for metformin and 0.88 for sulfonylureas; conversely, insulin was nonsigniicantly directly associated (OR = 1.90). Compared to nondiabetic subjects who were never smokers, those who were diabetics and ever smokers had an OR of 6.61 (95% CI 3.31–13.25). Conclusion. Our study conirms an over 2-fold excess HCC risk in diabetics, with a stronger excess risk in diabetic subjects who are also tobacco smokers. Metformin may decrease the risk of HCC, whereas insulin may increase the risk. 1. Introduction Liver cancer is the seventh most common cancer and the third cause of cancer deaths worldwide [1, 2]. In Italy, 2950 deaths from liver cancer were registered in 2008 in men (3% of all cancer deaths) and 1500 (2% of all cancer deaths) in women [3]. Hepatocellular carcinoma (HCC) is the most common histological type of liver cancer, accounting for up to 85% of cases [4]. he major recognized factors for HCC are chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infec- tions, heavy alcohol drinking, and tobacco smoking [4–8]. Several epidemiological studies have indicated that type 2 diabetes mellitus is also associated with an increased risk of HCC [9–15]. A meta-analysis of epidemiological studies pub- lished up to February 2011 reported a signiicant relative risk (RR) of 2.4 from 17 case-control studies, 2.2 from 25 cohort studies, and a RR of 2.4 from 7 cohort studies on mortality from HCC [13]. A signiicant trend with duration of diabetes was observed in 6 studies, with a RR of 3.3 for 10 years since diabetes diagnosis. Moreover, the presence of diabetes has been associated with metastatic HCC and with worse prog- nosis [16, 17]. Although data on the role of drugs for the treatment of type 2 diabetes in HCC are limited, there are indications that metformin, sulfonylureas [18], and thiazolidinediones [19] are associated with a reduced risk of HCC, whereas insulin may increase the risk [20]. We have further analyzed the role of diabetes and antidia- betic treatments in HCC risk using data from a hospital-based case-control study conducted in Italy. Hindawi Publishing Corporation Gastroenterology Research and Practice Volume 2015, Article ID 570356, 5 pages http://dx.doi.org/10.1155/2015/570356