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      Incident Hepatocellular Carcinoma Risk in Patients Treated with a Sulfonylurea: A Nationwide, Nested, Case-Control Study

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          Abstract

          Several studies have shown that the use of sulfonylureas in patients with type 2 diabetes mellitus (T2DM) is associated with a higher risk of hepatocellular carcinoma (HCC). In this study, we investigated the effects of individual sulfonylureas on HCC development using the National Health Insurance Service-National Sample Cohort in South Korea. Among 47,738 subjects aged 40 years or older who had newly diagnosed with diabetes, 241 incident HCC cases and 1205 matched controls were identified. Adjusted odds ratios (ORs) as estimates of the relative risk of HCC were calculated using logistic regression analysis. Compared to patients never treated with a sulfonylurea, those treated with a sulfonylurea had a 1.7-fold increased risk of HCC development. Of the different types of sulfonylureas, the exclusive use of glimepiride was associated with a significantly elevated risk of HCC (OR = 1.89, 95% CI = 1.02–3.47) compared to those who were never treated with sulfonylureas. No significant associations were observed between exclusive gliclazide use and incident HCC (OR = 2.04, 95% CI = 0.75–5.52). In conclusion, the association between the use of sulfonylureas and risk of HCC was different according to the type of sulfonylurea, in patients with new-onset T2DM. Further prospective studies are warranted to confirm these results and translate them into clinical practice.

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          Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.

          An association between diabetes and chronic liver disease has been reported. However, the temporal relationship between these conditions remains unknown. We identified all patients with a hospital discharge diagnosis of diabetes between 1985 and 1990 using the computerized records of the Department of Veterans Affairs. We randomly assigned 3 patients without diabetes for every patient with diabetes. We excluded patients with concomitant liver disease. The remaining cohort was followed through 2000 for the occurrence of chronic nonalcoholic liver disease (CNLD) and hepatocellular carcinoma (HCC). Hazard rate ratios (HRR) were determined in Cox proportional hazard survival analysis. The study cohort comprised 173,643 patients with diabetes and 650,620 patients without diabetes. Most were men (98%). Patients with diabetes were older (62 vs. 54 years) than patients without diabetes. The incidence of chronic nonalcoholic liver disease was significantly higher among patients with diabetes (incidence rate: 18.13 vs. 9.55 per 10,000 person-years, respectively, P < 0.0001). Similar results were obtained for HCC (incidence rate: 2.39 vs. 0.87 per 10,000 person-years, respectively, P < 0.0001). Diabetes was associated with an HRR of 1.98 (95% CI: 1.88 to 2.09, P < 0.0001) of CNLD and an HRR of 2.16 (1.86 to 2.52, P < 0.0001) of hepatocellular carcinoma. Diabetes carried the highest risk among patients with longer than 10 years of follow-up. Among men with diabetes, the risk of CNLD and HCC is doubled. This increase in risk is independent of alcoholic liver disease, viral hepatitis, or demographic features.
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            Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis.

            Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. Given that the burden of chronic liver disease is expected to rise owing to increasing rates of alcoholism, hepatitis B and C prevalence and obesity-related fatty liver disease, it is expected that the incidence of HCC will also increase in the foreseeable future. This article summarizes the international epidemiology, the risk factors and the pathogenesis of HCC, including the roles of viral hepatitis, toxins, such as alcohol and aflatoxin, and insulin resistance.
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              Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis.

              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.
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                Author and article information

                Contributors
                cmnam@yuhs.ac
                edgo@yuhs.ac
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                12 June 2019
                12 June 2019
                2019
                : 9
                : 8532
                Affiliations
                [1 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Internal Medicine, , Yonsei University College of Medicine, ; Seoul, Republic of Korea
                [2 ]Department of Preventive Medicine, Eulgi University College of Medicine, Daejeon, Republic of Korea
                [3 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Preventive Medicine, , Yonsei University College of Medicine, ; Seoul, Republic of Korea
                Author information
                http://orcid.org/0000-0002-0364-4675
                Article
                44447
                10.1038/s41598-019-44447-1
                6561966
                31189966
                058ced6e-7f2e-4629-aee8-cb0d1ae62479
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 October 2018
                : 17 May 2019
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                © The Author(s) 2019

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                epidemiology,risk factors
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                epidemiology, risk factors

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