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      Pharmacologic Therapy of Diabetes and Overall Cancer Risk and Mortality: A Meta-Analysis of 265 Studies

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          Abstract

          Different anti-diabetic medications (ADMs) may modify cancer risk and mortality in patients with diabetes. We conducted a systematic review and meta-analysis to estimate the magnitude of association and quality of supporting evidence for each ADM. A total of 265 studies (44 cohort studies, 39 case-control studies, and 182 randomized controlled trials (RCT)) were identified, involving approximately 7.6 million and 137,540 patients with diabetes for observational studies and RCTs, respectively. The risk of bias overall was moderate. Meta-analysis demonstrated that the use of metformin or thiazolidinediones was associated with a lower risk of cancer incidence (RR = 0.86, 95% CI 0.83-0.90, I 2 = 88.61%; RR = 0.93, 95% CI 0.91-0.96, I 2 = 0.00% respectively). On the other hand, insulin, sulfonylureas and alpha glucosidase inhibitor use was associated with an increased risk of cancer incidence (RR = 1.21, 95% CI 1.08-1.36, I 2 = 96.31%; RR = 1.20, 95% CI 1.13-1.27, I 2 = 95.02%; RR = 1.10, 95% CI 1.05-1.15, I 2 = 0.00% respectively). Use of other types of ADMs was not significantly associated with cancer risk. This study indicates that some ADMs may modify the risk of cancer in individuals with diabetes. Knowledge of this risk may affect the choice of ADM in individuals concerned about cancer or at increased risk for cancer.

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          The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.

          Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.
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            Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin.

            Numerous studies have identified an increased risk of cancer in type 2 diabetes. We explored the association between antidiabetic therapies and cancer-related mortality in patients with type 2 diabetes, postulating that agents that increase insulin levels might promote cancer. This was a population-based cohort study using administrative databases from Saskatchewan Health. Cancer-related mortality was compared among inception cohorts of metformin users and sulfonylurea monotherapy users. Multivariate Cox regression was used to estimate the hazard ratio (HR) of cancer-related mortality, after adjusting for age, sex, insulin use, and chronic disease score. All statistical tests were two-sided. We identified 10,309 new users of metformin or sulfonylureas with an average follow-up of 5.4 +/- 1.9 years (means +/- SD). The mean age for the cohort was 63.4 +/- 13.3 years, and 55% were men. Cancer mortality over follow-up was 4.9% (162 of 3,340) for sulfonylurea monotherapy users, 3.5% (245 of 6,969) for metformin users, and 5.8% (84 of 1,443) for subjects who used insulin. After multivariate adjustment, the sulfonylurea cohort had greater cancer-related mortality compared with the metformin cohort (adjusted HR 1.3 [95% CI 1.1-1.6]; P = 0.012). Insulin use was associated with an adjusted HR of cancer-related mortality of 1.9 (95% CI 1.5-2.4; P < 0.0001). Patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin. It is uncertain whether this increased risk is related to a deleterious effect of sulfonylurea and insulin or a protective effect of metformin or due to some unmeasured effect related to both choice of therapy and cancer risk.
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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

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                15 June 2015
                2015
                : 5
                : 10147
                Affiliations
                [1 ]Center for Clinical and Translational Science, Mayo Clinic , Rochester, Minnesota
                [2 ]Program of Quantitative Methods in Education, University of Minnesota , Minneapolis, Minnesota
                [3 ]Mayo Clinic Libraries, Mayo Clinic , Rochester, Minnesota
                [4 ]Division of Preventive Medicine, Mayo Clinic , Rochester, Minnesota
                [5 ]Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic , Rochester, Minnesota
                Author notes
                Article
                srep10147
                10.1038/srep10147
                4467243
                26076034
                a68f5cdd-771e-4660-bc19-75c46eb9531e
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0.

                History
                : 18 December 2014
                : 31 March 2015
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