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      Metformin therapy associated with survival benefit in lung cancer patients with diabetes

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          Abstract

          The purpose of this study is to summarize the currently available evidence regarding the concerned issue by performing a comprehensive meta-analysis. Relevant publications reporting the association of metformin use with survival of lung cancer patients with diabetes were electronically searched to identify eligible studies. The meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures for disease-free survival(DFS) and overall survival(OS) estimates. A total of 17 individual studies from 10 publications were included in the meta-analysis. Overall, the results revealed a significant association of metformin use with a better survival of lung cancer patients with diabetes(for DFS: HR = 0.65, 95%CI = 0.52-0.83; for OS: HR = 0.78, 95%CI = 0.64-0.93). The subgroup analyses showed similar association in Asian region(for DFS:HR = 0.69, 95%CI = 0.59-0.80; for OS: HR = 0.55, 95%CI = 0.46-0.67) but not in Western region. Such association was also presented in small cell lung cancer (for DFS: HR = 0.54, 95%CI = 0.38-0.77; for OS: HR = 0.52, 95%CI = 0.39-0.69) and in non-small cell lung cancer(for DFS: HR = 0.70, 95%CI = 0.51-0.96; for OS: HR = 0.75, 95%CI = 0.58-0.97). Analyses stratified by treatment strategy showed a reduction in the risk of cancer-related mortality in patients receiving chemotherapy(for DFS: HR = 0.71, 95%CI = 0.64-0.83; for OS: HR = 0.58, 95%CI = 0.47-0.71) but not in patients receiving chemoradiotherapy. The meta-analysis demonstrated that metformin use was significantly associated with a favorable survival outcome of lung cancer patients with diabetes.

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          Most cited references30

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          Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults.

          Several studies have suggested that diabetes mellitus may alter the risk of developing a variety of cancers, and the associations are biologically plausible. To learn more about the relation between diabetes and cancer mortality, the authors examined associations with selected cancers in a large, prospective US cohort of 467,922 men and 588,321 women who had no reported history of cancer at enrollment in 1982. After 16 years of mortality follow-up, diabetes was significantly associated with fatal colon cancer in men (multivariate relative risk (RR) = 1.20, 95% confidence interval (CI): 1.06, 1.37) and women (RR = 1.24, 95% CI: 1.07, 1.43) and with pancreatic cancer in men (RR = 1.48, 95% CI: 1.27, 1.73) and women (RR = 1.44, 95% CI: 1.21, 1.72). For men, diabetes was significantly associated with liver cancer (RR = 2.19, 95% CI: 1.76, 2.72) and bladder cancer (RR = 1.43, 95% CI: 1.14, 1.80). In addition, diabetes was significantly associated with breast cancer in women (RR = 1.27, 95% CI: 1.11, 1.45). These associations were not explained by high body mass. Our findings suggest that diabetes is an independent predictor of mortality from cancer of the colon, pancreas, female breast, and, in men, of the liver and bladder.
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            Mortality After Incident Cancer in People With and Without Type 2 Diabetes

            OBJECTIVE Type 2 diabetes is associated with an increased risk of several types of cancer and with reduced survival after cancer diagnosis. We examined the hypotheses that survival after a diagnosis of solid-tumor cancer is reduced in those with diabetes when compared with those without diabetes, and that treatment with metformin influences survival after cancer diagnosis. RESEARCH DESIGN AND METHODS Data were obtained from >350 U.K. primary care practices in a retrospective cohort study. All individuals with or without diabetes who developed a first tumor after January 1990 were identified and records were followed to December 2009. Diabetes was further stratified by treatment regimen. Cox proportional hazards models were used to compare all-cause mortality from all cancers and from specific cancers. RESULTS Of 112,408 eligible individuals, 8,392 (7.5%) had type 2 diabetes. Cancer mortality was increased in those with diabetes, compared with those without (hazard ratio 1.09 [95% CI 1.06–1.13]). Mortality was increased in those with breast (1.32 [1.17–1.49]) and prostate cancer (1.19 [1.08–1.31]) but decreased in lung cancer (0.84 [0.77–0.92]). When analyzed by diabetes therapy, mortality was increased relative to nondiabetes in those on monotherapy with sulfonylureas (1.13 [1.05–1.21]) or insulin (1.13 [1.01–1.27]) but reduced in those on metformin monotherapy (0.85 [0.78–0.93]). CONCLUSIONS This study confirmed that type 2 diabetes was associated with poorer prognosis after incident cancer, but that the association varied according to diabetes therapy and cancer site. Metformin was associated with survival benefit both in comparison with other treatments for diabetes and in comparison with a nondiabetic population.
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              Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP.

              Metformin is an antidiabetic drug commonly used to treat type 2 diabetes. The aim of the study was to determine whether metformin regulates hepatic gluconeogenesis through the orphan nuclear receptor small heterodimer partner (SHP; NR0B2). We assessed the regulation of hepatic SHP gene expression by Northern blot analysis with metformin and adenovirus containing a constitutive active form of AMP-activated protein kinase (AMPK) (Ad-AMPK) and evaluated SHP, PEPCK, and G6Pase promoter activities via transient transfection assays in hepatocytes. Knockdown of SHP using siRNA SHP was conducted to characterize the metformin-induced inhibition of hepatic gluconeogenic gene expression in hepatocytes, and metformin-and adenovirus SHP (Ad-SHP)-mediated hepatic glucose production was measured in B6-Lep(ob/ob) mice. Hepatic SHP gene expression was induced by metformin, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), and Ad-AMPK. Metformin-induced SHP gene expression was abolished by adenovirus containing the dominant negative form of AMPK (Ad-DN-AMPK), as well as by compound C. Metformin inhibited hepatocyte nuclear factor-4alpha-or FoxA2-mediated promoter activity of PEPCK and G6Pase, and the inhibition was blocked with siRNA SHP. Additionally, SHP knockdown by adenovirus containing siRNA SHP inhibited metformin-mediated repression of cAMP/dexamethasone-induced hepatic gluconeogenic gene expression. Furthermore, oral administration of metformin increased SHP mRNA levels in B6-Lep(ob/ob) mice. Overexpression of SHP by Ad-SHP decreased blood glucose levels and hepatic gluconeogenic gene expression in B6-Lep(ob/ob) mice. We have concluded that metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of SHP.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                7 June 2016
                20 April 2016
                : 7
                : 23
                : 35437-35445
                Affiliations
                1 Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
                Author notes
                Correspondence to: Fengjun Cao, fengjuncaoshiyan@ 123456126.com
                Article
                8881
                10.18632/oncotarget.8881
                5085241
                27105507
                b0d22e48-fb03-4e36-8ac5-9f9bfe396998
                Copyright: © 2016 Wan et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 October 2015
                : 11 April 2016
                Categories
                Clinical Research Paper

                Oncology & Radiotherapy
                lung cancer,metformin,survival,diabetes,meta-analysis
                Oncology & Radiotherapy
                lung cancer, metformin, survival, diabetes, meta-analysis

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