Metformin use improves survival of diabetic liver cancer patients: systematic review and meta-analysis

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sorafenib 6 endocrinologydiseasesdrugs
diabetes mellitus 3 endocrinologydiseases
metformin 73 endocrinologydiseasesdrugs

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metformin 755 liver cancer among diabetic patients. This work was performed to illustrate the association between metformin use and survival of diabetic liver cancer patients. We conducted a comprehensive literature search of
metformin 1234 studies involving 3452 liver cancer patients fulfilled the inclusion criteria. Meta-analyses showed that metformin use was associated with better survival (HR = 0.59; 95% CI, 0.42-0.83; p = 0.002) of liver cancer patients,
metformin 1614 adjusting for age, etiology, index of tumor severity and treatment of liver cancer, the association between metformin use and better survival of liver cancer patients was stable, pooled HR ranged from 0.47 to 0.57. The
metformin 1748 of liver cancer patients was stable, pooled HR ranged from 0.47 to 0.57. The results indicated that metformin use improved survival of diabetic liver cancer patients. However, the results should be interpreted
metformin 2000 residual confounding. Further prospective studies are still needed to confirm the prognostic benefit of metformin use.INTRODUCTIONLiver cancer is one of the leading malignancies worldwide, with an overall 5-year survival
metformin 2708 received great attention for its anti-tumor activity. Accumulating studies have researched the role of metformin in both cancer prevention and treatment. Survival benefits of metformin have been demonstrated in a
metformin 2780 have researched the role of metformin in both cancer prevention and treatment. Survival benefits of metformin have been demonstrated in a wide range of malignancies including breast cancer, prostate cancer, pancreatic
metformin 3102 one previous meta-analysis involving two related studies summarized evidence on survival effect of metformin in liver cancer patients [[13]]. It is still uncertain whether use of metformin could also generate
metformin 3182 survival effect of metformin in liver cancer patients [[13]]. It is still uncertain whether use of metformin could also generate better clinical outcomes for patients with liver cancer.Preclinical studies have
metformin 3348 patients with liver cancer.Preclinical studies have demonstrated indirect and direct beneficial effects of metformin on cultured human hepatocellular carcinoma (HCC) cell lines, in xenograft tumors model in vivo, and
metformin 3560 animal livers [[14]-[17]]. Simultaneously, a growing number of observational studies have compared metformin with non-metformin treatment on prognostic outcomes of liver cancer patients, showing somewhat inconsistent
metformin 3579 [[14]-[17]]. Simultaneously, a growing number of observational studies have compared metformin with non- metformin treatment on prognostic outcomes of liver cancer patients, showing somewhat inconsistent results [[18]-[20]].
metformin 3740 patients, showing somewhat inconsistent results [[18]-[20]]. Given that understanding the efficacy of metformin in liver cancer treatment may lead to better clinical management, we embarked a systematic review and
metformin 3899 clinical management, we embarked a systematic review and meta-analysis to illustrate the association of metformin use with survival of liver cancer patients.RESULTSDescription of included studiesThe flow diagram for
metformin 4406 [[18]-[20], [23]-[30]] and 3452 liver cancer patients were included in our overall analysis of the effect of metformin on survival of liver cancer patients.The characteristics of included cohort studies are listed in Table
metformin 4974 were without this restriction. Meanwhile, 3 studies [[18]-[20]] also compared survival of diabetic metformin users with non-diabetic non-metformin users. Seven studies [[18], [19], [24], [27]-[30]] reported estimations
metformin 5012 Meanwhile, 3 studies [[18]-[20]] also compared survival of diabetic metformin users with non-diabetic non- metformin users. Seven studies [[18], [19], [24], [27]-[30]] reported estimations defining the metformin exposure
metformin 5107 non-metformin users. Seven studies [[18], [19], [24], [27]-[30]] reported estimations defining the metformin exposure as taking metformin after the diagnosis of liver cancer, including those [[18], [19], [29]]
metformin 5136 studies [[18], [19], [24], [27]-[30]] reported estimations defining the metformin exposure as taking metformin after the diagnosis of liver cancer, including those [[18], [19], [29]] taking metformin on the date
metformin 5225 as taking metformin after the diagnosis of liver cancer, including those [[18], [19], [29]] taking metformin on the date of diagnosis and continued during the follow-up period. Meanwhile 4 studies [[20], [23],
metformin 5388 follow-up period. Meanwhile 4 studies [[20], [23], [24], [30]] reported estimations defining as taking metformin before the cancer diagnosis. In addition to age [[18]-[20], [23]-[25], [27]-[30]], most studies adjusted
metformin 5823 meta-analysisStudy (year)DesignLocationNOS scoreData sourceTime periodStudy populationDefinition of metformin exposureTotal subjectMean follow-upAdjustment variablesChen 2011 [[18]]Retrospective cohortChina7Tungs'
metformin 7513 of IRST IRCCS2008.03-2014.08HCC patients with DM consecutively treated with sorafenib twice dailyOn metformin for at least 5 years when HCC was diagnosis42NRAge, sex, smoking habits and etiologyJang 2015 [[28]]Retrospective
metformin 7739 cohortKorea7Four institutions2003.03-2012.12HCC patients who were treated with SBRT or HypoRTReceived metformin for at least 1 year during radiotherapy7615 monthsAge, sex, diabetic status, ECOG PS, etiology, number
metformin 9457 intervals (CIs) are shown in Figure 2. Meta-analysis of 11 studies [[18]-[20], [23]-[30]] showed that metformin use was associated with a 41% significant decreased mortality in 3452 liver cancer patients (HR = 0.59;
metformin 10188 Begg's test (p = 0.276) nor from Egger's test (p = 0.676).Figure 2Forest plot of the association between metformin use and survival of liver cancer patientsSubgroup analysesSubgroup analyses were performed to further
metformin 10498 overall analysis (Table 2). Stratified analyses by study quality found that the decreased mortality in metformin users lost significance in 7 high quality studies (HR = 0.61; 95% CI, 0.35-1.05; p = 0.072). Subgroup
metformin 10664 0.61; 95% CI, 0.35-1.05; p = 0.072). Subgroup analysis of 3 Asian studies showed an exaggeration in metformin 's effect (HR = 0.37; 95% CI, 0.30-0.47; p < 0.001). When defined the exposure as taking metformin before
metformin 10762 in metformin's effect (HR = 0.37; 95% CI, 0.30-0.47; p < 0.001). When defined the exposure as taking metformin before cancer diagnosis, the beneficial effect on survival lost significance (HR = 0.69; 95% CI, 0.37-1.29;
metformin 10916 effect on survival lost significance (HR = 0.69; 95% CI, 0.37-1.29; p = 0.249). When the controlled non- metformin users were restricted to liver cancer patients with DM, the beneficial effect for metformin use was
metformin 11008 controlled non-metformin users were restricted to liver cancer patients with DM, the beneficial effect for metformin use was stable (HR = 0.64; 95% CI, 0.42-0.97; p= 0.035), and persisted in controlled population without
metformin 11225 this restriction (HR = 0.47; 95% CI, 0.31-0.71; p < 0.001). However, when compared to non-diabetic non- metformin users, diabetic metformin users showed worse survival (HR = 1.35; 95% CI, 0.99-1.82; p = 0.054). After
metformin 11251 95% CI, 0.31-0.71; p < 0.001). However, when compared to non-diabetic non-metformin users, diabetic metformin users showed worse survival (HR = 1.35; 95% CI, 0.99-1.82; p = 0.054). After adjusting for age, etiology,
metformin 11446 adjusting for age, etiology, index of tumor severity and treatment of liver cancer, the association between metformin use and better survival of liver cancer patients was stable, pooled HRs (95% CIs) were 0.57 (0.38-0.85),
metformin 11698 and 0.47 (0.27-0.84), respectively.Table 2Summary results of subgroup analyses of association between metformin use and survival of liver cancer patientsSubgroupNo. of studiesTotal subjectSummary resultI2 (%)HR (95%
metformin 11987 (0.38-0.91)0.01874.1LocationAsian38800.37 (0.30-0.47)< 0.0010Western825720.70 (0.49-0.98)0.04176.9Definition of metformin Before cancer diagnosis420840.69 (0.37-1.29)0.24979.8After cancer diagnosis#723010.60 (0.39-0.93)0.02384.4Controlled
metformin 12559 interval; DM, diabetes mellitus; Non-DM, non-diabetes mellitus; HR, hazard ratio.#included those taking metformin on the date of diagnosis and continued during the follow-up period.Significant heterogeneity was present
metformin 13190 meta-analysis of 11 cohort studies and 3452 liver cancer patients, we found that, relative to non-use, use of metformin significantly reduced mortality (HR = 0.59; 95% CI, 0.42-0.83; p = 0.002). This significant effect was
metformin 13443 However, stratified analyses by study quality got a conflicting result that the decreased mortality in metformin users lost significance in 7 high quality studies (HR = 0.61; 95% CI, 0.35-1.05; p = 0.072). Referring
metformin 13693 study by Casadei et al [[20]] might be the outlier, which reported a significant unfavorable effect of metformin in DM patients with advanced HCC receiving sorafenib (HR = 5.16; 95% CI, 1.53-17.63; p = 0.008). It
metformin 14031 pooled result of remaining 6 high quality studies further validated the significant beneficial effect of metformin (HR = 0.49; 95% CI, 0.29-0.81; p = 0.006). More accurately from a clinical point of view, this study
metformin 14157 CI, 0.29-0.81; p = 0.006). More accurately from a clinical point of view, this study suggested that metformin did not enhance the activity of sorafenib during the development of HCC. However, a synergistic effect
metformin 14300 sorafenib during the development of HCC. However, a synergistic effect against HCC was found between metformin and radiotherapy [[18], [28]]. Synergistic benefits were also found between metformin and chemotherapy/radiotherapy
metformin 14386 found between metformin and radiotherapy [[18], [28]]. Synergistic benefits were also found between metformin and chemotherapy/radiotherapy against certain cancer types [[31]-[35]]. The interactions may be related
metformin 14564 [[31]-[35]]. The interactions may be related to their molecular mechanisms.Although the anti-tumor action of metformin has been reported by accumulating preclinical in vitro and in vivo studies [[16]], the potential molecular
metformin 15075 mechanisms [[37], [38]]. Sorafenib has been reported to act through the same AMPK activation pathway as metformin [[39]]. Thus a possible explanation for sorafenib-resistance is that, tumors are more likely to have
metformin 15224 sorafenib-resistance is that, tumors are more likely to have intrinsic mechanisms of resistance to metformin during chronic treatment with it, which may also lead to resistance to sorafenib, for their similar
metformin 15447 [[20]]. However, the hypothesis does warrant further investigation. Given that anti-tumor activity of metformin as a single agent is limited, investigating the safety and efficacy of metformin acting as adjuvant
metformin 15528 anti-tumor activity of metformin as a single agent is limited, investigating the safety and efficacy of metformin acting as adjuvant or neo-adjuvant therapies is an essential task. Further studies should take the complex
metformin 16051 thought to account for the majority of HCC [[40]]. Our subgroup analyses found a stronger effect of metformin in Asian liver cancer population (HR = 0.37; 95% CI, 0.30-0.47; p < 0.001), suggested that metformin
metformin 16152 metformin in Asian liver cancer population (HR = 0.37; 95% CI, 0.30-0.47; p < 0.001), suggested that metformin might be just sensitive to certain etiological types of liver cancer, which needed to be further confirmed.
metformin 16307 etiological types of liver cancer, which needed to be further confirmed. Stratified analysis by definition of metformin suggested that the beneficial effect on survival lost significance (HR = 0.69; 95% CI, 0.37-1.29; p
metformin 16462 survival lost significance (HR = 0.69; 95% CI, 0.37-1.29; p = 0.249) when defined the exposure as taking metformin before cancer diagnosis. In addition to statistical sake, the finding might be explained by the potential
metformin 16578 cancer diagnosis. In addition to statistical sake, the finding might be explained by the potential metformin -resistance resulted from long-term use before liver cancer diagnosis, as well as the absence of synergistic
metformin 16713 long-term use before liver cancer diagnosis, as well as the absence of synergistic benefits between metformin and conventional cancer treatments before diagnosis.DM is not only an important risk factor for HCC
metformin 16943 an unfavorable predictor for survival [[41]]. Subgroup analyses validated the beneficial effect of metformin use when the population was restricted to liver cancer patients with DM (HR = 0.64; 95% CI, 0.42-0.97;
metformin 17147 0.42-0.97; p = 0.035). Theoretically, adverse effects of DM itself might cover the curative effect of metformin when compared DM patients with non-DM patients. Actually, our subgroup analysis found worse survival
metformin 17312 Actually, our subgroup analysis found worse survival (HR = 1.35; 95% CI, 0.99-1.82; p = 0.054) in diabetic metformin users when compared with non-diabetic non-users, while the result might also be partially explained
metformin 17970 index of tumor severity and treatment of liver cancer, the beneficial effects on overall survival for metformin use were significant and stable (pooled HR ranged from 0.47 to 0.57). However, in addition to the presence
metformin 19195 states and their prior treatments were also various. Although we found that the beneficial effect for metformin use persisted in DM patients and on analyses after adjusting for tumor severity and treatment, whether
metformin 19644 were simultaneously on multiple ADMs, with changes in pharmacotherapy over time. The comparison for metformin users and non-users had doped effects of other ADMs (had their own inherent cancer-modifying effects),
metformin 19793 of other ADMs (had their own inherent cancer-modifying effects), led to a biased association between metformin and outcome. However, it was difficult to perform stratified analysis by controlled ADMs or adjust for
metformin 20611 important to adjust for residual confounding and provide a more indepth understanding of the nature of metformin use [[47]], while most studies failed to provide these comprehensive information.In summary, our meta-analysis
metformin 20770 these comprehensive information.In summary, our meta-analysis of observational studies implies that metformin use significantly benefits the survival of diabetic liver cancer patients. The study somewhat strengthens
metformin 20898 benefits the survival of diabetic liver cancer patients. The study somewhat strengthens the role of metformin as a potential candidate for chemo-therapy drug in diabetic liver cancer patients. However, limited
metformin 21201 prospective studies are needed to confirm the prognostic benefits and to assess the possibility of metformin as an anti-diabetic regimen in the treatment for a wider range of cancer populations.MATERIALS AND METHODSLiterature
metformin 21591 In order to include more potential literature, our overall search strategy only included terms for metformin (e.g., “metformin” and “biguanide”) and liver cancer (e.g., “liver or hepatic cancer/carcinoma/tumor/neoplasm”,
metformin 21611 more potential literature, our overall search strategy only included terms for metformin (e.g., “ metformin ” and “biguanide”) and liver cancer (e.g., “liver or hepatic cancer/carcinoma/tumor/neoplasm”,
metformin 22457 were included if they (i) evaluated a liver cancer patient population, (ii) reported the exposure to metformin or biguanide, and provided effective comparison groups, (iii) evaluated mortality or survival outcome,
metformin 23120 publication year, study design, location, data source, time period, study population, definition of metformin exposure, mean follow-up, comparison groups, mean age, gender, total subject, outcomes, HRs and 95%
metformin 23611 included studies, we used a cut-point for dichotomizing liver cancer patients into users and non-users of metformin in the final analysis about exposure. If several risk estimations were reported in the same article,
metformin 25988 subgroup analyses by stratifying original studies according to study quality, location, definition of metformin exposure, and different controlled populations. Analyses of adjusted HRs were emphasized on studies
metformin 26482 radiotherapy, sorafenib, transarterial chemoembolization, liver resection), given their modifying effects on metformin activity on prognostic outcomes of liver cancer patients. Publication bias (considered present if p
sorafenib 7489 cohortItaly6Medical records databases of IRST IRCCS2008.03-2014.08HCC patients with DM consecutively treated with sorafenib twice dailyOn metformin for at least 5 years when HCC was diagnosis42NRAge, sex, smoking habits and
sorafenib 13746 which reported a significant unfavorable effect of metformin in DM patients with advanced HCC receiving sorafenib (HR = 5.16; 95% CI, 1.53-17.63; p = 0.008). It was greatly different from the beneficial effects reported
sorafenib 14199 from a clinical point of view, this study suggested that metformin did not enhance the activity of sorafenib during the development of HCC. However, a synergistic effect against HCC was found between metformin
sorafenib 15125 to act through the same AMPK activation pathway as metformin [[39]]. Thus a possible explanation for sorafenib -resistance is that, tumors are more likely to have intrinsic mechanisms of resistance to metformin during
sorafenib 15305 mechanisms of resistance to metformin during chronic treatment with it, which may also lead to resistance to sorafenib , for their similar mechanisms [[20]]. However, the hypothesis does warrant further investigation. Given
sorafenib 26387 stage and metastasis), and treatment of liver cancer (e.g., radiofrequency ablation, radiotherapy, sorafenib , transarterial chemoembolization, liver resection), given their modifying effects on metformin activity
Select Disease Character Offset Disease Term Instance
diabetes mellitus 8673 biologically equivalent dose; BMI, body mass index; CA19-9, cancer antigen 19-9; CCA, cholangiocarcinoma; DM, diabetes mellitus ; ECOG PS, Eastern Cooperative Oncology Group performance status; HbA1c, hemoglobin A1c; HBV, hepatitis
diabetes mellitus 12469 (0.35-0.82)0.00475.7Treatment of liver cancer611080.47 (0.27-0.84)0.01177.6Note: Abbreviations: CI, confidence interval; DM, diabetes mellitus ; Non-DM, non-diabetes mellitus; HR, hazard ratio.#included those taking metformin on the date of diagnosis
diabetes mellitus 12500 (0.27-0.84)0.01177.6Note: Abbreviations: CI, confidence interval; DM, diabetes mellitus; Non-DM, non- diabetes mellitus ; HR, hazard ratio.#included those taking metformin on the date of diagnosis and continued during the

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