Metformin Use Is Associated with Reduced Incidence and Improved Survival of Endometrial Cancer: A Meta-Analysis.

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metformin 73 endocrinologydiseasesdrugs
obesity 3 endocrinologydiseases
Insulin 2 endocrinologydiseasesdrugs
endometrial carcinoma 1 endocrinologydiseases
hyperglycemia 1 endocrinologydiseases
hyperlipidemia 1 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 14915 the level of IGF-1 is significantly higher in EC compared with that in the normal endometrium [[40]]. Insulin /IGF-1 signaling is initiated by its binding to transmembrane receptors, which results in activation
Insulin 15246 subsequently activated. P85 is the regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) [[41]]. Insulin /IGF-1/PI3-K pathway plays a role in the carcinogenesis via mTOR, which is a key effector of PI3-K. In
metformin 575 ChinaPublication date (ppub): /2017Publication date (epub): 3/2017AbstractStudies have suggested that metformin can potentially decrease the incidence of cancer and improve survival outcomes. However, the association
metformin 698 potentially decrease the incidence of cancer and improve survival outcomes. However, the association between metformin use and the incidence and survival of endometrial cancer (EC) remains controversial. So, a meta-analysis
metformin 1088 confidence intervals (CIs) comparing the EC incidence and survival in patients treated with and without metformin . Eleven studies involving 766,926 participants were included in this study. In the pooled analysis of
metformin 1248 were included in this study. In the pooled analysis of five studies which evaluated the association of metformin use with the incidence of EC, we found that metformin use was associated with a 13% reduction in EC
metformin 1302 five studies which evaluated the association of metformin use with the incidence of EC, we found that metformin use was associated with a 13% reduction in EC risk among patients with diabetes (RR = 0.87, 95% CI:
metformin 1521 0.80–0.95; p = 0.006). In the pooled analysis of six retrospective cohort studies evaluating the effect of metformin on the survival of EC patients, we found that, relative to nonuse, metformin use significantly improved
metformin 1598 evaluating the effect of metformin on the survival of EC patients, we found that, relative to nonuse, metformin use significantly improved the survival of EC patients (HR = 0.63, 95% CI: 0.45–0.87; p = 0.006).
metformin 1731 improved the survival of EC patients (HR = 0.63, 95% CI: 0.45–0.87; p = 0.006). This study showed that metformin use was significantly associated with a decreased incidence of EC in diabetes and a favorable survival
metformin 2820 antineoplastic properties. Recent epidemiological studies have reported potential beneficial effects of metformin on gynecological cancers. Metformin use significantly decreased the risk or improved some survival outcomes
metformin 3056 with cervical, breast, and ovarian cancer [[6]–[8]]. Moreover, several meta-analyses have shown that metformin use decreased the incidence and improved the survival of a wide range of malignant tumors, such as liver
metformin 3347 Although the exact mechanism is still not fully understood, studies in vivo and vitro have shown that metformin likely exerts its antitumorigenic effects directly or through other downstream targets to inhibit the
metformin 3869 levels and hyperglycemia [[17]].Thus far, several clinical researches have investigated the effect of metformin on the incidence of EC in diabetic patients. However, it is still uncertain whether the use of metformin
metformin 3974 metformin on the incidence of EC in diabetic patients. However, it is still uncertain whether the use of metformin could decrease the incidence of EC owing to the contradictory results of these studies. Tseng reported
metformin 4103 incidence of EC owing to the contradictory results of these studies. Tseng reported that the use of metformin in women with diabetes was associated with an overall significantly lower risk of EC [[18]]. However,
metformin 4253 with an overall significantly lower risk of EC [[18]]. However, Franchi et al.'s study indicated that metformin did not meaningfully affect the risk of EC [[19]]. Moreover, studies have also investigated the association
metformin 4379 meaningfully affect the risk of EC [[19]]. Moreover, studies have also investigated the association between metformin use and survival of EC patients. However, whether metformin use could generate better clinical outcomes
metformin 4439 also investigated the association between metformin use and survival of EC patients. However, whether metformin use could generate better clinical outcomes in EC patients also remains unclear. Ko et al. reported
metformin 4561 generate better clinical outcomes in EC patients also remains unclear. Ko et al. reported that the non metformin users had 2.3-fold increased risk of death when compared with the metformin users after adjusting for
metformin 4637 al. reported that the nonmetformin users had 2.3-fold increased risk of death when compared with the metformin users after adjusting for age, stage, grade, histology, and adjuvant treatment [[20]]. Conversely, Al
metformin 4817 treatment [[20]]. Conversely, Al Hilli et al. reported that overall survival was similar between the metformin users and nonusers of EC patients after adjusting for confounding covariates [[21]]. Based on these
metformin 4960 after adjusting for confounding covariates [[21]]. Based on these studies, the association between metformin use and the incidence and survival of EC is still uncertain; thus, a meta-analysis is needed to confirm
metformin 5089 incidence and survival of EC is still uncertain; thus, a meta-analysis is needed to confirm the effects of metformin .2. Materials and Methods2.1. Literature SearchA comprehensive literature search was performed to identify
metformin 5459 to the articles published in English. We developed a search strategy using the following terms: “ metformin ” or “biguanide” and “endometrial cancer” or “endometrial carcinoma”. Additionally, we
metformin 5990 studies, nested case-control studies, and cohort studies; (b) studies evaluating the association between metformin use and incidence of EC in diabetes or those evaluating the effect of metformin on survival of EC patients;
metformin 6070 association between metformin use and incidence of EC in diabetes or those evaluating the effect of metformin on survival of EC patients; (c) studies reporting relative risks (RRs) or hazard ratios (HRs) with corresponding
metformin 7669 third party (Xu) assessment when necessary.2.4. Statistical AnalysesTo assess the association between metformin use and the incidence and survival of EC, summary RRs and HRs with their corresponding 95% CIs were
metformin 9447 studies were based in the USA. Of the included studies, adjusted multivariate analyses for the effect of metformin were performed in 9 studies, and unadjusted univariate analyses were performed in 2 studies. The NOS
metformin 9838 Endometrial CancerBased on the combined results of the five studies, compared with the reference groups, metformin use was significantly associated with a decreased incidence of EC in diabetes (RR = 0.87, 95% CI: 0.80–0.95;
metformin 10153 meta-analysis of five studies in total (I2 = 0.0%). Stratification according to study design showed that metformin use was significantly associated with a decreased incidence of EC for retrospective studies (RR = 0.85,
metformin 10535 CI: 0.82–1.41, p = 0.625).3.2.2. Metformin Use and Survival of Endometrial CancerCompared with no metformin use, metformin use was associated with survival improvement of EC patients (HR = 0.63, 95% CI: 0.45–0.87;
metformin 10550 0.82–1.41, p = 0.625).3.2.2. Metformin Use and Survival of Endometrial CancerCompared with no metformin use, metformin use was associated with survival improvement of EC patients (HR = 0.63, 95% CI: 0.45–0.87; p = 0.006;
metformin 10761 0.006; Figure 3). Figure 3 also shows the HRs (95% CI) for each individual study comparing the group of metformin use with the reference group (no metformin use). There was obvious between-study heterogeneity in this
metformin 10804 (95% CI) for each individual study comparing the group of metformin use with the reference group (no metformin use). There was obvious between-study heterogeneity in this meta-analysis of six studies in total (I2
metformin 11193 0.000) with low heterogeneity (I2 = 0.0%). However, two studies without adjusting variables showed that metformin use was not associated with the overall survival of patients with EC (HR = 0.92, 95% CI: 0.70–1.19;
metformin 11404 p = 0.512; I2 = 0.0%). Stratified analyses by reference group showed that the beneficial effect of metformin use was stable (HR = 0.47, 95% CI: 0.33–0.67; p = 0.000; I2 = 0.0%), when the controlled nonmetformin
metformin 11508 metformin use was stable (HR = 0.47, 95% CI: 0.33–0.67; p = 0.000; I2 = 0.0%), when the controlled non metformin users were restricted to EC patients with diabetes. However, when compared with nonmetformin users with
metformin 11601 controlled nonmetformin users were restricted to EC patients with diabetes. However, when compared with non metformin users with and without diabetes, the beneficial effect on survival lost significance (HR = 0.84, 95%
metformin 12559 0.806 for incidence and survival, resp.).4. DiscussionIn this study, we analyzed the association of metformin use with the incidence and survival of EC using a meta-analysis to obtain a powerful conclusion. To
metformin 12781 our knowledge, this is the first meta-analysis providing comprehensive insights into the effects of metformin use on the incidence and survival of EC. In the pooled analysis of five studies which evaluated the
metformin 12906 incidence and survival of EC. In the pooled analysis of five studies which evaluated the association of metformin use with the incidence of EC, we found that metformin use was associated with a 13% reduction in EC
metformin 12960 five studies which evaluated the association of metformin use with the incidence of EC, we found that metformin use was associated with a 13% reduction in EC risk among patients with diabetes (RR = 0.87, 95% CI:
metformin 13187 0.006). In the pooled analysis of six retrospective cohort studies which investigated the effect of metformin use on the survival of EC patients, we found that, relative to nonuse, metformin use significantly improved
metformin 13268 investigated the effect of metformin use on the survival of EC patients, we found that, relative to nonuse, metformin use significantly improved the survival of EC patients (HR = 0.63, 95% CI: 0.45–0.87; p = 0.006).Metformin,
metformin 13805 cervical cancer [[32]]. In the past decade, many epidemiological studies showed the association between metformin use and the reduced risk and improved survival of patients with several types of cancers, including
metformin 13964 patients with several types of cancers, including gynecological cancers. The beneficial effects of metformin use on EC may depend on common anticancer mechanisms present in other gynecological cancers [[33]] and
metformin 15431 key effector of PI3-K. In up to 80% of human cancers, mTOR is aberrantly activated [[42]]. Moreover, metformin use can also exert its direct antitumorigenic effects by activating AMPK, which participates in cellular
metformin 16054 strengths. First, the major strength of this study is that we comprehensively assessed the effects of metformin use on EC, using incidence and survival as the primary outcomes. Second, no obvious heterogeneity was
metformin 16546 detected. Given these characteristics, this meta-analysis can be considered the most comprehensive study of metformin effects on EC, thus far.However, several limitations in our study should be acknowledged. First, two
metformin 17041 controlled. These aspects would be important to provide a more in-depth understanding of the nature of metformin use [[45]]. Second, the population of this study was based on Western and Asian populations. The lack
metformin 17488 might also introduce publication bias. Finally, even though we found an obvious association between metformin use and the survival of patients with EC, current studies are unable to provide a conclusive result,
metformin 17836 are warranted.5. ConclusionsIn summary, our meta-analysis of observational studies demonstrated that metformin use reduces the incidence of EC among patients with diabetes and improves the overall survival of patients
metformin 17993 with diabetes and improves the overall survival of patients with EC. Our study results suggest that metformin may be a potential alternative treatment for patients with diabetes at high risk of EC and patients
metformin 18503 these results.Figure 1Flow diagram of study selection.Figure 2Forest plot of the association between metformin use and incidence of endometrial cancer.Figure 3Forest plot of the association between metformin use
metformin 18600 between metformin use and incidence of endometrial cancer.Figure 3Forest plot of the association between metformin use and survival of endometrial cancer.Figure 4Begg's funnel plots for publication bias test on the
metformin 18725 survival of endometrial cancer.Figure 4Begg's funnel plots for publication bias test on the association of metformin use with the incidence of endometrial cancer (p = 0.231 for Egger's test and p = 0.707 for Begg's test).Figure
metformin 18915 0.707 for Begg's test).Figure 5Begg's funnel plots for publication bias test on the association of metformin use with the survival of endometrial cancer (p = 0.220 for Egger's test and p = 0.806 for Begg's test).Table
metformin 19078 0.220 for Egger's test and p = 0.806 for Begg's test).Table 1Characteristics of the included studies of metformin use and incidence of endometrial cancer.Study (year)RegionStudy designDate sourceCases/total subjectsReference
metformin 19353 et al. 2013 [[22]]UKCase-control studyUK-based General Practice Research Database (GPRD)291/1746Non metformin 1995–20120.88 (0.58, 1.32)BMI, smoking, and diabetes duration Luo et al. 2014 [[23]]USARetrospective
metformin 19512 diabetes duration Luo et al. 2014 [[23]]USARetrospective cohort studyWomen's Health Initiative71/4247Non metformin 2005–20100.97 (0.60, 1.58)BMI Ko et al. 2015 [[24]]USARetrospective cohort studyTruven Health Analytics'
metformin 19688 [[24]]USARetrospective cohort studyTruven Health Analytics' MarketScan® and Medicare supplemental databasesNR/272411Non metformin 2000–20110.89 (0.68, 1.17)Age, Charlson index, PCOS, endometrial hyperplasia, obesity, combination
metformin 19943 2015 [[18]]TaiwanRetrospective cohort studyNational Health Insurance database of Taiwan2885/478921Non metformin 1996–20090.842 (0.761, 0.931)Age, hypertension, COPD, stroke, nephropathy, ischemic heart disease,
metformin 20286 2016 [[19]]ItalyNested case-control studyThe healthcare utilizationdatabases of Lombardy376/7485Non metformin 1997–20121.07 (0.82, 1.41)BMIRR, relative risk; 95% CI, 95% confidence interval; NR, not reported;
metformin 20399 Lombardy376/7485Nonmetformin1997–20121.07 (0.82, 1.41)BMIRR, relative risk; 95% CI, 95% confidence interval; NR, not reported; Non metformin , patients treated with other hypoglycemic drugs but not metformin.Table 2Characteristics of the included
metformin 20465 confidence interval; NR, not reported; Nonmetformin, patients treated with other hypoglycemic drugs but not metformin .Table 2Characteristics of the included studies of metformin use and survival of endometrial cancer.Study
metformin 20525 treated with other hypoglycemic drugs but not metformin.Table 2Characteristics of the included studies of metformin use and survival of endometrial cancer.Study (year)RegionStudy designDate sourceSample sizeStageReference
metformin 20794 et al. 2014 [[20]]USARetrospective cohort studyNCI and NCCN designated academic institutions363AllNon metformin 2005–20100.43 (0.24, 0.77)Age, stage, grade, histology, and adjuvant treatment Nevadunsky et al. 2014
metformin 21018 [[25]]USARetrospective cohort studyMontefiore Medical Center (MMC)/Albert Einstein College of Medicine985AllNon metformin 1999–20090.54 (0.30, 0.97)Age, clinical stage, grade, chemotherapy treatment, radiation treatment,
metformin 21302 [[26]]PolandRetrospective cohort studyDepartment of Gynecologic Oncology of Poznan University of Medical Sciences107AllNon metformin 2002–20101.08 (0.46, 2.56)NR Ezewuiro et al. 2016 [[27]]USARetrospective cohort studyThe University
metformin 21473 [[27]]USARetrospective cohort studyThe University of Chicago Medical Center (UCMC)58III, IV, and recurrenceNon metformin 1992–20110.42 (0.23, 0.78)Study site, stage (III versus IV/recurrent), and age at chemotherapy Seebacher
metformin 21737 studyDepartment of Gynaecology and Gynaecological Oncology ofthe Medical University of Vienna465AllNon metformin 1995–20010.90 (0.69, 1.20)NR Al Hilli et al. 2016 [[21]]USARetrospective cohort studyPatient database
metformin 21895 2016 [[21]]USARetrospective cohort studyPatient database of Mayo Clinic, Rochester, Minnesota138AllNon metformin 1999–20080.61 (0.30, 1.23)Propensity scoreHR, hazard ratio; 95% CI, 95% confidence interval; NR, not
metformin 22020 (0.30, 1.23)Propensity scoreHR, hazard ratio; 95% CI, 95% confidence interval; NR, not reported; Non metformin , patients treated with other hypoglycemic drugs but not metformin
metformin 22086 confidence interval; NR, not reported; Nonmetformin, patients treated with other hypoglycemic drugs but not metformin
Select Disease Character Offset Disease Term Instance
endometrial carcinoma 5526 strategy using the following terms: “metformin” or “biguanide” and “endometrial cancer” or “ endometrial carcinoma ”. Additionally, we screened bibliographies of the selected original studies and review articles to
hyperglycemia 3778 mechanisms may be the inhibition of liver gluconeogenesis, resulting in a decrease in insulin levels and hyperglycemia [[17]].Thus far, several clinical researches have investigated the effect of metformin on the incidence
hyperlipidemia 21143 (0.30, 0.97)Age, clinical stage, grade, chemotherapy treatment, radiation treatment, andpresence of hyperlipidemia Lemańska et al. 2015 [[26]]PolandRetrospective cohort studyDepartment of Gynecologic Oncology of Poznan
obesity 2073 female reproductive system, and its incidence is increasing worldwide [[1], [2]]. Both diabetes and obesity are risk factors which promote the development and progression of EC [[3]]. Primary surgical treatment
obesity 19777 databasesNR/272411Nonmetformin2000–20110.89 (0.68, 1.17)Age, Charlson index, PCOS, endometrial hyperplasia, obesity , combination oral contraceptive use, and ultrasoundTseng 2015 [[18]]TaiwanRetrospective cohort studyNational
obesity 20095 hypertension, COPD, stroke, nephropathy, ischemic heart disease, peripheral arterial disease, eye disease, obesity , dyslipidemia, urinary tract disease, other cancers, and other drugs Franchi et al. 2016 [[19]]ItalyNested

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