Effect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis.

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Insulin 1 endocrinologydiseasesdrugs
everolimus 1 endocrinologydiseasesdrugs
type 2 diabetes mellitus 8 endocrinologydiseases
lactic acidosis 1 endocrinologydiseases
metformin 62 endocrinologydiseasesdrugs
obesity 2 endocrinologydiseases
polycystic ovary syndrome 1 endocrinologydiseases
sorafenib 1 endocrinologydiseasesdrugs
diabetes mellitus 10 endocrinologydiseases
endometrial carcinoma 1 endocrinologydiseases
hyperlipidemia 1 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 3656 worldwide at low cost.Type 2 diabetes mellitus is a well-established risk factor for EC [[16], [17]]. Insulin resistance has been suggested to be one of the critical biological processes that contribute to EC [[18],
everolimus 22756 Notably, these molecular targets are similar to the targets of current drugs, such as sorafenib and everolimus . A phase I clinical trial of 21 cases, including 4 patients with advanced EC, showed that the combination
metformin 27 Title: BMC CancerEffect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysisDanxia ChuJie
metformin 358 (pmc-release): 4/2018Publication date (collection): /2018AbstractBackgroundPrevious studies have suggested that metformin may be useful for preventing and treating endometrial cancer (EC), while the results have been inconsistent.
metformin 563 inconsistent. This systematic review and meta-analysis aimed to investigate the association between metformin use and risk and prognosis of patients with EC.MethodsPubMed, Embase, and the Cochrane Library databases
metformin 743 and the Cochrane Library databases were searched for observational studies evaluating the effect of metformin on EC prevention or treatment. The odds ratio (OR) was used for analyzing risks, and the hazard ratio
metformin 1033 for data analysis.ResultsSeven studies reported data on EC risk. The pooled results suggested that metformin was not significantly associated with a lower risk of EC [OR = 1.05, 95% confidence interval (CI) 0.82–1.35,
metformin 1193 of EC [OR = 1.05, 95% confidence interval (CI) 0.82–1.35, P = 0.70]. For patients with diabetes, metformin showed no advantage in reducing the EC risk compared with other interventions (OR = 0.99, 95% CI 0.78–1.26,
metformin 1412 P = 0.95). Further, seven studies were included for survival analysis. The pooled data showed that metformin could significantly improve the overall survival of patients with EC (HR = 0.61, 95% CI 0.48–0.77,
metformin 1630 0.05) and reduce the risk of EC recurrence (OR = 0.50, 95% CI 0.28–0.92, P < 0.05) Finally, we noted metformin was associated with significantly improving the overall survival of EC patients among diabetes (HR =
metformin 1825 diabetes (HR = 0.47; 95%CI 0.33–0.67, P < 0.05).ConclusionsThis meta-analysis did not prove that metformin was beneficial for preventing EC. However, metformin could prolong the overall survival of patients
metformin 1878 0.05).ConclusionsThis meta-analysis did not prove that metformin was beneficial for preventing EC. However, metformin could prolong the overall survival of patients with EC and reduce their risk of cancer relapse.Electronic
metformin 3038 EC, including aromatase inhibitors [[5]], aspirin [[6]], statins [[7]], hormone therapy [[8]], and metformin [[9], [10]]. Metformin has several advantages in addition to its anticancer activity. First, it is a
metformin 3258 first-line pharmacologic treatment for patients with type 2 diabetes mellitus [[11]]. Second, in addition to metformin use for diabetes, it is also safely prescribed for various nondiabetic conditions, including polycystic
metformin 3523 2 diabetes mellitus and cardiovascular diseases [[13], [14]], and obesity control [[15]]. Finally, metformin is readily available worldwide at low cost.Type 2 diabetes mellitus is a well-established risk factor
metformin 4409 Finally, the risk of EC is increased in women who have higher endogenous estrogen levels [[25]], and metformin has been reported to hinder estrogen-mediated endometrial proliferation [[26]].Several studies have
metformin 4533 reported to hinder estrogen-mediated endometrial proliferation [[26]].Several studies have reported that metformin is a promising intervention for preventing and treating EC. However, these studies had conflicting results,
metformin 4801 Therefore, this systematic review and meta-analysis was performed to evaluate the effectiveness of metformin for the risk and survival outcomes in patients with EC.MethodsSearch strategyThis meta-analysis was
metformin 5240 1980 and July 2016. The following key words and medical terms were used for the literature search: ( metformin OR glucophage OR dimethylbiguanide OR dimethylguanylguanidine) AND (endometrial cancer OR endometrial
metformin 5705 studies.Inclusion criteriaArticles were included in the study if they met the following criteria: (1) used metformin for preventing or treating EC; (2) evaluated the incidence of EC or survival outcomes; the survival
metformin 6636 year, region, study design, sample size, age, patient characteristics, EC incidence, percentage of metformin use in DM patients, proportion of patients with diabetes, reported effect estimates, degree of adjustment,
metformin 10961 endometrial cancerAuthor (year)RegionDesignNo. of patientsMean/Median age (year)EC incidencePercentage of metformin use in DM patients (%)Measurement of outcomeAdjusted variablesSubgroupsStudy periodBecker et al. (2013)
metformin 14169 ECSeven studies were eligible for the meta-analysis. Becker et al. analyzed the risk based on different metformin prescriptions (1–24 and ≥ 25) [[34]]. The data were first pooled in a fixed-effects model. Six
metformin 14346 pooled in a fixed-effects model. Six studies presented the adjusted ORs. The pooled data showed that metformin use was not associated with the risk of EC (OR = 1.05, 95% CI 0.82–1.35, P = 0.70) (Fig. 2).
metformin 15406 publication bias by using the trim and fill method [[46]].Fig. 2Forest plot of the association between metformin use and risk of endometrial cancerFig. 3Funnel plot of the included studies: a Studies presenting the
metformin 15538 endometrial cancerFig. 3Funnel plot of the included studies: a Studies presenting the association between metformin use and risk of endometrial cancer (EC). b Studies presenting an adjusted hazard ratio for the association
metformin 15663 endometrial cancer (EC). b Studies presenting an adjusted hazard ratio for the association between metformin use and overall survival of ECThe association between metformin and EC risk was further investigated
metformin 15727 hazard ratio for the association between metformin use and overall survival of ECThe association between metformin and EC risk was further investigated in patients with diabetes. Franchi et al., Tseng et al. and Arima
metformin 16070 with type 2 diabetes mellitus [[34]–[36]]. The pooled data showed that patients with diabetes using metformin did not have a substantially lower risk of EC compared with those receiving other interventions (OR = 0.99,
metformin 16354 heterogeneity was detected (I2 = 89.9%, P < 0.05).Fig. 4Forest plot of the association between metformin use and risk of endometrial cancer among patients with diabetesMetformin and OS of ECSix retrospective
metformin 16605 analysis. Ezewuiro et al. and Al Hilli et al. separately reported data for patients with diabetes not using metformin and those without diabetes [[43], [44]]. The data from the subgroups within a single study were first
metformin 16781 subgroups within a single study were first pooled using a fixed-effects model. The pooled data showed that metformin use in patients with EC was significantly associated with longer OS compared with patients with EC not
metformin 16900 patients with EC was significantly associated with longer OS compared with patients with EC not using metformin (HR = 0.61, 95% CI 0.48–0.77, P < 0.05) (Fig. 5). Low heterogeneity was identified, which
metformin 17995 test (P = 0.78) or the Begg’s test (P = 0.45).Fig. 5Forest plot of the association between metformin use and overall survival of endometrial cancerThe efficacy of metformin was further investigated among
metformin 18067 of the association between metformin use and overall survival of endometrial cancerThe efficacy of metformin was further investigated among patients with EC having diabetes. Three studies reported relevant data.
metformin 18446 heterogeneity was detected (I2 = 0%, P = 0.69).Fig. 6Forest plot of the association between metformin use and overall survival of endometrial cancer among patients with diabetesMetformin and recurrence
metformin 18667 studies reported data on the recurrence of EC [[10], [44], [45]]. The pooled results suggested that metformin use in patients with EC did not significantly reduce the risk of recurrence (OR = 0.50, 95% CI 0.28–0.92,
metformin 18919 heterogeneity was identified (I2 = 0%, P = 0.98).Fig. 7Forest plot of the association between metformin use and recurrence of endometrial cancerDiscussionThis meta-analysis on the prevention of EC with metformin
metformin 19027 metformin use and recurrence of endometrial cancerDiscussionThis meta-analysis on the prevention of EC with metformin included 7 studies and a total of 5,293,039 participants. The pooled data suggested that the use of
metformin 19137 included 7 studies and a total of 5,293,039 participants. The pooled data suggested that the use of metformin could not substantially prevent the development of EC. When analyzing the subgroup of patients with
metformin 19325 subgroup of patients with diabetes, who were at a higher risk of EC, a significant protective effect of metformin against EC still could not be detected compared with patients with diabetes treated with other antidiabetic
metformin 19501 diabetes treated with other antidiabetic therapies. Differences in the duration of use and dose of metformin might have limited the statistical power of this study. The protective effects of metformin might be
metformin 19593 dose of metformin might have limited the statistical power of this study. The protective effects of metformin might be time and dose dependent [[47]]. However, most included studies failed to conduct dose-escalation
metformin 19832 meta-analysis also comprised 7 studies with a total of 3923 patients with EC who were treated with metformin . It was found that metformin could substantially improve the OS and reduce the risk of recurrence. The
metformin 19861 7 studies with a total of 3923 patients with EC who were treated with metformin. It was found that metformin could substantially improve the OS and reduce the risk of recurrence. The benefit for OS remained significant
metformin 20096 subgroup of patients with diabetes.A previous meta-analysis based on 19 studies and illustrated effects of metformin on reversal of atypical endometrial hyperplasia, cellular proliferation biomarkers expression and overall
metformin 20246 hyperplasia, cellular proliferation biomarkers expression and overall survival. Further, they point out metformin could reverse atypical endometrial hyperplasia to normal endometrial histology, reduction of cell proliferation
metformin 20588 risk of certain cancer was not evaluated [[48]]. The study conducted by Perez-Lopez et al. suggested metformin therapy was associated with a reduced risk of overall mortality in T2DM women with EC. Whereas this
metformin 20763 in T2DM women with EC. Whereas this study focused on patients with T2DM and the preventive effect of metformin on EC risk was not illustrated [[49]]. Tang et al. conducted a meta-analysis based on 11 studies and
metformin 20884 was not illustrated [[49]]. Tang et al. conducted a meta-analysis based on 11 studies and indicated metformin therapy are significantly improvement EC risk and prognosis of EC. However, this study with incomplete
metformin 21108 searches and the result of recurrence of EC were not calculated [[50]]. This novel meta-analysis of metformin use for preventing and treating EC analyzed both risk and survival scenarios. The most comprehensive
metformin 21614 studies sufficiently adjusted for various clinicopathological confounding factors. Moreover, the role of metformin was specifically assessed among patients with diabetes.Abundant preclinical in vitro and in vivo studies
metformin 21768 with diabetes.Abundant preclinical in vitro and in vivo studies have reported the anticancer effect of metformin on various malignancies. Nevertheless, the exact molecular mechanisms remain unknown. Metformin may
metformin 22099 the conversion of epithelial cells into mesenchymal cells [[52]]. Several studies have reported that metformin can reverse endometrial hyperplasia [[53], [54]]. Thus, metformin may have multiple functions mediated
metformin 22165 Several studies have reported that metformin can reverse endometrial hyperplasia [[53], [54]]. Thus, metformin may have multiple functions mediated through direct and indirect mechanisms [[51]]. The indirect effect
metformin 22893 of 21 cases, including 4 patients with advanced EC, showed that the combination of temsirolimus and metformin was a promising treatment [[56]]. Metformin is nontoxic and may be extremely useful for enhancing the
metformin 23060 and may be extremely useful for enhancing the treatment efficacy of the targeted drugs [[51]]. Since metformin has been used for more than 50 years, its safety profile has been well established. Although it can
metformin 23519 meta-analysis had several limitations. It only identified a small number of studies exploring the role of metformin for prevention and treatment. Further, stratified results according to individuals characteristics were
metformin 23992 low level of evidence. Furthermore, whether patients had taken different antidiabetic drugs before metformin administration could not be determined. Their glycemic control might also be inadequate. Moreover, this
metformin 24478 large randomized controlled trial that enrolled patients with gastrointestinal malignancies showed that metformin was helpful for the chemoprevention of colorectal cancer [[58]], but did not significantly improve the
metformin 24717 pancreatic cancer [[59]]. Most of the studies included in this meta-analysis did not report the effect of metformin dose or duration. Although most of the studies performed sufficient adjustment of variables, little
metformin 25165 cohorts were included. Therefore, this comprehensive meta-analysis just provided relative results on metformin use for EC prevention and treatment.ConclusionsIn conclusion, a preventive effect of metformin on the
metformin 25260 results on metformin use for EC prevention and treatment.ConclusionsIn conclusion, a preventive effect of metformin on the development of EC was not observed in this meta-analysis. However, metformin was beneficial in
metformin 25344 preventive effect of metformin on the development of EC was not observed in this meta-analysis. However, metformin was beneficial in improving the OS and reducing the relapse risk for patients with EC. More prospective
sorafenib 22742 pathways [[55]]. Notably, these molecular targets are similar to the targets of current drugs, such as sorafenib and everolimus. A phase I clinical trial of 21 cases, including 4 patients with advanced EC, showed
Select Disease Character Offset Disease Term Instance
diabetes mellitus 3209 its anticancer activity. First, it is a first-line pharmacologic treatment for patients with type 2 diabetes mellitus [[11]]. Second, in addition to metformin use for diabetes, it is also safely prescribed for various
diabetes mellitus 3426 nondiabetic conditions, including polycystic ovarian syndrome [[12]], primary prevention of type 2 diabetes mellitus and cardiovascular diseases [[13], [14]], and obesity control [[15]]. Finally, metformin is readily
diabetes mellitus 3583 [14]], and obesity control [[15]]. Finally, metformin is readily available worldwide at low cost.Type 2 diabetes mellitus is a well-established risk factor for EC [[16], [17]]. Insulin resistance has been suggested to be one
diabetes mellitus 3827 biological processes that contribute to EC [[18], [19]]. Approximately 30% of patients with EC have type 2 diabetes mellitus , and up to 36% have undiagnosed insulin resistance [[20]]. Metformin use could reduce the risk of type
diabetes mellitus 3950 up to 36% have undiagnosed insulin resistance [[20]]. Metformin use could reduce the risk of type 2 diabetes mellitus and delay its progression. It reduces insulin resistance by increasing insulin receptor tyrosine kinase
diabetes mellitus 12293 forms of medication.None1996–2011BMI Body mass index, COPD chronic obstructive pulmonary disease, DM diabetes mellitus , EC endometrial cancer, EH endometrial hyperplasia, HR hazard ratio, HRT hormone replacement therapy,
diabetes mellitus 15882 patients with diabetes. Franchi et al., Tseng et al. and Arima et al. included only patients with type 2 diabetes mellitus [[37]–[40]]. Three other studies reported data for subpopulations with type 2 diabetes mellitus [[34]–[36]].
diabetes mellitus 15980 2 diabetes mellitus [[37]–[40]]. Three other studies reported data for subpopulations with type 2 diabetes mellitus [[34]–[36]]. The pooled data showed that patients with diabetes using metformin did not have a substantially
diabetes mellitus 17450 (HR = 0.59, 95% CI 0.45–0.76, P < 0.05). When stratified by the percentage of patients with type 2 diabetes mellitus (< 50% vs ≥50%), the overall effect had no substantial change. The meta-regression analysis revealed
diabetes mellitus 17715 (P = 0.81), proportion of stages I–II patients (P = 0.88), or percentage of patients with type 2 diabetes mellitus (P = 0.84) to account for the heterogeneity. The funnel plot seemed to be symmetrical (Fig. 3b).
endometrial carcinoma 5340 (metformin OR glucophage OR dimethylbiguanide OR dimethylguanylguanidine) AND (endometrial cancer OR endometrial carcinoma OR endometrial hyperplasia OR endometrial proliferation OR endometrial thickness). The language was
hyperlipidemia 13007 OSNone2005–2010Nevadunsky et al. (2014) [[9]]USARetrospective759856475Age, clinical stage, grade, chemotherapy, radiation, hyperlipidemia OSDiabetes1999–2009Lemanska et al. (2015) [[42]]PolandRetrospective751076464Age, diabetes, hypertension,
lactic acidosis 23213 safety profile has been well established. Although it can cause potentially dangerous toxicity from lactic acidosis , the risk is mainly confined to patients aged more than 80 years, patients with alcohol abuse, or those
obesity 3490 [[12]], primary prevention of type 2 diabetes mellitus and cardiovascular diseases [[13], [14]], and obesity control [[15]]. Finally, metformin is readily available worldwide at low cost.Type 2 diabetes mellitus
obesity 11816 [[38]]ChinaRetrospective4,478,921560.6%40.3Adjusted HRAge, hypertension, COPD, stroke, heart disease, obesity , metabolic profiles, various drugsDuration, dose1998–2002Franchi et al. (2016) [[39]]ItalyCase–control7861> 404.8%36.1Adjusted
polycystic ovary syndrome 12455 hyperplasia, HR hazard ratio, HRT hormone replacement therapy, OR odds ratio, PA physical activity, PCOS polycystic ovary syndrome , UK United Kingdom, USA the United States of AmericaTable 2Characteristics of included studies on the
type 2 diabetes mellitus 3202 addition to its anticancer activity. First, it is a first-line pharmacologic treatment for patients with type 2 diabetes mellitus [[11]]. Second, in addition to metformin use for diabetes, it is also safely prescribed for various
type 2 diabetes mellitus 3419 various nondiabetic conditions, including polycystic ovarian syndrome [[12]], primary prevention of type 2 diabetes mellitus and cardiovascular diseases [[13], [14]], and obesity control [[15]]. Finally, metformin is readily
type 2 diabetes mellitus 3820 biological processes that contribute to EC [[18], [19]]. Approximately 30% of patients with EC have type 2 diabetes mellitus , and up to 36% have undiagnosed insulin resistance [[20]]. Metformin use could reduce the risk of type
type 2 diabetes mellitus 3943 mellitus, and up to 36% have undiagnosed insulin resistance [[20]]. Metformin use could reduce the risk of type 2 diabetes mellitus and delay its progression. It reduces insulin resistance by increasing insulin receptor tyrosine kinase
type 2 diabetes mellitus 15875 in patients with diabetes. Franchi et al., Tseng et al. and Arima et al. included only patients with type 2 diabetes mellitus [[37]–[40]]. Three other studies reported data for subpopulations with type 2 diabetes mellitus [[34]–[36]].
type 2 diabetes mellitus 15973 with type 2 diabetes mellitus [[37]–[40]]. Three other studies reported data for subpopulations with type 2 diabetes mellitus [[34]–[36]]. The pooled data showed that patients with diabetes using metformin did not have a substantially
type 2 diabetes mellitus 17443 (HR = 0.59, 95% CI 0.45–0.76, P < 0.05). When stratified by the percentage of patients with type 2 diabetes mellitus (< 50% vs ≥50%), the overall effect had no substantial change. The meta-regression analysis revealed
type 2 diabetes mellitus 17708 (P = 0.81), proportion of stages I–II patients (P = 0.88), or percentage of patients with type 2 diabetes mellitus (P = 0.84) to account for the heterogeneity. The funnel plot seemed to be symmetrical (Fig. 3b).

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