Metformin is associated with survival benefit in pancreatic cancer patients with diabetes: a systematic review and meta-analysis.

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metformin 61 endocrinologydiseasesdrugs
obesity 2 endocrinologydiseases
type 2 diabetes mellitus 4 endocrinologydiseases
diabetes mellitus 5 endocrinologydiseases
hyperinsulinemia 1 endocrinologydiseases

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metformin 910 (epub): 2/2017AbstractBackgroundPancreatic cancer is a highly lethal disease with a poor prognosis while metformin has been associated with a decreased risk of pancreatic cancer. Although the benefit of metformin was
metformin 1008 while metformin has been associated with a decreased risk of pancreatic cancer. Although the benefit of metformin was observed for pancreatic cancer prevention, it is not clear whether it can also affect the survival
metformin 1258 type 2 diabetes mellitus. A systematic review and meta-analysis was conducted to assess the effect of metformin on the survival of pancreatic cancer patients with type 2 diabetes mellitus.MethodsTwo independent authors
metformin 1835 included articles. We also investigated treatment effects by different countries, quality and the time of metformin initiation.RESULTSWe found that there was a relative survival benefit associated with metformin treatment
metformin 1931 of metformin initiation.RESULTSWe found that there was a relative survival benefit associated with metformin treatment compared with non-metformin treatment in both overall survival (OS) ([HR] 0.84; 95% confidence
metformin 1969 found that there was a relative survival benefit associated with metformin treatment compared with non- metformin treatment in both overall survival (OS) ([HR] 0.84; 95% confidence interval [CI]: 0.73 – 0.96). These
metformin 2220 subgroups of Asian countries and high quality articles.ConclusionsOur results support the notion that metformin maybe the best anti-diabetic medicine of choice in patients with pancreatic cancer and concurrent type
metformin 2460 perspectives of enhancing survival of pancreatic cancer patients with diabetes mellitus by the use of metformin deserve more attention in future research and clinical practice.INTRODUCTIONPancreatic cancer (PC) is
metformin 3326 increased incidence for PC [[9], [10]].Therapies for diabetes include exogenous insulin, sulfonylureas and metformin . Metformin is the most commonly used therapy for DM worldwide [[11]]. It works mechanistically by reducing
metformin 3684 [12]], gastric cancer [[13]]and ovarian cancer [[14]]. Recent epidemiological studies also showed that metformin might decrease the risk of PC incidence [[15], [16]].Although the benefit of using metformin was observed
metformin 3777 showed that metformin might decrease the risk of PC incidence [[15], [16]].Although the benefit of using metformin was observed with PC prevention, it is not clear whether it can also effect on the survival of PC patients
metformin 3974 survival of PC patients with DM. Since 2009, a growing number of articles focus on the effectiveness of metformin on survival of PC patients with DM, but the results are remarkably inconsistent. Here we conduct a systematic
metformin 4172 conduct a systematic review and meta-analyses of the literature to better understand the effect of metformin on the survival of PC patients with DM.RESULTSSelection of articles and characteristicsThe selection
metformin 4744 [[17]–[25]] were available for inclusion in the quantitative analysis of the survival benefits of metformin for PC patients concurrent with DM, with one study [[25]] including two comparisons. Finally, 10 comparisons
metformin 5048 total number of individuals in the studies was 9, 265 patients with PC and DM. 4871 patients received metformin alone or in combination with other anti-diabets medicine while the rest (4394 patients) received non-metformin
metformin 5159 alone or in combination with other anti-diabets medicine while the rest (4394 patients) received non- metformin treatment such as thiazolidinedione, insulin, sulfonylurea, thiazolidinedione, and dipeptidylpeptidase-4
metformin 6180 al.2012USARetrospective cohort8302(117/185)Y11.4 monthsCurrie et al.2012UKCohort65016(2843/2173)YNRAbbreviations: met, metformin ; non-met, non-metformin; NR, not reported.These studies were conducted in America and Europe (6 studies,
metformin 6204 cohort8302(117/185)Y11.4 monthsCurrie et al.2012UKCohort65016(2843/2173)YNRAbbreviations: met, metformin; non-met, non- metformin ; NR, not reported.These studies were conducted in America and Europe (6 studies, 94.7%) [[17]–[19],
metformin 6754 conditions. Three studies [[17], [22], [25]] performed analysis comparing patients who had received metformin before PC diagnosis. Meanwhile, patients in three studies [[18], [20], [25]] had DM at the time of PC
metformin 7149 analysisThe survival analysis was based on 9 trials, 9318 patients, and 657 deaths. When compared with non- metformin treated patients, the pooled HR of death was 0.84 (95% CI, 0.73 to 0.96; P, 0.01) for metformin users
metformin 7245 non-metformin treated patients, the pooled HR of death was 0.84 (95% CI, 0.73 to 0.96; P, 0.01) for metformin users (Figure 2). This corresponds to an absolute survival benefit at 16% with metformin. We next performed
metformin 7334 0.01) for metformin users (Figure 2). This corresponds to an absolute survival benefit at 16% with metformin . We next performed subgroup analysis by countries (Asian or Western countries). In the subgroup of Asian
metformin 7460 performed subgroup analysis by countries (Asian or Western countries). In the subgroup of Asian countries, metformin was still associated with reduced death risk by fixed model (HR 0.65; 95% CI: 0.52 – 0.80; p 0.830
metformin 8225 heterogeneity; I 2 63.1%) (Table 2). We also performed subgroup analyses to examine the effects of metformin according to timing of metformin initiation. Metformin use before PC diagnose showed no benefit of survival
metformin 8258 2). We also performed subgroup analyses to examine the effects of metformin according to timing of metformin initiation. Metformin use before PC diagnose showed no benefit of survival (HR 0.89; 95% CI: 0.83 –
metformin 8518 (Table 2).Figure 2Forest plot (random effects model) of pooled Hazard ratios(HRs) of overall survival by metformin versus non-metformin treatmentEach study is shown by the point estimate of the HR (the size of the square
metformin 8539 plot (random effects model) of pooled Hazard ratios(HRs) of overall survival by metformin versus non- metformin treatmentEach study is shown by the point estimate of the HR (the size of the square is proportional
metformin 8810 (extending lines). The diamond represents the summary HR and 95% CI.Table 2Pooled analysis of association of metformin use and survival of PC concurrent with DMNSample sizeHRPhI2Total1093180.840.00660.8%(0.73-0.96)Country Asian35440.65(0.52-0.80)0.830.0% Western787740.90(0.78-1.03)0.02857.6%Quality High784950.81(0.70-0.95)0.01263.3% Low38230.88(0.60-1.29)0.6763.1%Exposure Before
metformin 10185 our knowledge, our meta-analysis is the first quantitative study to inspect the association between metformin treatment and survival of patients with PC and type 2 DM concurrently. Our study included 9318 patients
metformin 10403 9 independently published investigations, and the pooled results provided evidence that the use of metformin is associated with improved OS in the treatment of patients with PC and type 2 DM.Pancreatic cancer
metformin 11794 clinical studies to investigate its anticancer activity [[35]–[37]]. Most proposed mechanisms of metformin can be attributed to inhibiting respiratory complex I of the mitochondria, thereby reducing oxidative
metformin 12196 “energy thermostat” that plays a key role in regulating energy metabolism [[43]]. Anticancer role of metformin was related to the activation of AMPK and consequent inhibition of the mammalian target of rapamycin
metformin 12421 pathways that are frequently present in malignant cells [[44]–[48]]. In addition, it has been shown that metformin can inhibit pancreatic tumor growth in obese, prediabetic mice through inhibiting transforming growth
metformin 12735 in pancreatic cancer cells via targeted binding of miR-34a [[49]]. Although the mechanisms by which metformin influences tumor growth have recently been reviewed, it is uncertain whether the use of metformin can
metformin 12833 which metformin influences tumor growth have recently been reviewed, it is uncertain whether the use of metformin can lead to better clinical outcomes for PC patients concurrent with DM.Several studies have reported
metformin 12969 clinical outcomes for PC patients concurrent with DM.Several studies have reported that patients receiving metformin show a significantly increased survival compared with breast, ovarian cancer patients with DM without
metformin 13081 show a significantly increased survival compared with breast, ovarian cancer patients with DM without metformin treatment [[50]–[52]]. Retrospective studies comparing survival outcomes between metformin and non-metformin
metformin 13174 without metformin treatment [[50]–[52]]. Retrospective studies comparing survival outcomes between metformin and non-metformin treatment in PC patients with DM have appeared up to 2012. In our meta-analysis the
metformin 13192 treatment [[50]–[52]]. Retrospective studies comparing survival outcomes between metformin and non- metformin treatment in PC patients with DM have appeared up to 2012. In our meta-analysis the included patients
metformin 13744 pancreatic cancer and concurrent type 2 diabetes were included in the meta-analysis. We found that metformin use is associated with a decreased mortality of PC. Compared with non-metformin treatment, metformin
metformin 13824 meta-analysis. We found that metformin use is associated with a decreased mortality of PC. Compared with non- metformin treatment, metformin treatment with an OS benefit was equipped with a 14% reduction of death in the
metformin 13845 metformin use is associated with a decreased mortality of PC. Compared with non-metformin treatment, metformin treatment with an OS benefit was equipped with a 14% reduction of death in the patients (HR 0.84; 95%
metformin 14230 Asian countries (HR 0.65; 95% CI: 0.52 – 0.80). Although our meta-analysis shows that the use of metformin is associated with an increase of pancreatic cancer survival among Asian individuals, we found no such
metformin 14695 resistance, hyperinsulinemia and central obesity, might benefit from several of the putative benefits of metformin therapy [[53]]. Together, these factors might lead to the different effects of metformin on PC patients
metformin 14784 benefits of metformin therapy [[53]]. Together, these factors might lead to the different effects of metformin on PC patients in Asian and Western groups.With respect to survival, the disregard of the initiation
metformin 14903 patients in Asian and Western groups.With respect to survival, the disregard of the initiation time of metformin use may bring about unintended biases, leading to the over estimation of the drug's effect. We perform
metformin 15056 leading to the over estimation of the drug's effect. We perform subgroup analysis by initiation time of metformin use, of 9 eligibly articles, 5 cohorts [[17], [18], [20], [22], [25]] examined the impact of metformin
metformin 15159 metformin use, of 9 eligibly articles, 5 cohorts [[17], [18], [20], [22], [25]] examined the impact of metformin use classification on survival. The results suggested that metformin use either before or after PC diagnose
metformin 15228 [22], [25]] examined the impact of metformin use classification on survival. The results suggested that metformin use either before or after PC diagnose also has no significant benefit in survival (HR 1.00; 95% CI:
metformin 15597 limited sample size in the subgroups and are prone to incomplete information about the initiation time of metformin use.There are several limitations inherent to our meta-analysis of the published studies. First, according
metformin 15850 assessed as low quality, thus restricting the interpretation of the results. Subgroup analysis show that metformin use lost significant benefit in 3 low quality publications. On the other hand, high quality studies
metformin 15986 benefit in 3 low quality publications. On the other hand, high quality studies confirmed the findings of metformin benefit. Second, following the criteria, we included only a limited number of trials (n=9). The low
metformin 16589 from various countries. Lastly, the results may be influenced by the different levels and durations of metformin exposure. It is extremely difficult to determine the beneficial dose and duration of metformin for improved
metformin 16684 durations of metformin exposure. It is extremely difficult to determine the beneficial dose and duration of metformin for improved survival because few studies have provided the related information.Based on the meta-analysis
metformin 16838 have provided the related information.Based on the meta-analysis results, our study demonstrates that metformin use in individuals with PC and concurrent type 2 DM can increase OS compared with those without the
metformin 16955 individuals with PC and concurrent type 2 DM can increase OS compared with those without the use of metformin . Our results suggest that metformin might be the anti-diabetic medicine of choice in patients with pancreatic
metformin 16991 type 2 DM can increase OS compared with those without the use of metformin. Our results suggest that metformin might be the anti-diabetic medicine of choice in patients with pancreatic cancer and concurrent type
metformin 17290 systematic literature search to identify studies that investigated treatment of PC patients with DM with metformin . All relevant articles of English language published before August 2016 were identified from PubMed
metformin 17450 published before August 2016 were identified from PubMed and Web of Science. The search terms used were “ metformin ”, “diabetes”, “prognosis or survival or mortality” and “pancreatic cancer or neoplasm or
metformin 18742 Newcastle – Ottawa scale [[54]].Data analysesWe compared the outcomes of ratios in patients treated with metformin versus a control group (placebo or other anti-diabetics medication). For the network meta-analysis of
metformin 19078 Subgroup analyses were conducted for country location of the studies, article quality and history of metformin used in patients.We evaluated the between-study heterogeneity using a Cochran Q test, with a p-value
Select Disease Character Offset Disease Term Instance
diabetes mellitus 1163 prevention, it is not clear whether it can also affect the survival of pancreatic cancer patients with type 2 diabetes mellitus . A systematic review and meta-analysis was conducted to assess the effect of metformin on the survival
diabetes mellitus 1326 conducted to assess the effect of metformin on the survival of pancreatic cancer patients with type 2 diabetes mellitus .MethodsTwo independent authors searched PubMed and Web of science up to 08/07/2016. We assessed studies
diabetes mellitus 2335 the best anti-diabetic medicine of choice in patients with pancreatic cancer and concurrent type 2 diabetes mellitus . The perspectives of enhancing survival of pancreatic cancer patients with diabetes mellitus by the
diabetes mellitus 2428 type 2 diabetes mellitus. The perspectives of enhancing survival of pancreatic cancer patients with diabetes mellitus by the use of metformin deserve more attention in future research and clinical practice.INTRODUCTIONPancreatic
diabetes mellitus 3176 and dietary/endocrine factors [[8]]. Recently, several studies have reported that obesity and type 2 diabetes mellitus (DM) are associated with increased incidence for PC [[9], [10]].Therapies for diabetes include exogenous
hyperinsulinemia 14602 styles. In addition, Asian subjects, possibly attributable to having increased insulin resistance, hyperinsulinemia and central obesity, might benefit from several of the putative benefits of metformin therapy [[53]].
obesity 3157 chronic pancreatitis, and dietary/endocrine factors [[8]]. Recently, several studies have reported that obesity and type 2 diabetes mellitus (DM) are associated with increased incidence for PC [[9], [10]].Therapies
obesity 14631 subjects, possibly attributable to having increased insulin resistance, hyperinsulinemia and central obesity , might benefit from several of the putative benefits of metformin therapy [[53]]. Together, these factors
type 2 diabetes mellitus 1156 prevention, it is not clear whether it can also affect the survival of pancreatic cancer patients with type 2 diabetes mellitus . A systematic review and meta-analysis was conducted to assess the effect of metformin on the survival
type 2 diabetes mellitus 1319 was conducted to assess the effect of metformin on the survival of pancreatic cancer patients with type 2 diabetes mellitus .MethodsTwo independent authors searched PubMed and Web of science up to 08/07/2016. We assessed studies
type 2 diabetes mellitus 2328 metformin maybe the best anti-diabetic medicine of choice in patients with pancreatic cancer and concurrent type 2 diabetes mellitus . The perspectives of enhancing survival of pancreatic cancer patients with diabetes mellitus by the
type 2 diabetes mellitus 3169 pancreatitis, and dietary/endocrine factors [[8]]. Recently, several studies have reported that obesity and type 2 diabetes mellitus (DM) are associated with increased incidence for PC [[9], [10]].Therapies for diabetes include exogenous

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