DIAB-6045; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Review
Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis Zheng Wang a,c,1, Song-tao Lai a,c,1, Li Xie b,c, Jian-dong Zhao a,c, Ning-yi Ma a,c, Ji Zhu a,b,c, Zhi-gang Ren a,c,*, Guo-liang Jiang a,c a
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Department of Statistics, Fudan University Shanghai Cancer Center, Shanghai, China c Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China b
article info
abstract
Article history:
Aims: Recent epidemiological studies indicated that use of metformin might decrease the
Received 7 November 2013
risk of various cancers among patients with type 2 diabetes mellitus (T2DM). However, its
Accepted 9 April 2014
influence on pancreatic cancer was controversial. Therefore, we did a meta-analysis of
Available online xxx
currently available observational studies on the issue. Methods: We did a PubMed and ISI Web of Science search for observational articles. The
Keywords:
pooled relative risk (RR) was estimated using a random-effect model. Heterogeneity was
Metformin
evaluated using I2 statistic. Subgroup analysis was performed to explore the source of
Diabetes mellitus
heterogeneity and confirm the overall estimates. Publication bias was also examined.
Pancreatic cancer
Results: The analysis included 11 articles (13 studies) comprising 10 cohort studies and 3
Meta-analysis
case–control studies. Use of metformin was associated with a significant lower risk of pancreatic cancer [RR 0.63, 95% confidence internal (CI) 0.46–0.86, p = 0.003]. In a total 11 subgroup analyses, 5 provided the consistent result with pooled effect estimates of overall analysis. No publication bias was detected by Begg’s (Z = (t =
0.79, p = 0.428) and Egger’s test
0.92, p = 0.378).
Conclusions: From present observational studies, use of metformin appears to be associated with a reduced risk of pancreatic cancer in patients with T2DM. Further investigation is needed. # 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
000 000 000
* Corresponding author at: Department of Radiation Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, China. Tel.: +86 21 64175590; fax: +86 21 64439052. E-mail address: [email protected] (Z.-g. Ren). 1
These authors contributed equally to this work. http://dx.doi.org/10.1016/j.diabres.2014.04.007 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Wang Z, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.04.007
DIAB-6045; No. of Pages 8
2
diabetes research and clinical practice xxx (2014) xxx–xxx
3. 4. 5.
1.
Data extraction and statistical analyses . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction
Pancreatic cancer is the fourth cause of cancer-related deaths in Western countries. In the United States, 43,920 patients are newly diagnosed with this malignancy per annum [1]. Due to its highly aggressive and treatment-resistant properties, the overall 5 year survival rate has not exceeded 5% and the median survival period remains less than 6 months in spite of progressive optimization of the combined treatments [2–4]. Metabolic disorders, type 2 diabetes mellitus (T2DM) and obesity, have been widely considered as risk factors for pancreatic cancer [5]. Nearly 80% pancreatic cancer patients appear with either new-onset T2DM or impaired glucose tolerance when initially diagnosed [6,7]. Metformin is a widely prescribed oral antihyperglycemic drug for the treatment of T2DM [8]. Increasing attention has been focused on its potential antitumorigenic effects that are deemed to be independent of its hypoglycemic activities. The major mechanisms of metformin against cancer have been attributed to its ability to activate the LKB1/AMPK/mTOR signaling pathway, as well as to block the insulin-induced tumor growth by decreasing its circulating levels [9,10]. A number of in vitro studies have revealed that metformin probably inhibits cancer cell proliferation, migration, invasion, and preferentially kills cancer stem cells [11–13]. These intriguing results have also been confirmed in in vivo studies [14]. Considering all the findings above, it is natural to regard metformin as a novel, promising and well-tolerated agent for prevention and treatment of various cancers. In addition to those preclinical studies, several clinical trials (NCT01167738, NCT01210911) that are designed to examine the efficacy of metformin in combination with chemotherapy in pancreatic cancer are under way. In addition, metformin has also been associated with cancer risk reduction in patients with T2DM in recent epidemiologic studies [15,16]. However, data on its influence on pancreatic cancer are still limited and controversial. In this study, we did a systematic literature review and a meta-analysis of currently available observational studies to better define and quantitatively assess the effect of metformin on the risk of pancreatic cancer in patients with T2DM.
2.
Materials and methods
2.1.
Search strategy and selection criteria
We performed a comprehensive literature search for all potentially relevant articles using the PubMed and ISI Web of Science databases in July 2013. The MeSH terms and keywords for searching included metformin, biguanides, cancer, neoplasms, pancreatic cancer, pancreatic neoplasms, pancreatic adenocarcinoma. The search was limited to observational studies consisting of case–control studies and cohort studies in humans. Our goal was to pick out the studies
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that examined the influence of metformin on incidence of pancreatic cancer in patients with T2DM. In addition, a manual retrieve was also done of references from recently published review articles to identify other possible eligible articles that were not found in our primary search. Those studies, in which detailed information on sample size, risk estimate including odds ratio, relative risk or hazard ratio, and their corresponding 95% CIs was provided or could be calculated based on the existing data, were ultimately included in our statistical analysis. If there were multiple papers coming from the same study, only the most intact and more recent publications were given precedence. Furthermore, if two independent comparison groups were arranged in one study, we regarded these studies as two standalone studies in view of the relatively limited number of potential eligible articles according to our initiatory search. Abstract and full text of each possibly eligible article, as well as the decision for inclusion or exclusion was critically assessed by two of the authors independently. Any discrepancies between the two authors were resolved by a re-evaluation of the original article.
3.
Data extraction and statistical analyses
For each included study, we collected detailed information on the first author, publication year, country or area, study design, total participants, origin of control group, reference group, study period or follow-up time and confounding adjustment. The fully adjusted odds ratio, relative risk or hazard ratio with their 95% CIs were extracted as the common measure of association across studies. The GRADE system was used to evaluate the quality of included studies [17]. In this system, observational studies can be categorized as either low quality (GRADE 2) or very low quality (GRADE 1). The bias risk, consistency, accuracy, effect size, adjustment of confounder, publication bias were the factors that together determined the ultimate grade. We finally used the pooled RR and its 95% CI to estimate the risk of pancreatic cancer in T2DM patients with metformin treatment in the present study. The value was calculated selecting the random effects model (DerSimonian and Laird method) with inverse variance weighting [18]. To evaluate the total variation among studies which was due to heterogeneity rather than chance, we computed the I2 statistic, whose value of more than 50% was regarded as significant heterogeneity [19]. In order to investigate the possible source of statistical heterogeneity among studies and to further define the stability and reliability of the overall estimates we performed sensitivity analysis on predesigned subgroups based on the region, study design, control selection, reference therapy and study quality. Furthermore, in the presence of a significant summary RR, we conducted an influence analysis by including one study
Please cite this article in press as: Wang Z, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.04.007
DIAB-6045; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
at a time to determine the impact degree of a certain study on the merged results. Finally, the publication bias for included studies, which could derive from unpublished small studies with negative outcomes, was assessed by visually examining the Begg’s funnel plot and performing Egger’s regression asymmetry test [20]. For all hypothesis tests, a two tailed p value of
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Review
Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis Zheng Wang a,c,1, Song-tao Lai a,c,1, Li Xie b,c, Jian-dong Zhao a,c, Ning-yi Ma a,c, Ji Zhu a,b,c, Zhi-gang Ren a,c,*, Guo-liang Jiang a,c a
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Department of Statistics, Fudan University Shanghai Cancer Center, Shanghai, China c Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China b
article info
abstract
Article history:
Aims: Recent epidemiological studies indicated that use of metformin might decrease the
Received 7 November 2013
risk of various cancers among patients with type 2 diabetes mellitus (T2DM). However, its
Accepted 9 April 2014
influence on pancreatic cancer was controversial. Therefore, we did a meta-analysis of
Available online xxx
currently available observational studies on the issue. Methods: We did a PubMed and ISI Web of Science search for observational articles. The
Keywords:
pooled relative risk (RR) was estimated using a random-effect model. Heterogeneity was
Metformin
evaluated using I2 statistic. Subgroup analysis was performed to explore the source of
Diabetes mellitus
heterogeneity and confirm the overall estimates. Publication bias was also examined.
Pancreatic cancer
Results: The analysis included 11 articles (13 studies) comprising 10 cohort studies and 3
Meta-analysis
case–control studies. Use of metformin was associated with a significant lower risk of pancreatic cancer [RR 0.63, 95% confidence internal (CI) 0.46–0.86, p = 0.003]. In a total 11 subgroup analyses, 5 provided the consistent result with pooled effect estimates of overall analysis. No publication bias was detected by Begg’s (Z = (t =
0.79, p = 0.428) and Egger’s test
0.92, p = 0.378).
Conclusions: From present observational studies, use of metformin appears to be associated with a reduced risk of pancreatic cancer in patients with T2DM. Further investigation is needed. # 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
000 000 000
* Corresponding author at: Department of Radiation Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, China. Tel.: +86 21 64175590; fax: +86 21 64439052. E-mail address: [email protected] (Z.-g. Ren). 1
These authors contributed equally to this work. http://dx.doi.org/10.1016/j.diabres.2014.04.007 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Wang Z, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.04.007
DIAB-6045; No. of Pages 8
2
diabetes research and clinical practice xxx (2014) xxx–xxx
3. 4. 5.
1.
Data extraction and statistical analyses . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
Introduction
Pancreatic cancer is the fourth cause of cancer-related deaths in Western countries. In the United States, 43,920 patients are newly diagnosed with this malignancy per annum [1]. Due to its highly aggressive and treatment-resistant properties, the overall 5 year survival rate has not exceeded 5% and the median survival period remains less than 6 months in spite of progressive optimization of the combined treatments [2–4]. Metabolic disorders, type 2 diabetes mellitus (T2DM) and obesity, have been widely considered as risk factors for pancreatic cancer [5]. Nearly 80% pancreatic cancer patients appear with either new-onset T2DM or impaired glucose tolerance when initially diagnosed [6,7]. Metformin is a widely prescribed oral antihyperglycemic drug for the treatment of T2DM [8]. Increasing attention has been focused on its potential antitumorigenic effects that are deemed to be independent of its hypoglycemic activities. The major mechanisms of metformin against cancer have been attributed to its ability to activate the LKB1/AMPK/mTOR signaling pathway, as well as to block the insulin-induced tumor growth by decreasing its circulating levels [9,10]. A number of in vitro studies have revealed that metformin probably inhibits cancer cell proliferation, migration, invasion, and preferentially kills cancer stem cells [11–13]. These intriguing results have also been confirmed in in vivo studies [14]. Considering all the findings above, it is natural to regard metformin as a novel, promising and well-tolerated agent for prevention and treatment of various cancers. In addition to those preclinical studies, several clinical trials (NCT01167738, NCT01210911) that are designed to examine the efficacy of metformin in combination with chemotherapy in pancreatic cancer are under way. In addition, metformin has also been associated with cancer risk reduction in patients with T2DM in recent epidemiologic studies [15,16]. However, data on its influence on pancreatic cancer are still limited and controversial. In this study, we did a systematic literature review and a meta-analysis of currently available observational studies to better define and quantitatively assess the effect of metformin on the risk of pancreatic cancer in patients with T2DM.
2.
Materials and methods
2.1.
Search strategy and selection criteria
We performed a comprehensive literature search for all potentially relevant articles using the PubMed and ISI Web of Science databases in July 2013. The MeSH terms and keywords for searching included metformin, biguanides, cancer, neoplasms, pancreatic cancer, pancreatic neoplasms, pancreatic adenocarcinoma. The search was limited to observational studies consisting of case–control studies and cohort studies in humans. Our goal was to pick out the studies
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000 000 000 000
that examined the influence of metformin on incidence of pancreatic cancer in patients with T2DM. In addition, a manual retrieve was also done of references from recently published review articles to identify other possible eligible articles that were not found in our primary search. Those studies, in which detailed information on sample size, risk estimate including odds ratio, relative risk or hazard ratio, and their corresponding 95% CIs was provided or could be calculated based on the existing data, were ultimately included in our statistical analysis. If there were multiple papers coming from the same study, only the most intact and more recent publications were given precedence. Furthermore, if two independent comparison groups were arranged in one study, we regarded these studies as two standalone studies in view of the relatively limited number of potential eligible articles according to our initiatory search. Abstract and full text of each possibly eligible article, as well as the decision for inclusion or exclusion was critically assessed by two of the authors independently. Any discrepancies between the two authors were resolved by a re-evaluation of the original article.
3.
Data extraction and statistical analyses
For each included study, we collected detailed information on the first author, publication year, country or area, study design, total participants, origin of control group, reference group, study period or follow-up time and confounding adjustment. The fully adjusted odds ratio, relative risk or hazard ratio with their 95% CIs were extracted as the common measure of association across studies. The GRADE system was used to evaluate the quality of included studies [17]. In this system, observational studies can be categorized as either low quality (GRADE 2) or very low quality (GRADE 1). The bias risk, consistency, accuracy, effect size, adjustment of confounder, publication bias were the factors that together determined the ultimate grade. We finally used the pooled RR and its 95% CI to estimate the risk of pancreatic cancer in T2DM patients with metformin treatment in the present study. The value was calculated selecting the random effects model (DerSimonian and Laird method) with inverse variance weighting [18]. To evaluate the total variation among studies which was due to heterogeneity rather than chance, we computed the I2 statistic, whose value of more than 50% was regarded as significant heterogeneity [19]. In order to investigate the possible source of statistical heterogeneity among studies and to further define the stability and reliability of the overall estimates we performed sensitivity analysis on predesigned subgroups based on the region, study design, control selection, reference therapy and study quality. Furthermore, in the presence of a significant summary RR, we conducted an influence analysis by including one study
Please cite this article in press as: Wang Z, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.04.007
DIAB-6045; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
at a time to determine the impact degree of a certain study on the merged results. Finally, the publication bias for included studies, which could derive from unpublished small studies with negative outcomes, was assessed by visually examining the Begg’s funnel plot and performing Egger’s regression asymmetry test [20]. For all hypothesis tests, a two tailed p value of
