only 10%20% of patients with pancreatic cancer qualify for surgery and the prognosis of this disease is poor ; median survival for patients undergoing surgery ranges from 20 to 23 months . for patients receiving solely chemotherapy , survival approximately ranges from 3 to 11 months . with this limited prognosis , there is a high and urgent need for new therapies to improve outcome .
smoking , obesity , and type 2 diabetes are considered to be important risk factors for the development of pancreatic cancer .
metformin is the first - line treatment for patients with type 2 diabetes and is therefore the most prescribed oral glucose - lowering drug ( ogld ) .
the decision to prescribe metformin depends on patient characteristics ; metformin use is contraindicated in patients with renal failure , cardiac dysfunction , and hepatic insufficiency .
metformin is a biguanide antihyperglycemic agent and has 3 working mechanisms : it decreases the hepatic glucose production by inhibition of gluconeogenesis and glycogenolysis in muscles , it subsequently improves peripheral insulin sensitivity , and reduces glucose absorption .
mouse models suggest that metformin could inhibit the proliferation of xenografted human pancreatic cancer cells within 30 days , but other studies point toward a systemic effect of metformin on cancer by improving the metabolic profile of patients , rather than a direct effect on tumor cells .
recent epidemiologic cohort studies in patients with type 2 diabetes have suggested that patients using metformin have a decreased risk of developing cancer and , possibly , a reduced cancer mortality .
several meta - analysis pointed out that the reduced cancer incidence was not present in all types of cancer ; use of metformin seems to be associated with a reduced risk of developing cancer in patients with pancreatic , colorectal , and hepatocellular cancer , with conflicting results for breast cancer , and no association is seen in patients with lung and prostate cancers .
preceding epidemiologic studies assessing the effect of metformin on the risk of cancer and survival may have been subject to several time - related biases , for example , misclassifying exposure to metformin , which could have inflated the estimates .
what additionally complicates observational studies on this subject , is that patients using metformin often have other comorbidities supplementary to type 2 diabetes , compared with nonusers .
alternative treatment for type 2 diabetes are sulfonylurea derivatives ( sd ) which have been used previously as a comparator group in addition to nonusers .
the aim of this study was to assess the association between the use of metformin and overall survival in patients with pancreatic cancer with the use of appropriate methodology , a pitfall of the previous studies .
data from the eindhoven cancer registry ( ecr ) were linked on patient level to the pharmo database network covering a demographic region in the south - eastern part of the netherlands of 1.5 million inhabitants .
the ecr is maintained by the netherlands comprehensive cancer organisation and registers newly diagnosed cancer patients from 10 different hospitals located in this region .
patients are informed about this registration and are registered except patients who objected to be registered .
the netherlands cancer registry is obliged to work according to the law about protection of privacy data and all procedures to privacy of doctors and patients is fixed in regulations .
an independent committee of privacy reassures that the netherlands cancer registry is compliant to these regulations .
the pharmo database network is a population - based network of healthcare databases and combines data from different healthcare settings in the netherlands . for this study
, the outpatient pharmacy database is used containing drug - dispensing records from community pharmacies .
all dispensed drugs are coded according to the anatomical therapeutic chemical ( atc ) classification ( www.whocc.no/atc_ddd_index ) , and the records include information on type of product , date , dosage , and quantity .
all patients diagnosed with a malignancy of the pancreas ( classified according to the international statistical classification of diseases and related health problems  10th revision code c-25 ) between 1998 and 2011 were selected from the ecr - pharmo cohort . to reduce confounding by indication , metformin users were , in addition to nonusers , compared with sd users .
excluded were malignancies with the following morphology : squamous cell carcinoma , epithelial carcinoma , cystic / mucinous / serous carcinoma , or gastrointestinal stromal tumor because of the differences in disease course .
patients using metformin ( atc - code : a10ba02 ) or sd ( atc - code : a10bb ) for at least 30 days were defined as users .
users were defined as patients using metformin before and after diagnosis , or only after diagnosis , and not using contemporary sd users .
the period of metformin or sd use was defined from the first dispensing of metformin or sd to the end of the follow - up period .
follow - up time was determined from date of diagnosis ( t0 ) until death or end of the study period at 31 december 2012 .
cancer registry data were linked to municipal population registries to obtain vital status . to determine time - dependent exposure ,
patients were defined as nonusers from t0 to the date of first metformin or sd use .
differences in patient characteristics between metformin users and nonusers and between metformin users and sd users were analyzed using the independent samples t - test and the chi square test .
a kaplan  meier survival curve was constructed to compare overall survival between patients using metformin , sd , and nonusers .
a parametric survival model with exponential ( poisson ) distribution was used to model the effect of metformin use on overall survival , where death of any cause was coded as event .
metformin use and sd use were included as time - varying covariates in the model .
adjustments were made for age , number of comorbidities ( 0 , 1 , or 2 , excluding diabetes mellitus ) , tumor - node - metastasis ( tnm ) stage ( categorical ) , year of diagnosis ( 19982003 , 20042007 , and 20082011 ) , surgery ( yes / no ) , chemotherapy ( yes / no ) , and radiotherapy ( yes / no ) .
information about comorbidities was available for lung disease , cardiovascular disease , diabetes , disorders of the gastrointestinal tract , urinary tract , nervous system , musculoskeletal system , and a group of other comorbidities .
the difference between overall survival in metformin users and sd users was analyzed with the same model that was used for the analysis of metformin versus nonusers .
the results of the model should be interpreted as a favorable association with survival when the result shows a rate ratio < 1 in relation to the comparison group .
statistical tests were 2-sided and considered significant at the p  <  0.05 level .
data from the eindhoven cancer registry ( ecr ) were linked on patient level to the pharmo database network covering a demographic region in the south - eastern part of the netherlands of 1.5 million inhabitants .
the ecr is maintained by the netherlands comprehensive cancer organisation and registers newly diagnosed cancer patients from 10 different hospitals located in this region .
patients are informed about this registration and are registered except patients who objected to be registered .
the netherlands cancer registry is obliged to work according to the law about protection of privacy data and all procedures to privacy of doctors and patients is fixed in regulations .
an independent committee of privacy reassures that the netherlands cancer registry is compliant to these regulations .
the pharmo database network is a population - based network of healthcare databases and combines data from different healthcare settings in the netherlands . for this study
, the outpatient pharmacy database is used containing drug - dispensing records from community pharmacies .
all dispensed drugs are coded according to the anatomical therapeutic chemical ( atc ) classification ( www.whocc.no/atc_ddd_index ) , and the records include information on type of product , date , dosage , and quantity .
all patients diagnosed with a malignancy of the pancreas ( classified according to the international statistical classification of diseases and related health problems  10th revision code c-25 ) between 1998 and 2011 were selected from the ecr - pharmo cohort . to reduce confounding by indication , metformin users were , in addition to nonusers , compared with sd users .
excluded were malignancies with the following morphology : squamous cell carcinoma , epithelial carcinoma , cystic / mucinous / serous carcinoma , or gastrointestinal stromal tumor because of the differences in disease course .
patients using metformin ( atc - code : a10ba02 ) or sd ( atc - code : a10bb ) for at least 30 days were defined as users .
users were defined as patients using metformin before and after diagnosis , or only after diagnosis , and not using contemporary sd users .
the period of metformin or sd use was defined from the first dispensing of metformin or sd to the end of the follow - up period .
follow - up time was determined from date of diagnosis ( t0 ) until death or end of the study period at 31 december 2012 .
cancer registry data were linked to municipal population registries to obtain vital status . to determine time - dependent exposure ,
patients were defined as nonusers from t0 to the date of first metformin or sd use .
differences in patient characteristics between metformin users and nonusers and between metformin users and sd users were analyzed using the independent samples t - test and the chi square test .
a kaplan  meier survival curve was constructed to compare overall survival between patients using metformin , sd , and nonusers .
a parametric survival model with exponential ( poisson ) distribution was used to model the effect of metformin use on overall survival , where death of any cause was coded as event .
metformin use and sd use were included as time - varying covariates in the model .
adjustments were made for age , number of comorbidities ( 0 , 1 , or 2 , excluding diabetes mellitus ) , tumor - node - metastasis ( tnm ) stage ( categorical ) , year of diagnosis ( 19982003 , 20042007 , and 20082011 ) , surgery ( yes / no ) , chemotherapy ( yes / no ) , and radiotherapy ( yes / no ) .
information about comorbidities was available for lung disease , cardiovascular disease , diabetes , disorders of the gastrointestinal tract , urinary tract , nervous system , musculoskeletal system , and a group of other comorbidities .
the difference between overall survival in metformin users and sd users was analyzed with the same model that was used for the analysis of metformin versus nonusers .
the results of the model should be interpreted as a favorable association with survival when the result shows a rate ratio < 1 in relation to the comparison group .
statistical tests were 2-sided and considered significant at the p  <  0.05 level .
in total , 1111 patients with pancreatic cancer were diagnosed in the period 19982011 ; 91 patients were excluded because of morphology ( as described above ) and 48 patients were excluded because of using merely metformin before diagnosis ( fig . 1 , flow chart of the study population ) .
this resulted in a study population of 907 patients , of which 77 patients used metformin and 43 used sd as drug for diabetes type 2 .
863 events were reported . in the metformin group , 64 patients deceased during study period , and in the sd group 41 patients deceased .
there were no significant differences between the groups concerning tnm stage and treatment ( chemotherapy , radiotherapy , and surgery ) .
metformin users had more additional comorbidities ( p  <  0.001 ) compared with both nonusers and sd users .
incidence of diabetes did not differ between the group of metformin users and sd users .
contemporary insulin use was 36% for metformin users versus 33% among patients using sd ( p  =  0.70 ) .
patients who used metformin were diagnosed in more recent years than sd users or nonusers ( p  <  0.001 ) .
finally , median survival of metformin users was 5.7 months ( interquartile range [ iqr ] : 2.214.7 ) , sd users had a median survival of 6.0 ( iqr : 1.621.2 ) months , whereas nonusers had a median survival of 4.0 months ( iqr : 1.59.2 ) . characteristics of the cohort .
for all patients with pancreatic cancer , metformin use was associated with an improved overall survival compared with patients not using metformin , rate ratio ( rr ) 0.76 ( 95% ci : 0.590.98 ; p  =  0.04 ; table 2 ) .
this association was no longer significant after adjusting for age , number of comorbidities , stage , year of diagnosis , surgery , chemotherapy , and radiotherapy .
multivariable rr for metformin users compared with nonusers was 0.86 ( 95% ci : 0.661.12 ; p  =  0.26 ) .
overall survival was additionally assessed between the following 3 groups : patients not using ogld , metformin users , and sd users ( fig .
2 , table 2 ) . overall survival for metformin users versus nonusers was rr 0.74 ( 95% ci : 0.570.95
the rr for overall survival of metformin users versus nonusers was 0.85 ( 95% ci : 0.651.11 ; p  =  0.23 ) .
overall survival for sd users compared with nonusers was rr = 0.60 ( 95% ci : 0.440.82 ; p  =  0.001 ) , and multivariable analysis showed an rr = 0.82 ( 95% ci : 0.591.13 ; p  =  0.23 ) .
meier estimation of survival curves in patients with pancreatic cancer grouped according to medication use .
rr was 0.78 ( 95% ci : 0.531.15 ; p  =  0.21 ) and adjusted rr was 0.86 ( 95% ci : 0.501.46 ; p  =  0.57 ) .
this retrospective , observational cohort study showed no association between the use of metformin and overall survival in patients with pancreatic cancer .
these studies found no association between the use of metformin and survival in patients with ( advanced ) pancreatic cancer ; however , these studies were only done in respectively 44 and 516 patients with type 2 diabetes mellitus .
similarly , 2 recently published randomized controlled trials  carried out in 121 patients in the netherlands and 60 patients in italy  also showed no effect of metformin on survival . despite differences in design , such as cancer stage , chemotherapy regime , blinding , and use of placebo ,
both trials show a consistent no effect of metformin on survival in patients with advanced pancreatic cancer .
the results of the randomized controlled trials and our study are in conflict with numerous other observational studies describing a beneficial effect of metformin , not only in pancreatic cancer .
mortality decrease for patients with pancreatic cancer using metformin was consistently 27%40% in previous studies ; however , these cohorts were smaller than the cohort that was analyzed in this study , with respectively 302 , 764 , and 349 patients who were analyzed . this discrepancy could be partly explained by the difference in methodology .
suissa and azoulay studied the effect of time - related biases in observational drug studies of metformin on cancer .
these studies could not demonstrate any association between metformin and cancer incidence or the observed incidence reduction was considerably smaller than previous results .
another explanation could be the high number of patients with irresectable pancreatic cancer ( 89% ) in our study , whereas other studies found a survival benefit in patients with resectable pancreatic cancer .
in addition , differences in patient characteristics could partly explain the results of our study .
patients using sd had less comorbidities than metformin users . before 2006 , the guidelines recommended prescription of metformin for patients with a body mass index ( bmi ) > 27 .
it could therefore be possible that a majority of the patients who were prescribed metformin ( 35% ) before 2006 were overweight .
obese patients have a worse prognosis and overall survival , partly because of a higher risk surgical risk .
this observation could also partly explain the observed trend toward a better survival for patients using sd , however no information on bmi was available in the present dataset .
for the direct action of metformin on cancer cells , the effective drug concentrations achieved in neoplastic tissue are crucial .
it is possible that the required concentration in the target tissue is not attained with the present dose of metformin . because of the retrospective nature of this study , no information is available about sufficient concentrations of the effect on tumor cells .
the dutch randomized controlled trial has also addressed this aspect , where an effect on survival was found in a subset of patients reaching adequate insulin level decrease .
first , this is one of the largest cohorts so far to analyze the association between the use of metformin and survival in patients with pancreatic cancer .
second , our data are linked through 2 validated databases  ecr and pharmo  preventing both recall and information bias .
third , this is the first observational study adressing the association between the use of metformin and overall survival in patients with pancreatic cancer , taking into account the time between the beginning of the follow up and the first drug prescription , which prevents time - related biases .
not including the time - varying covariate in our model also revealed a highly significant survival benefit for metformin users .
additionally , metformin users were compared with sd users , a group of patients with a more similar baseline prognosis .
lastly , previous articles focused on the effect of metformin on overall survival limited to patients with pancreatic cancer and type 2 diabetes , whereas this study included all patients with pancreatic cancer . a limitation to this observational study
could be the small number of patients who received ogld in a large cohort , which also complicated a subgroup analysis , for example , in patients who underwent a resection .
only 43 patients were solely using sd , and because of this small number of users , no robust statements can be made .
however , because of the wide interest in a growing field , this remains a relevant study , complementing the existing evidence .
moreover , because of the retrospective nature of the study , the amount of information available is limited .
there is no detailed information about the population such as smoking , bmi , glycemic control , or cause of death
. it could hypothetically be possible that the nonsignificant relative risk reduction of 15% found in the adjusted analysis was not significant due to a lack of power .
however , in the randomized controlled trials recently published , no effect of metformin on survival of patients with pancreatic cancer could be proven , and these trials were of course designed with a power calculation .
this observational study contributes to the mounting evidence against an association between improved survival in patients with pancreatic cancer using metformin .
these findings could discourage new trials to be designed for metformin as adjuvant therapy in pancreatic cancer , as this disease is generally discovered in an advanced stage were the anti - tumor effect of metformin will not be able to sufficiently inhibit tumor growth .
however , this study does not exclude the opportunity that metformin could be a valuable adjuvant therapy in other cancer types or only in patients with resectable , early stage pancreatic cancer .
nowadays , new oncology drugs are very expensive and drug repurposing is an attractive strategy to offer more effective options for patients with cancer .
 abstractseveral studies have suggested an association between use of metformin and an increased overall survival in patients diagnosed with pancreatic cancer , however with several important methodological limitations . 
 the aim of the study was to assess the association between overall survival , pancreatic cancer , and metformin use.a retrospective cohort study of 1111 patients with pancreatic cancer was conducted using data from the netherlands comprehensive cancer organization ( 19982011 ) . 
 data were linked to the pharmo database network containing drug - dispensing records from community pharmacies . 
 patients were classified as metformin user or sulfonylurea derivatives user from the moment of first dispensing until the end of follow up . 
 the difference in overall survival between metformin users and nonusers was assessed , and additionally between metformin users and sulfonylurea derivatives users . 
 univariable and multivariable parametric survival models were used and use of metformin and sulfonylurea derivatives was included as time - varying covariates.of the 1111 patients , 91 patients were excluded because of differences in morphology , 48 patients because of using merely metformin before diagnosis , and 57 metformin - users ever used contemporary sulfonylurea derivatives and were therefore excluded . 
 lastly , 8 patients with a survival of zero months were excluded . 
 this resulted in 907 patients for the analysis . 
 overall , 77 users of metformin , 43 users of sulfonylurea derivatives , and 787 nonusers were identified . the adjusted rate ratio for overall survival for metformin users versus nonusers was 0.86 ( 95% ci : 0.661.11 ; p  =  0.25 ) . 
 the difference in overall survival between metformin users and sulfonylurea derivatives users showed an adjusted rate ratio of 0.90 ( 95% ci : 0.591.40 ; p  =  0.67).no association was found between overall survival , pancreatic cancer , and metformin use . 
 this was in concordance with 2 recently published randomized controlled trials . 
 future research should focus on the use of adjuvant metformin in other cancer types and the development or repurposing of other drugs for pancreatic cancer . 