the present study is part of the zwolle outpatient diabetes project integrating available care ( zodiac ) study ( 18 ) , which started in 1998 and is part of a diabetes shared care project . in this project , general practitioners are assisted in their care of type 2 diabetic patients by hospital - based diabetes specialist nurses . at baseline , patients with a very short life expectancy ( including patients with active cancer ) or insufficient cognitive abilities were excluded from this study . therefore , general practitioners excluded 5% of patients treated in primary care from participating in the study . nearly 90% ( n = 1,357 ) of the remaining patients agreed to participate , but 4 patients were also excluded because of insufficient baseline data . the zodiac study was approved by the medical ethics committee of the isala clinics in zwolle , the netherlands . baseline data were collected in 1998 and 1999 and consisted of a medical history , including macrovascular complications , diabetes duration , medication use , and tobacco consumption . laboratory and physical assessment data were collected annually and included the following variables : a1c , nonfasting lipid profile , serum creatinine , urinary albumin - to - creatinine ratio , blood pressure , weight , and height . at the beginning of 2009 , life status and cause of death were retrieved from records maintained by the hospital and general practitioners . thirteen baseline variables were selected for their possible confounding effects in the relationship between metformin use and cancer mortality : smoking ( yes or no ) , age , sex , diabetes duration , a1c , serum creatinine , bmi , blood pressure , total cholesterol  to  hdl ratio , albuminuria , insulin use , sulfonylurea use , and macrovascular complications ( yes or no ) . to study the incidence of cancer mortality , standardized mortality ratios ( smrs ) were calculated for total mortality and cardiovascular and cancer mortality using general mortality reference rates from the netherlands ( http://statline.cbs.nl/statweb/ ) . we used a cox proportional hazards model to investigate the association between metformin use and cancer mortality with and without adjustment of the selected confounders . model 2 included factors directly related to cancer mortality : age , sex , bmi , insulin use , and sulfonylurea use . to evaluate the relationship with dose of metformin , we repeated the analyses and included the dose of metformin per day as a continuous variable . we also investigated which variable was an actual confounder in the relation between metformin and cancer mortality . confounding was defined as a 10% change in the  coefficient of the hazard ratio ( hr ) . all tests were two - sided , and analyses were performed with spss ( version 15.0.1 ; spss , chicago , il ) . baseline data were collected in 1998 and 1999 and consisted of a medical history , including macrovascular complications , diabetes duration , medication use , and tobacco consumption . laboratory and physical assessment data were collected annually and included the following variables : a1c , nonfasting lipid profile , serum creatinine , urinary albumin - to - creatinine ratio , blood pressure , weight , and height . at the beginning of 2009 , life status and cause of death were retrieved from records maintained by the hospital and general practitioners . thirteen baseline variables were selected for their possible confounding effects in the relationship between metformin use and cancer mortality : smoking ( yes or no ) , age , sex , diabetes duration , a1c , serum creatinine , bmi , blood pressure , total cholesterol  to  hdl ratio , albuminuria , insulin use , sulfonylurea use , and macrovascular complications ( yes or no ) . to study the incidence of cancer mortality , standardized mortality ratios ( smrs ) were calculated for total mortality and cardiovascular and cancer mortality using general mortality reference rates from the netherlands ( http://statline.cbs.nl/statweb/ ) . we used a cox proportional hazards model to investigate the association between metformin use and cancer mortality with and without adjustment of the selected confounders . model 2 included factors directly related to cancer mortality : age , sex , bmi , insulin use , and sulfonylurea use . to evaluate the relationship with dose of metformin , we repeated the analyses and included the dose of metformin per day as a continuous variable . we also investigated which variable was an actual confounder in the relation between metformin and cancer mortality . confounding was defined as a 10% change in the  coefficient of the hazard ratio ( hr ) . all tests were two - sided , and analyses were performed with spss ( version 15.0.1 ; spss , chicago , il ) . after a median follow - up time of 9.6 years , a total of 570 ( 42% ) patients had died . there were 122 ( 21% ) cancer deaths , of which 26 ( 21% ) related to lung cancer and 21 ( 17% ) to abdominal cancer . baseline characteristics data are means  sd , median ( interquartile range ) for nonnormally distributed data , or % . p < 0.001 , two - sided parametric test ( student t ) and nonparametric test ( mann - whitney u ) as appropriate . the smr for total mortality was 2.22 ( 95% ci 2.032.42 ) , for cardiovascular mortality was 2.45 ( 2.152.79 ) , and for cancer mortality was 1.47 ( 1.221.76 ) . the unadjusted hr of metformin use for cancer mortality was 0.54 ( 95% ci 0.320.91 ) . for model 1 , taking all 13 possible variables into account , the adjusted hr of metformin use for cancer mortality was 0.43 ( 0.230.80 ) ( fig . furthermore , only sulfonylurea use and macrovascular complications were confounders in the relationship between metformin use and cancer mortality . furthermore , after exclusion of mortality in the first 3 years after baseline , the results remained similar ( hr 0.38 [ 95% ci 0.180.81 ] ) . sulfonylurea use was not significantly associated with cancer mortality ( 0.69 [ 0.361.34 ] ) nor was insulin use ( 0.70 [ 0.361.34 ] ) . the hr of metformin as a continuous variable for cancer mortality was 0.58 ( 95% ci 0.360.93 ) . the hazard for cancer mortality decreased by 42% for every 1-g increase in the metformin dose . after adjustment for all covariates , the hrs for total and cardiovascular mortality among metformin users were 0.94 ( 95% ci 0.731.22 ) and 2.27 ( 1.363.78 ) , respectively ( figs . 2 and 3 ) . the hr for all other causes of death was 0.97 ( 0.721.30 ) ( fig . a significant interaction between metformin and sulfonylurea use was observed in the cardiovascular mortality analysis and an interaction term was added to the model . the proportional hazard assumptions were met for all analyses . cumulative survival curve for total mortality . cumulative survival for non - cancer and non - cardiovascular ( cv ) ( all other causes ) mortality . the smr for total mortality was 2.22 ( 95% ci 2.032.42 ) , for cardiovascular mortality was 2.45 ( 2.152.79 ) , and for cancer mortality was 1.47 ( 1.221.76 ) . the unadjusted hr of metformin use for cancer mortality was 0.54 ( 95% ci 0.320.91 ) . for model 1 , taking all 13 possible variables into account , the adjusted hr of metformin use for cancer mortality was 0.43 ( 0.230.80 ) ( fig . furthermore , only sulfonylurea use and macrovascular complications were confounders in the relationship between metformin use and cancer mortality . with adjustment only for macrovascular complications and sulfonylurea , the outcome did not change . furthermore , after exclusion of mortality in the first 3 years after baseline , the results remained similar ( hr 0.38 [ 95% ci 0.180.81 ] ) . sulfonylurea use was not significantly associated with cancer mortality ( 0.69 [ 0.361.34 ] ) nor was insulin use ( 0.70 [ 0.361.34 ] ) . the hr of metformin as a continuous variable for cancer mortality was 0.58 ( 95% ci 0.360.93 ) . the hazard for cancer mortality decreased by 42% for every 1-g increase in the metformin dose . after adjustment for all covariates , the hrs for total and cardiovascular mortality among metformin users were 0.94 ( 95% ci 0.731.22 ) and 2.27 ( 1.363.78 ) , respectively ( figs . 2 and 3 ) . the hr for all other causes of death was 0.97 ( 0.721.30 ) ( fig . 4 ) . a significant interaction between metformin and sulfonylurea use was observed in the cardiovascular mortality analysis and an interaction term was added to the model . the proportional hazard assumptions were met for all analyses . cumulative survival curve for total mortality . cumulative survival for cardiovascular mortality . cumulative survival for non - cancer and non - cardiovascular ( cv ) ( all other causes ) mortality . for the first time in a prospective study , we found ( after a median follow - up time of 9.6 years ) that metformin use at baseline was associated with less cancer - related mortality and that this association appeared to be dose - dependent . patients with type 2 diabetes who were not taking metformin showed an increased cancer mortality ratio compared with that for the general population . ( 2 ) suggested an increased cancer risk for patients taking insulin and with metformin a decrease in this risk to a level as observed in the general population . another study , in which population - based sampling was used , showed a reduced cancer risk for patients taking metformin compared with patients taking a sulfonylurea drug ( 12 ) . the researchers suggested a dose - response relation : the greater the metformin exposure , the stronger the risk reduction . it is not clear whether the researchers excluded or adjusted for the use of insulin in this study . a third study , a large administrative database study , showed that patients exposed to a sulfonylurea drug and insulin were more likely to have a cancer - related death than patients using metformin ( 17 ) . the researchers of this retrospective study had no data about cardiovascular mortality and did not adjust for some essential confounders such as bmi and smoking . first , our study is the first observational study with a prospective design investigating the relation between metformin and cancer ( mortality ) . second , we adjusted for more potential confounders than the researchers in the previous study ( 17 ) . third , we were able to present data on non  cancer - related mortality and compared our results with those for the general population in the netherlands . fourth , the number of deaths in the 10-year follow - up period was sufficient to make reliable estimates regarding associations with mortality . if there is an association between cancer mortality and metformin use , a long - term follow - up is needed , because cancer takes a long time to develop , and it takes time before patients die of cancer . cancer mortality depends on the type and aggressiveness of the cancer and the effectiveness of the cancer treatment . diabetes or diabetes treatment may have an effect on the intensity of the cancer treatment or on the choice of a specific cancer treatment regimen . furthermore , no adjustment could be made for a history of cancer in our analyses because these data were imprecise . however , after excluding the first 3 years of follow - up from the analysis , the relationship remained highly significant . excluding the first 3 years of follow - up could correct for undiagnosed cancer at the start of the study , which could influence outcome . furthermore , we were not able to perform analyses for site - specific cancers , because our analyses were based on only 122 cancer deaths . finally , the study started in 1998 . at that time , metformin was not a first - choice treatment , a fact that is also confirmed by the relatively small group of patients using metformin at baseline . patients who were taking metformin at the beginning of this study ( in 1998 ) might also be different from patients taking metformin at this time . our study confirms that the cancer mortality risk for metformin users is lower compared with that of nonusers . in our opinion , this finding further strengthens the position of metformin as the treatment of first choice in patients with type 2 diabetes . further research is needed to establish whether metformin is a definite beneficial causal factor in lowering the risk of cancer mortality .
objectiveseveral studies have suggested an association between specific diabetes treatment and cancer mortality . 
 we studied the association between metformin use and cancer mortality in a prospectively followed cohort.research design and methodsin 1998 and 1999 , 1,353 patients with type 2 diabetes were enrolled in the zwolle outpatient diabetes project integrating available care ( zodiac ) study in the netherlands . 
 vital status was assessed in january 2009 . 
 cancer mortality rate was evaluated using standardized mortality ratios ( smrs ) , and the association between metformin use and cancer mortality was evaluated with a cox proportional hazards model , taking possible confounders into account.resultsmedian follow - up time was 9.6 years , average age at baseline was 68 years , and average a1c was 7.5% . 
 of the patients , 570 died , of which 122 died of malignancies . 
 the smr for cancer mortality was 1.47 ( 95% ci 1.221.76 ) . in patients taking metformin compared with patients not taking metformin at baseline , the adjusted hazard ratio ( hr ) for cancer mortality was 0.43 ( 95% ci 0.230.80 ) , and the hr with every increase of 1 g of metformin was 0.58 ( 95% ci 0.360.93).conclusionsin general , patients with type 2 diabetes are at increased risk for cancer mortality . in our group , metformin use was associated with lower cancer mortality compared with nonuse of metformin . although the design can not provide a conclusion about causality , our results suggest a protective effect of metformin on cancer mortality .