Lee et al. BMC Cancer 2011, 11:20 http://www.biomedcentral.com/1471-2407/11/20 et al for metformin in its prevention in Taiwanese women. Taiwan is experiencing increasing incidences of breast cancer and CRC [27] towards rates seen in Eur- opean populations which may extend its relevance beyond Orientals. We found a significant lower relative risk for pancrea- tic cancer in metformin users as have previous observa- tions [6,7]. However, the CID in diabetes was not significantly different to that of non-DM. Li’s study [7] which demonstrated potential pancreatic cancer protec- tion by metformin, was hospital-based and case-control in the US. Ours was a representative population-base cohort of DM-cancer-free subjects at baseline. Our study resolves some of the outstanding issues in the US study in regard to generalizability and the possible con- founding effects of other DM pharmacotherapy, other diseases and their treatment. However, ours is princi- pally an oriental and Li’s a mainly white population so that cross-ethnic robustness remains to be elucidated. Metformin might operate to prevent or check tumori- genesis through a basic underlying mechanism and dis- order, with generalizability. It may help sort out the pathogenetic, preventive and management differences for site-specific cancers. With incidence, the endpoint of our study, when a subject develops a cancer, this can be considered in relation to the oral anti-hyperglycemic agent used to that point and need not be confused by changes in medication subsequent to the diagnosis. There are gender differences in the development of body fat distribution with relatively earlier and greater abdominal fatness (and fatty liver) in men [28] and in the protective role of estrogen against insulin resistance [29-33]. We found gender differences in the effect of metformin against CRC and HCC. While the prevalence of HCC and CRC is greater in men, women lose some protection against CRC after the menopause [34,35]. Where there has been a decline in CRC incidence in Canada, it has been mainly in women [36]. In Taiwan, hepatitis B and C with aflatoxin exposure is a more likely cause of cirrhosis and HCC than alcohol excess, although alcohol may be a contributor to the gender dif- ference [27] and abdominal obesity through non-alco- holic steatohepatitis with cirrhosis may play a role. Gender disparity in HCC may be due to differences in MyD88-dependent IL-6 production [37]. Hepatic estro- gen receptor status may also affect the progression of HCC [38]. In our study for CRC, metformin users were older than the others (data not shown), a somewhat elderly estrogen-deficient group. Nevertheless, insulin resistance is related to estrogen deficiency and/or andro- gen excess as evidenced in the polycystic ovarian syn- drome and this is responsive to metformin [39,40]. Therefore, metformin might act differentially and Page 8 of 10 favorably on estrogen-deficient women. The opposite may be the case in men where there is a gender differ- ence in susceptibility to HCC along with altered estro- gen metabolism and insulin resistance in cirrhosis [41]. The present study has several limitations. Firstly, we have required that for an eligible event to be counted it had to be diagnosed one year after metformin com- menced. Consequently, for DM subjects and their non- exposure counterparts in the last year (2007), there would have been no chance to count their cancer out- come. Secondly, obesity is a risk factor for DM and can- cer and should be considered as a confounder. However, this administrative dataset does not have systematic clin- ical measurements available for BMI or obesity. Body weight could differ in patients treated with different anti-DM drugs. This could lead to an underestimation of the true effect of metformin (the use of sulphonylour- eas and gliazones is associated with weight gain and metformin with weight loss). While BMI data are not available, we can presume that the adverse outcomes of BMI outside acceptable limits will be manifest to some extent, in comorbidities. These we have taken into account in the CCI adjustment. Thirdly, for some can- cers studied, the events were few and did not allow us to judge whether metformin is protective or not. Fourthly, we do not have direct linkage of the NHI data- base to death certificates. If a subject leaves the cohort, that death or migration is the likely reason. There were no differences in the disappearance rates among the three DM groups which might have led to erroneous interpretations of our data. In addition, there are caveats about populations to which extrapolations from our findings may be made. The population studied is domi- nantly Orientals. The problem of DM and its sequelae is nevertheless similar to that in Europeans [15-18]. At least for North East Asia, where living and eating pat- terns are similar, our large population findings should be relevant. Metformin may reduce cancer risk and randomized- trials should be conducted. Our study provides evidence to encourage evaluation of the risk of cancer in DM patients. This is because the cohort evidence of DM antedating major cancers like those of breast and CRC, along with experimental, points to cause and effect. Moreover, our study shows that low dose metformin can prevent certain common cancers (CRC and HCC) and probably certain less common cancers (pancreas) for Taiwanese. Metformin has few adverse side effects; including that of lactic acidosis [42]. The gastrointestinal side effects are manageable if starting dose is low. Cau- tion is required about effects on vitamin B-12 and homocysteine status and more work is required in large population studies to evaluate this [43].