Lee et al. BMC Cancer 2011, 11:20 http://www.biomedcentral.com/1471-2407/11/20 Table 3 Hazard ratios in metformin-treated type 2 diabetes for cancer incidence Cancer type cancer cases/total ID† Model 1‡ HR (95%CI) Total cancer Comparator†† Metformin users Esophagus cancer Comparator†† Metformin users Stomach cancer Comparator†† Metformin users Colorectal cancer Comparator†† Metformin users Liver cancer Comparator†† Metformin users Pancreas cancer Comparator†† Metformin users 140/4327 199/11390 6/4193 21/11212 10/4197 24/11215 26/4213 30/11221 28/4215 45/11236 7/4194 21/11212 91.7 44.8 4.03 4.78 6.71 5.46 17.4 6.83 18.7 10.2 4.70 4.78 ref. 0.47 (0.38-0.59)*** ref. 1.15 (0.46-2.84) ref. 0.78 (0.37-1.63) ref. 0.38 (0.23-0.65)*** ref. 0.53 (0.33-0.85)** ref. 0.99 (0.42-2.33) Model 2§ HR (95%CI) ref. 0.50 (0.40-0.62)*** ref. 1.27 (0.51-3.16) ref. 0.86 (0.41-1.81) ref. 0.42 (0.25-0.71)** ref. 0.54 (0.34-0.87)* ref. 1.11 (0.47-2.62) Page 6 of 10 Model 3¶ HR (95%CI) ref. 0.12 (0.08-0.19)*** ref. 0.44 (0.07-2.61) ref. 1.41 (0.42-4.73) ref. 0.36 (0.13-0.98)* ref. 0.06 (0.02-0.16)*** ref. 0.15 (0.03-0.79)* †: Incidence density per 10,000 person-years. ‡: Unadjusted hazard ratio, HR, (95% confidence interval, 95% CI), by Cox regression. §: Adjusted for age group, and gender. ¶: Adjusted for age group, gender, other oral anti-hyperglycemic medication, CCI score, and duration of metformin exposure which was treated as a time dependent variable ††: Diabetes patients who had no metformin, but might have used any other oral anti-hyperglycemic medication. *P < .05, **P < .01, ***P < .001 protection. The study of Bowker et al. raises similar con- cerns about sulfonylureas [17] which may increase the risk of cancer in DM. We, therefore, considered dose and found it unlikely that increasing severity and its correc- tion was the sole explanation for our findings. However, the finding that total and CRC CIDs may drop below that in the non-DM may still be attributed in part to the presence of unrecognized pre-DM. We also adjusted for other oral agent usage and found that this decreased the HR even further in the metformin users. Since there are possible comorbidities which may modify the relation between DM, metformin and cancer, we further adjusted for CCI score in the analyses. The results were even more convincing after these adjust- ments and suggest that the comorbidities seen with DM may themselves be important in increasing cancer risk. The most likely candidate disease mechanism, common to most comorbidities, including obesity, would be inflammation which is one of the bases for cancer [21]. The CCI adjustment would have allowed for the more complete effect of metformin to be revealed. A potential selection bias in this study comes from the prescription of metformin. On the one hand, those who were prescribed metformin might have been more likely to be obese, one of the well recognized cancer risks. So, the cancer protection effect of metformin illustrated in this study would be underestimated. On the other hand, those taking metformin might also have had their renal function better preserved (serum creatinine <1.5 mg/ dL), which would have led to an underestimation of cancer risk incurred through severe kidney disease and an overestimation of metformin effect. Other DM treat- ment than oral agents could also affect risk of cancer in DM. In our study, the CIDs for total and site-specific cancers of those with DM but without medication were similar to those with DM but without metformin. We excluded patients who ever used insulin except briefly during a hospital admission. Sulfonylureas may increase risk of cancer [17], and we controlled for any other oral anti-hyperglycemic agents ever used before diagnosis of cancer. Our findings are referable to the entire Taiwanese population and provided sufficient power to detect a metformin effect at several sites. The second Scottish study detected a favorable reduction in unadjusted CRC, breast and lung cancer incidences, and a significant adjusted CRC incidence, with metformin [15,16] in a population at high risk. Likewise, the Taiwanese popula- tion has a relatively high incidence of HCC and we report the first evidence to our knowledge that metfor- min use is linked to its reduction in the DM population. In the case of CRC, our report supports that of Libby