Total cancer Male Female Esophagus Male Female Stomach Male female Colorectal Male female Liver Male Female Pancreas Male female 49.9 59.3 41.2 1.14 2.09 0.20 2.64 3.49 1.86 7.31 8.63 6.06 6.55 9.25 3.90 0.99 1.17 0.81 Non DM (n = 10491) 46.0 (39.5-52.6)ab 50.3 (41.0-59.6)ab 41.0 (31.9-50.1)ab 2.94 (1.28-4.60) 3.63 (1.11-6.15) 2.13 (0.04-4.21) 3.91 (1.99-5.83) 3.63 (1.12-6.15) 4.23 (1.30-7.17) 7.07 (4.50-9.64)ab 6.78 (3.35-10.2)a 7.40 (3.53-11.3)a 5.88 (3.53-8.23)ab 8.64 (4.76-12.5)ab 2.65 (0.33-4.98)a 2.45 (0.93-3.96) 2.72 (0.54-4.90) 2.13 (0.04-4.21) 97.6 (86.9-108)ac 122 (104-139)ac 75.7 (62.6-88.8)ac 5.14 (2.62-7.66) 7.45 (3.05-11.9) 3.05 (0.38-5.73) 5.14 (2.62-7.66) 6.78 (2.58-11.0) 3.67 (0.73-6.60) 19.8 (14.9-24.8)ac 23.6 (15.8-31.4)ab 16.4 (10.2-22.6)b 24.3 (18.8-29.7)ac 32.3 (23.2-41.4)ac 17.0 (10.7-23.3)a 5.14 (2.62-7.66) 5.42 (1.67-9.18) 4.88 (1.50-8.27) 91.7 (76.6-107)bd 107 (84.9-130)bd 74.0 (54.1-93.8)bd 4.03 (0.81-7.26) 5.09 (0.10-10.1) 2.84 (-1.10-6.78) 6.71 (2.55-10.9) 8.90 (2.31-15.5) 4.26 (-0.56-9.09) 17.4 (10.7-24.1)bd 12.7 (4.83-20.6) 22.6 (11.6-33.7)ac 18.7 (11.8-25.7)b 29.1 (17.2-41.0)bd 7.10 (0.88-13.3) 4.70 (1.22-8.18) 5.09 (0.10-10.1) 4.26 (-0.56-9.09) Lee et al. BMC Cancer 2011, 11:20 http://www.biomedcentral.com/1471-2407/11/20 Table 2 Cancer incidence density by diabetes and metformin using status Cancer type† Taiwanese population Incidence‡ Incidence density (95%CI) of study cohort (per 10,000 person-years) DM without medication DM without metformin DM with metformin (n = 8130) (n = 4327) (n = 11390) † ICD-9-CM also incorporates the A-code for cancer which was used in Taiwan in ambulatory care settings before the year 2000. Total cancer (140-208/A08-A14), esophagus cancer (150/A090), stomach cancer (151/A091), colorectal cancer (153-154/A093-A094), liver cancer (155/A095), pancreas cancer (157/A096). ‡ Age-gender-standardized cancer incidence per 10,000 persons (95% confidence intervals) in the Taiwanese Cancer Registry Annual Report for 2007. a, b, c, d: Statistical significance was estimated by using the overlap rule for 95% CIs. Where there is the same superscript it means that there is significant difference between the two groups. suggests that some caution is required in the extrapola- tion of the findings for women to men. The same is not the case for gender and hepatocellular cancer (HCC), where, if women experience the higher incidence seen in men, they may benefit from metformin protection. A shared pathogenesis for DM and certain cancers is possible, e.g., in beta oxidation of fatty acids or mito- chondrial function. The prevention or management of the one might lead to corresponding outcomes for the other, as seems to be the case for metformin [8,12]. Metformin might protect against tumorigenesis through several mechanisms [8,10,11]. Metformin stimulates per- ipheral AMP-activated protein kinase (AMPK) with reduced hepatic gluconeogenesis, increased hepatic fatty acid oxidation and insulin sensitivity in muscle. In phy- siological circumstances, AMPK acts as an intracellular fuel sensor and is activated when the cellular AMP/ATP ratio increases. It is of interest to those cancers for which energy imbalance is a risk factor [22]. Dependent on cellular p53 and cyclin status, tumor cell cycle and growth is impaired by metformin. Metformin may counter age-related metabolic phenomena, such as sar- copenia, increased body fat and osteopenia, insulin sen- sitivity and adipokines. In our study, we have considered the role of age to any effect of metformin on the DM- cancer nexus; adjustment for age makes no discernable difference to the findings. Since the mechanism is likely to be through regulation of cellular energy metabolism, this has implications for measures designed to enhance energy expenditure by physical activity and avoid excess energy intake as well. Severity and duration of DM is likely to be important for the effectiveness of metformin. In this administrative cohort, we do not have a direct measure of DM severity like glycated hemoglobin or of BMI. In Taiwan, the usual first line oral anti-hyperglycemic therapeutic agents for T2DM are sulfonylureas and biguanides (metformin). It can be inferred that, where DM is more difficult to con- trol, the dose of one or both of these classes of oral anti- hyperglycemic agents will be increased. On the other hand, other anti-hyperglycemic agents may mask or miti- gate against some of this metformin-dependent cancer Page 5 of 10 44.8 (38.6-51.0)cd 47.7 (39.0-56.4)cd 41.2 (32.4-50.1)cd 4.78 (2.74-6.83) 5.83 (2.78-8.89) 3.52 (0.91-6.13) 5.46 (3.28-7.65) 4.58 (1.88-7.29) 6.53 (2.98-10.1) 6.83 (4.39-9.27)cd 9.57 (5.66-13.5)b 3.52 (0.91-6.12)bc 10.2 (7.24-13.2)c 12.5 (8.01-16.9)cd 7.54 (3.72-11.3) 4.78 (2.74-6.83) 5.41 (2.47-8.36) 4.02 (1.24-6.81)