Lee et al. BMC Cancer 2011, 11:20 http://www.biomedcentral.com/1471-2407/11/20 Table 1 Characteristics of study subjects by diabetes and metformin using status Non-DM† DM without medication‡ DM without metformin§ Descriptor (n = 10491) (n = 8130) (n = 4327) DM with metformin¶ (n = 11390) Age, n (%) 20-49 yr 50-59 yr 60-69 yr ≥70 yr Female gender, n (%) Geographical area, n (%) North Central South East Off-shore Charlson comorbidity index score Mean ± SD Median ± IQR Min-Max Follow-up time (yr) Mean ± SD Median ± IQR Min-Max Withdrawal from NHI, n (%) Mean daily metformin dose, n (%) ≤500 mg 500-1000 mg ≥1000 mg Metformin use duration (day) Mean ± SD Median ± IQR Min-Max 2685 (25.6) 3483 (33.2) 2406 (22.9) 1917 (18.3) 4822 (46.0) 4938 (47.1) 2472 (23.6) 2761 (26.3) 250 (2.38) 70 (0.67) 0.25 ± 1.28 0.00 ± 0.00 0-15 3.94 ± 2.09 3.80 ± 3.49 0.50-7.99 451 (4.30) 2230 (27.4) 2202 (27.1) 1639 (20.2) 2059 (25.3) 4177 (51.4) 4145 (51.0) 1739 (21.4) 2032 (25.0) 150 (1.85) 64 (0.79) 5.29 ± 3.68 5.00 ± 6.00 0-17 3.94 ± 2.14 3.80 ± 3.65 0.50-7.99 157 (1.93) 1067 (24.7) 1156 (26.7) 940 (21.7) 1164 (26.9) 1966 (45.4) 1731 (40.0) 1052 (24.3) 1359 (31.4) 138 (3.19) 47 (1.09) 4.79 ± 3.77 4.00 ± 5.00 0-21 3.52 ± 2.10 3.28 ± 3.47 0.50-7.99 88 (2.03) 2977 (26.1) 3638 (31.9) 2530 (22.2) 2245 (19.7) 5134 (45.1) 5031 (44.2) 2638 (23.2) 3285 (28.8) 357 (3.13) 79 (0.69) 4.38 ± 3.54 4.00 ± 6.00 0-20 3.90 ± 2.08 3.76 ± 3.44 0.50-7.99 240 (2.11) 3460 (30.4) 4012 (35.2) 3918 (34.4) 931 ± 765 755 ± 1200 1-2911 Page 4 of 10 P-value <0.001 <0.001 <0.001 <0.001 † Insured who had no diabetes (DM) and had not used diabetes medication during 1996-2007. ‡ Newly diagnosed DM patients who never used any DM medication during 2000-2007. § Newly diagnosed DM patients who never used insulin or metformin during 2000-2007. ¶ Newly diagnosed metformin-treated patients who never used insulin during 2000-2007. (HRs, 0.01-0.03), whereas there is a non-significant lower risk for females (HRs, 0.28-0.44) (data not shown). Cancer risk was significantly decreased with metformin, the dose can be as little as ≤500 mg per day, which may represent a threshold effect. Discussion Among cancer free individuals, we found that total and all 5 site-specific gastroenterological cancer incidences increased with T2DM, although this was only significant for total, CRC and liver cancers. With metformin treat- ment, incident total cancer was reduced to near or below non-DM incidence. This was seen for both gen- ders and at the lowest usual dose of metformin used in clinical practice (≤500 mg/day). This is unlikely to be due only to DM severity, because the dose-response is almost a plateau with higher doses, an indication of DM severity. In the case of CRC, the metformin-treated women have less cancer risk than the non-DM popula- tion. However, the interaction between gender and CRC