Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients

Table 1 Patient demographics and baseline clinical characteristics n (%)

	Metformin group, n = 185	Non-metformin group, n = 228	P value
Age at diagnosis in yr, mean ± SD	63.5 ± 8.789	63.49 ± 10.218	0.991
< 50	12 (6.5)	27 (11.8)	0.064
≥ 50	173 (93.5)	201 (88.2)
Sex			0.921
Male	125 (67.6)	153 (67.1)
Female	60 (32.4)	75 (32.9)
DM duration in yr, median (range)	8 (1-120)	6 (1-40)	0.068
Family history of CRC	8 (4.3)	13 (5.7)	0.526
BMI in kg/m2, mean ± SD	23.6 ± 3.0	23.5 ± 3.0	0.596
Normal < 25	148 (80.0)	173 (76.5)	0.300
Overweight 25-30	33 (17.8)	51 (22.6)
Obese ≥ 30	4 (2.2)	2 (0.9)
Smoking			0.371
Never-smoker	89 (48.1)	123 (53.9)
Ex-smoker	42 (22.7)	40 (17.5)
Current smoker	54 (29.2)	65 (28.5)
Alcohol			0.556
None	82 (44.3)	112 (49.1)
< 1 drink/d	42 (22.7)	51 (22.4)
≥ 1 drink/d	61 (33.0)	65 (28.5)
Aspirin use	50 (27.0)	39 (17.1)	0.015
Insulin use	17 (9.2)	27 (16.2)	0.035
Sulfonylurea use	116 (62.7)	153 (67.1)	0.350
Thiazolidinedione use	18 (9.7)	12 (5.3)	0.082
CEA in ng/mL, median (range)	4.7 (0.2-9100.0)	6.4 (0.1-5946.0)	0.359
HbA1c, mean ± SD	8.7 ± 16.7	7.3 ± 1.4	0.349
Glucose in mg/dL, AC ± SD	143.8 ± 46.1	132.4 ± 41.1	0.012
Cholesterol in mg/dL, total ± SD	167.9 ± 47.8	164.6 ± 39.6	0.483
Tumor stage			0.110
III	136 (73.5)	151 (66.2)
IV	49 (26.5)	77 (33.8)
Tumor site			0.940
Colon	106 (57.9)	130 (58.3)
Rectum	77 (42.1)	93 (41.7)
Histology			0.001
Adenocarcinoma	177 (97.8)	199 (89.6)
Mucinous carcinoma	4 (2.2)	23 (10.4)
Differentiation			0.155
Well differentiated	13 (7.4)	16 (7.8)
Moderately differentiated	148 (84.6)	174 (84.5)
Poorly differentiated	14 (8.0)	12 (5.8)
Resection margin +	3 (1.7)	1 (0.6)	0.371
Lymphovascular invasion	56 (25.9)	76 (50.0)	0.031
MSI state			0.670
MSi	78 (89.7)	68 (90.7)
MSI-low	6 (6.9)	6 (8.0)
MSI-high	3 (3.4)	1 (1.3)
Treatment modality			0.160
Resection only	9 (4.9)	20 (8.8)
Resection + adjuvant chemotherapy	115 (63.2)	126 (55.3)
Resection + chemoradiotherapy	22 (12.1)	24 (10.5)
Neoadjuvant chemotherapy + resection	17 (9.3)	17 (7.5)
Chemotherapy only	17 (9.3)	35 (15.4)
Conservative care	2 (1.1)	6 (2.6)

BMI: Body mass index; CEA: Carcinoembryonic antigen; CRC: Colorectal cancer; DM: Diabetes mellitus; MSI: Microsatellite instability.

Table 2 Multivariate logistic regression analysis for colorectal cancer-specific mortality

	HR	95%CI	P value
Age at diagnosis of ≥ 50 or < 50	0.723	0.312-1.675	0.449
Sex, female or male	0.592	0.357-0.982	0.042
BMI of ≥ 25 or < 25	0.514	0.287-0.919	0.025
Smoking history as yes or no	0.681	0.359-1.291	0.239
Aspirin use as yes or no	0.802	0.455-1.415	0.446
Metformin treatment duration in mo	0.985	0.974-0.997	0.012
Sulfonylurea use as yes or no	1.300	0.798-2.120	0.292
Insulin use as yes or no	1.041	0.511-2.121	0.912
Stage IV or III	8.401	5.285-13.355	< 0.001
Site as rectum or colon	0.823	0.521-1.299	0.403
Pathology	0.801	0.238-2.701	0.721
Diabetes duration	0.968	0.935-1.001	0.059
HbA1C	1.015	1.004-1.027	0.010

BMI: Body mass index; CRC: Colorectal cancer.

Table 3 Interaction analysis of metformin and relevant factors on colorectal cancer-specific mortality

	HR	95%CI	P value
Metformin-Sex	0.369	0.155-0.881	0.025
Metformin-BMI	1.000	0.974-1.026	0.972
Metformin-Site	0.941	0.441-2.006	0.875
Metformin-HbA1c	0.999	0.926-1.078	0.979

BMI: Body mass index.