Table 3

HR of cancer, cancer mortality, and all-cause mortality

Event	TZD (vs DPP4i)			Insulin (vs TZD)			Insulin (vs DPP4i)
Event	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Cancer	1.43	(1.25 to 1.63)	<0.001*	0.81	(0.72 to 0.91)	<0.001*	1.15	(1.02 to 1.30)	0.024*
Lip, oral cavity, and pharynx	1.66	(0.81 to 3.40)	0.165	0.56	(0.30 to 1.08)	0.083	0.94	(0.46 to 1.91)	0.870
Digestive organs	1.47	(1.19 to 1.81)	<0.001*	0.94	(0.78 to 1.13)	0.528	1.38	(1.14 to 1.68)	<0.001*
Esophagus, stomach, and small intestine	NA†			NA†			1.27	(0.66 to 2.44)	0.479
Colorectum	2.06	(1.55 to 2.74)	<0.001*	0.53	(0.41 to 0.69)	<0.001*	1.10	(0.82 to 1.47)	0.526
Colon	2.26	(1.64 to 3.12)	<0.001*	0.45	(0.33 to 0.61)	<0.001*	1.02	(0.72 to 1.43)	0.928
Rectum/anus	3.01	(1.94 to 4.65)	<0.001*	0.34	(0.23 to 0.51)	<0.001*	1.03	(0.64 to 1.67)	0.907
Liver	0.78	(0.47 to 1.28)	0.322	1.61	(1.02 to 2.53)	0.041*	1.25	(0.83 to 1.86)	0.287
Gallbladder and extrahepatic bile duct	8.14	(3.36 to 19.69)	<0.001*	0.74	(0.46 to 1.17)	0.194	5.98	(2.48 to 14.42)	<0.001*
Pancreas	0.43	(0.20 to 0.89)	0.022*	3.97	(2.00 to 7.88)	<0.001*	1.69	(1.08 to 2.64)	0.021*
Respiratory system	3.60	(2.52 to 5.16)	<0.001*	0.40	(0.30 to 0.54)	<0.001*	1.45	(1.00 to 2.11)	0.050*
Bone, skin, and soft tissue	0.79	(0.41 to 1.51)	0.478	1.18	(0.63 to 2.22)	0.621	0.93	(0.53 to 1.63)	0.803
Breast and genital organs (for females only)	0.65	(0.43 to 0.97)	0.034*	1.54	(1.04 to 2.29)	0.031*	0.99	(0.73 to 1.36)	0.975
Urinary organs	2.30	(1.46 to 3.62)	<0.001*	0.25	(0.16 to 0.39)	<0.001*	0.58	(0.34 to 0.99)	0.045*
Eye, brain, and central nervous system, endocrine glands	2.63	(1.18 to 5.88)	0.018*	0.58	(0.29 to 1.16)	0.123	1.51	(0.65 to 3.52)	0.340
Lymphatic and hematopoietic tissue	0.18	(0.07 to 0.48)	<0.001*	6.72	(2.64 to 17.12)	<0.001*	1.24	(0.79 to 1.95)	0.352
Cancer mortality	1.21	(0.92 to 1.58)	0.172	1.36	(1.09 to 1.71)	0.007*	1.65	(1.31 to 2.07)	<0.001*
All-cause mortality	0.99	(0.88 to 1.11)	0.873	2.46	(2.25 to 2.70)	<0.001*	2.44	(2.23 to 2.67)	<0.001*
Sensitivity analysis - Pioglitazone only in TZD drug class
Cancer	1.31	(1.13 to 1.50)	<0.001*	0.88	(0.77 to 1.00)	0.050	1.15	(1.01 to 1.30)	0.030*
Lip, oral cavity and pharynx	2.87	(1.44 to 5.69)	0.003*	0.30	(0.16 to 0.55)	<0.001*	0.85	(0.42 to 1.75)	0.674
Digestive organs	1.83	(1.49 to 2.25)	<0.001*	0.74	(0.62 to 0.89)	0.002*	1.36	(1.12 to 1.65)	0.002*
Esophagus, Stomach, and small intestine	NA†			NA†			1.27	(0.66 to 2.44)	0.481
Colorectum	2.45	(1.84 to 3.27)	<0.001*	0.45	(0.34 to 0.58)	<0.001*	1.09	(0.82 to 1.46)	0.564
Colon	2.65	(1.91 to 3.67)	<0.001*	0.38	(0.28 to 0.52)	<0.001*	1.01	(0.72 to 1.42)	0.965
Rectum / Anus	4.42	(2.87 to 6.82)	<0.001*	0.22	(0.15 to 0.33)	<0.001*	0.99	(0.61 to 1.60)	0.974
Liver	1.12	(0.69 to 1.80)	0.660	1.08	(0.70 to 1.68)	0.736	1.21	(0.81 to 1.81)	0.361
Gallbladder and extrahepatic bile duct	9.99	(4.14 to 24.07)	<0.001*	0.59	(0.37 to 0.93)	0.022*	5.87	(2.43 to 14.17)	<0.001*
Pancreas	0.55	(0.27 to 1.13)	0.105	3.02	(1.55 to 5.89)	0.001*	1.67	(1.07 to 2.62)	0.024*
Respiratory system	1.49	(0.98 to 2.26)	0.061	0.80	(0.56 to 1.15)	0.238	1.20	(0.82 to 1.75)	0.362
Bone, skin and soft tissue	0.97	(0.51 to 1.85)	0.931	0.99	(0.53 to 1.84)	0.966	0.95	(0.54 to 1.68)	0.881
Breast and genital organs (for female only)	0.36	(0.21 to 0.62)	<0.001*	2.88	(1.67 to 4.97)	<0.001*	1.04	(0.76 to 1.42)	0.823
Urinary organs	2.31	(1.40 to 3.80)	0.001*	0.32	(0.19 to 0.53)	<0.001*	0.73	(0.43 to 1.25)	0.259
Eye, brain and central nervous system, endocrine glands	3.36	(1.53 to 7.41)	0.003*	0.45	(0.23 to 0.89)	0.022*	1.51	(0.65 to 3.52)	0.346
Lymphatic and haematopoietic tissue	0.26	(0.10 to 0.67)	0.005*	4.66	(1.88 to 11.55)	<0.001*	1.23	(0.78 to 1.94)	0.378
Cancer mortality	1.51	(1.15 to 1.98)	0.003*	1.00	(0.80 to 1.26)	0.991	1.51	(1.20 to 1.91)	<0.001*
All-cause mortality	1.13	(1.00 to 1.27)	0.044*	2.18	(1.97 to 2.41)	<0.001*	2.46	(2.25 to 2.69)	<0.001*
Sensitivity analysis—basal insulin only in insulin class
Cancer	1.38	(1.21 to 1.57)	<0.001*	0.85	(0.75 to 0.95)	0.006*	1.17	(1.03 to 1.32)	0.015*
Lip, oral cavity, and pharynx	1.54	(0.70 to 3.42)	0.288	0.86	(0.45 to 1.65)	0.660	1.33	(0.64 to 2.77)	0.462
Digestive organs	1.25	(1.01 to 1.54)	0.038*	0.95	(0.78 to 1.15)	0.601	1.18	(0.98 to 1.43)	0.080
Esophagus, stomach, and small intestine	NA†			NA†			0.69	(0.38 to 1.27)	0.236
Colorectum	2.09	(1.56 to 2.80)	<0.001*	0.61	(0.47 to 0.79)	<0.001*	1.27	(0.95 to 1.70)	0.108
Colon	1.98	(1.41 to 2.79)	<0.001*	0.61	(0.45 to 0.82)	0.001*	1.21	(0.86 to 1.69)	0.283
Rectum/anus	3.14	(2.02 to 4.90)	<0.001*	0.39	(0.26 to 0.56)	<0.001*	1.21	(0.76 to 1.95)	0.433
Liver	0.47	(0.28 to 0.80)	0.005*	1.86	(1.12 to 3.06)	0.015*	0.88	(0.59 to 1.29)	0.517
Gallbladder and extrahepatic bile duct	3.98	(1.97 to 8.01)	<0.001*	0.55	(0.33 to 0.93)	0.026*	2.20	(1.08 to 4.46)	0.029*
Pancreas	0.39	(0.17 to 0.88)	0.023*	4.11	(1.90 to 8.89)	<0.001*	1.61	(1.00 to 2.59)	0.051
Respiratory system	4.47	(3.12 to 6.40)	<0.001*	0.37	(0.28 to 0.48)	<0.001*	1.63	(1.12 to 2.38)	0.010*
Bone, skin, and soft tissue	0.88	(0.44 to 1.75)	0.721	1.22	(0.64 to 2.34)	0.555	1.07	(0.59 to 1.95)	0.835
Breast and genital organs (for females only)	0.47	(0.30 to 0.73)	<0.001*	2.41	(1.58 to 3.67)	<0.001*	1.14	(0.84 to 1.54)	0.424
Urinary organs	1.82	(1.12 to 2.95)	0.015*	0.46	(0.30 to 0.70)	<0.001*	0.84	(0.51 to 1.38)	0.497
Eye, brain, and central nervous system, endocrine glands	2.20	(0.88 to 5.51)	0.092	0.79	(0.36 to 1.71)	0.562	1.74	(0.70 to 4.29)	0.234
Lymphatic and hematopoietic tissue	0.43	(0.20 to 0.90)	0.025*	3.42	(1.72 to 6.80)	<0.001*	1.47	(0.92 to 2.34)	0.106
Cancer mortality	0.91	(0.69 to 1.20)	0.507	1.44	(1.12 to 1.84)	0.004*	1.30	(1.04 to 1.63)	0.022*
All-cause mortality	0.89	(0.80 to 0.99)	0.027*	1.78	(1.63 to 1.95)	<0.001*	1.58	(1.45 to 1.72)	<0.001*
Sensitivity analysis—accounting for competing risk of death
Cancer	1.46	(1.28 to 1.65)	<0.001*	0.77	(0.68 to 0.86)	<0.001*	1.12	(0.99 to 1.26)	0.083
Lip, oral cavity, and pharynx	1.74	(0.85 to 3.57)	0.131	0.52	(0.27 to 1.02)	0.058	0.91	(0.45 to 1.81)	0.794
Digestive organs	1.49	(1.22 to 1.83)	<0.001*	0.90	(0.75 to 1.08)	0.261	1.34	(1.11 to 1.62)	0.003*
Esophagus, stomach, and small intestine	NA†			NA†			1.26	(0.64 to 2.47)	0.508
Colorectum	2.09	(1.59 to 2.74)	<0.001*	0.51	(0.39 to 0.66)	<0.001*	1.06	(0.80 to 1.42)	0.687
Colon	2.29	(1.69 to 3.11)	<0.001*	0.43	(0.32 to 0.58)	<0.001*	0.98	(0.70 to 1.37)	0.919
Rectum/anus	3.05	(2.01 to 4.63)	<0.001*	0.33	(0.22 to 0.49)	<0.001*	1.00	(0.62 to 1.61)	0.990
Liver	0.80	(0.51 to 1.25)	0.333	1.51	(0.98 to 2.34)	0.060	1.21	(0.81 to 1.81)	0.361
Gallbladder and extrahepatic bile duct	8.19	(3.42 to 19.60)	<0.001*	0.71	(0.44 to 1.14)	0.151	5.78	(2.40 to 13.91)	<0.001*
Pancreas	0.43	(0.20 to 0.93)	0.031*	3.80	(1.82 to 7.91)	<0.001*	1.64	(1.05 to 2.54)	0.028*
Respiratory system	3.66	(2.54 to 5.29)	<0.001*	0.38	(0.28 to 0.52)	<0.001*	1.40	(0.96 to 2.03)	0.080
Bone, skin, and soft tissue	0.80	(0.42 to 1.52)	0.508	1.12	(0.60 to 2.10)	0.737	0.90	(0.52 to 1.56)	0.716
Breast and genital organs (for females only)	0.65	(0.44 to 0.96)	0.030*	1.49	(1.01 to 2.21)	0.046*	0.96	(0.70 to 1.32)	0.829
Urinary organs	2.46	(1.63 to 3.72)	<0.001*	0.23	(0.15 to 0.35)	<0.001*	0.57	(0.33 to 0.96)	0.035*
Eye, brain, and central nervous system, endocrine glands	2.63	(1.25 to 5.51)	0.011*	0.56	(0.28 to 1.11)	0.099	1.47	(0.63 to 3.46)	0.381
Lymphatic and hematopoietic tissue	0.19	(0.08 to 0.46)	<0.001*	6.36	(2.58 to 15.64)	<0.001*	1.21	(0.75 to 1.93)	0.445

*Significantly different.
†Not available since no case for esophagus, stomach, and small intestine cancer with TZD as third-line medication.
DPP4i, dipeptidyl peptidase 4 inhibitor; TZD, thiazolidinediones.