Event | TZD (vs DPP4i) | Insulin (vs TZD) | Insulin (vs DPP4i) | ||||||
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.