Table 3.
Exclusion of Patients without History of Metformin: Bladder Cancer Incidence among Initiators of Pioglitazone, Dipeptidyl-peptidase-4, and Sulfonylureas
| Comparison | Drug | Follow-Up (Years), Median (IQR)* | N† | Events | Person-Time (Years) | Rate‡ | Unadjusted HR (95% CI)§ | Fully Adjusted HR (95% CI) || |
|---|---|---|---|---|---|---|---|---|
| As-Treated Analyses | ||||||||
| Overall | ||||||||
| PIO vs. DPP | PIO | 1.17(0.67–2.21) | 14,476 | 75 | 23,713 | 316.3 | 1.75(1.29–2.38) | 1.82(1.28–2.59) |
| DPP | 1.14(0.60–2.17) | 32,088 | 91 | 50,400 | 180.6 | 1 (reference) | 1 (reference) | |
| PIO vs. SU | PIO | 1.17(0.67–2.17) | 6,819 | 27 | 11,059 | 244.1 | 1.18(0.78–1.77) | 1.21(0.79–1.85) |
| SU | 1.31(0.65–2.58) | 43,281 | 161 | 77,736 | 207.1 | 1 (reference) | 1 (reference) | |
| Duration of Treatment Restricted To 2 Years | ||||||||
| PIO vs. DPP | PIO | 1.17(0.67–1.97) | 14,476 | 53 | 17,768 | 298.3 | 1.69(1.18–2.43) | 1.80(1.17–2.76) |
| DPP | 1.14(0.60–1.97) | 32,088 | 67 | 38,016 | 176.2 | 1 (reference) | 1 (reference) | |
| PIO vs. SU | PIO | 1.17(0.67–1.97) | 6,819 | 18 | 8,315 | 216.5 | 1.02(0.62–1.68) | 1.03(0.62–1.73) |
| SU | 1.31(0.65–1.97) | 43,281 | 115 | 54,678 | 210.3 | 1 (reference) | 1 (reference) | |
| Duration of Treatment after 2 Years | ||||||||
| PIO vs. DPP | PIO | 1.13(0.47–2.09) | 4,214 | 22 | 5,945 | 370.0 | 1.91(1.07–3.41) | 1.86(1.02–3.41) |
| DPP | 1.03(0.43–2.00) | 9,129 | 24 | 12,384 | 193.8 | 1 (reference) | 1 (reference) | |
| PIO vs. SU | PIO | 1.13(0.47–2.12) | 1,942 | <11 | NR | 328.0 | 1.65(0.81–3.38) | 1.65(0.81–3.37) |
| SU | 1.24(0.51–2.31) | 15,159 | 46 | 23,058 | 199.5 | 1 (reference) | 1 (reference) | |
| Initial-treatment Analyses | ||||||||
| Overall | ||||||||
| PIO vs. DPP | PIO | 3.41(1.57–4.86) | 17,081 | 133 | 56,079 | 237.2 | 1.40(1.10–1.79) | 1.31(1.00–1.72) |
| DPP | 1.90(0.84–3.31) | 36,450 | 140 | 81,932 | 170.9 | 1 (reference) | 1 (reference) | |
| PIO vs. SU | PIO | 3.32(1.46–4.80) | 8,022 | 51 | 25,684 | 198.6 | 1.07(0.79–1.45) | 1.11(0.81–1.52) |
| SU | 2.12(0.91–3.81) | 47,590 | 219 | 117,202 | 186.9 | 1 (reference) | 1 (reference) | |
| Time Since Treatment Initiation Restricted To 2 Years | ||||||||
| PIO vs. DPP | PIO | 1.97(1.57–1.97) | 17,081 | 71 | 28,215 | 251.6 | 1.43(1.05–1.96) | 1.38(0.96–1.99) |
| DPP | 1.90(0.84–1.97) | 36,450 | 91 | 51,710 | 176.0 | 1 (reference) | 1 (reference) | |
| PIO vs. SU | PIO | 1.97(1.46–1.97) | 8,022 | 23 | 13,063 | 176.1 | 0.87(0.56–1.36) | 0.88(0.56–1.38) |
| SU | 1.97(0.91–1.97) | 47,590 | 141 | 69,406 | 203.2 | 1 (reference) | 1 (reference) | |
| Time Since Treatment Initiation after 2 Years | ||||||||
| PIO vs. DPP | PIO | 2.27(1.29–3.32) | 11,993 | 62 | 27,865 | 222.5 | 1.37(0.93–2.00) | 1.24(0.84–1.84) |
| DPP | 1.39(0.62–2.65) | 17,644 | 49 | 30,222 | 162.1 | 1 (reference) | 1 (reference) | |
| PIO vs. SU | PIO | 2.21(1.27–3.29) | 5,506 | 28 | 12,621 | 221.9 | 1.34(0.87–2.06) | 1.43(0.92–2.23) |
| SU | 1.71(0.77–2.93) | 25,124 | 78 | 47,796 | 163.2 | 1 (reference) | 1 (reference) | |
CI, Confidence Interval; DPP, dipeptidyl-peptidase-4; HR, Hazard Ratio; IQR, interquartile range; NR, Not Reportable given number of events <11; PIO, pioglitazone; SU, sulfonylureas
Follow-up started on the cohort entry date (second dispensing) and was censored at first occurrence of outcome, death, end of study (December 2014), or end of enrollment. As-treated analyses additionally censored at treatment discontinuation (no subsequent fill of initiated drug class within days-supply plus a 90-day grace period). A 180-day induction period was imposed excluding time from the beginning of follow-up. The as-treated analyses additionally added a 180-day latency period to the end of follow-up when possible prior to death or end of patient data.
Number contributing with at least 180 days of follow-up. The number initiating PIO differs for each comparison due to exclusions of prior use of drugs included in comparison only.
Incidence Rate reported per 100 000 Person-Years
Cox proportional hazards models
Cox proportional hazards models adjusted for all variables in Table 1, except for metformin and those excluded within each comparison by incident user design, using propensity-score weighting (standardized to PIO population)