Bladder Cancer, Diabetes
Conditions
Keywords
Drug therapy
Brief summary
To assess the potential association between pioglitazone and bladder cancer compared with non-pioglitazone users among patients with type 2 diabetes mellitus.
Detailed description
Following guidance from the United States Food and Drug Administration (FDA) and European Medicines Agency, the University of Pennsylvania and Kaiser Permanente Northern California (KPNC) designed and conducted this study using the KPNC database to assess the potential association between pioglitazone and bladder cancer among patients with type 2 diabetes mellitus. The study was conducted over the course of 10 years, with a series of interim analyses undertaken during this period and provided to the sponsor (Takeda) and the appropriate regulatory agencies. In 2011, the planned 5-year interim analysis of this study was published in Diabetes Care. That report included data from 1 January 1997 to 30 April 2008. Following reporting of these data, there was a request from the FDA for an additional fourth interim analysis at 8 years including data from 1 January 1997 to 31 December 2010. In August 2011 the FDA requested inclusion of a sensitivity analysis to assess change of cohort entry criteria to minimize left censoring of exposure. Included in the FDA request was a duration analysis for other antidiabetic medications. In August 2014, the final 10-year analyses were completed and submitted to the sponsor and regulatory agencies. Interim results previously posted on clinicaltrials.gov are available in the public archive
Interventions
DRUGPioglitazone
Pioglitazone tablets.
Sponsors
Kaiser Permanente
Department of Epidemiology at University of Pennsylvania
Takeda
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The study cohort included both patients with an established diagnosis of diabetes mellitus prior to January 1, 1997 and those who were newly diagnosed prior to December 31, 2002. Patients were eligible for the study cohort if they met any of the following criteria: 1. As of January 1, 1997 they had been diagnosed with diabetes mellitus, were age 40 or older and were members of KPNC, 2. They had been diagnosed with diabetes mellitus, reached age 40 between January 1, 1997 and December 31, 2002 and were KPNC members on their 40th birthday, or 3. Had diabetes mellitus and were age 40 or older when they joined KPNC between January 1, 1997 and December 31, 2002.
Exclusion criteria
* Diagnosis of bladder cancer recorded in the KPNC cancer registry prior to entry to the cohort or within 6 months of entry into KPNC.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incident Diagnosis of Bladder Cancer (10-year Analysis) | January 1, 1997 to December 31, 2012 | Incident bladder cancers were identified from January 1, 1997 to December 31, 2012. |
Secondary
| Measure | Time frame |
|---|---|
| Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | January 1, 1997 to December 31, 2012 |
| Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | January 1, 1997 to December 31, 2012 |
| Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | January 1, 1997 to December 31, 2012 |
| Stage of Bladder Cancer (10 Year Analysis) | January 1, 1997 to December 31, 2012 |
Participant flow
Recruitment details
Not applicable (database study)
Pre-assignment details
Not applicable (database study)
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Exposed Group Patients ever exposed to pioglitazone. | 34,181 |
| Pioglitazone Unexposed Group Patients never exposed to pioglitazone. | 158,918 |
| Total | 193,099 |
Baseline characteristics
| Characteristic | Pioglitazone Exposed Group | Pioglitazone Unexposed Group | Total |
|---|---|---|---|
| Age, Customized 40-49 years | 29.2 percentage of participants | 22.1 percentage of participants | 51.3 percentage of participants |
| Age, Customized 50-59 years | 33.0 percentage of participants | 25.6 percentage of participants | 58.6 percentage of participants |
| Age, Customized 60-69 years | 25.7 percentage of participants | 26.2 percentage of participants | 51.9 percentage of participants |
| Age, Customized 70 years and older | 12.0 percentage of participants | 26.1 percentage of participants | 38.1 percentage of participants |
| Baseline Glycosylated Hemoglobin (HbA1c) ≥10% | 23.9 percentage of participants | 17.1 percentage of participants | 41 percentage of participants |
| Baseline Glycosylated Hemoglobin (HbA1c) <7% | 17.1 percentage of participants | 28.6 percentage of participants | 45.7 percentage of participants |
| Baseline Glycosylated Hemoglobin (HbA1c) 7-7.9% | 18.3 percentage of participants | 19.3 percentage of participants | 37.6 percentage of participants |
| Baseline Glycosylated Hemoglobin (HbA1c) 8-8.9% | 12.8 percentage of participants | 10.4 percentage of participants | 23.2 percentage of participants |
| Baseline Glycosylated Hemoglobin (HbA1c) 9-9.9% | 9.7 percentage of participants | 7.0 percentage of participants | 16.7 percentage of participants |
| Baseline Glycosylated Hemoglobin (HbA1c) Missing | 18.1 percentage of participants | 17.5 percentage of participants | 35.6 percentage of participants |
| Congestive heart failure at baseline | 3.0 percentage of participants | 6.9 percentage of participants | 9.9 percentage of participants |
| Current smoker | 20.4 percentage of participants | 17.4 percentage of participants | 37.8 percentage of participants |
| Diabetes duration at baseline 0-4 years | 60.1 percentage of participants | 62.8 percentage of participants | 122.9 percentage of participants |
| Diabetes duration at baseline 10 or more years | 9.1 percentage of participants | 10.9 percentage of participants | 20 percentage of participants |
| Diabetes duration at baseline 5-9 years | 9.2 percentage of participants | 6.0 percentage of participants | 15.2 percentage of participants |
| Diabetes duration at baseline Missing | 21.6 percentage of participants | 20.4 percentage of participants | 42 percentage of participants |
| Newly diagnosed with diabetes mellitus at the start of follow-up | 50.8 percentage of participants | 57.9 percentage of participants | 108.7 percentage of participants |
| Other cancer prior to baseline | 3.1 percentage of participants | 5.3 percentage of participants | 8.4 percentage of participants |
| Other diabetes medications Insulin | 52.7 percentage of participants | 29.4 percentage of participants | 82.1 percentage of participants |
| Other diabetes medications Metformin | 84.8 percentage of participants | 45.9 percentage of participants | 130.7 percentage of participants |
| Other diabetes medications Never treated with any diabetes medication | 0.0 percentage of participants | 14.3 percentage of participants | 14.3 percentage of participants |
| Other diabetes medications Other oral hypoglycemic drugs | 6.4 percentage of participants | 1.4 percentage of participants | 7.8 percentage of participants |
| Other diabetes medications Other thiazolidinediones | 8.2 percentage of participants | 1.5 percentage of participants | 9.7 percentage of participants |
| Other diabetes medications Sulfonylureas | 89.8 percentage of participants | 61.2 percentage of participants | 151 percentage of participants |
| Race/Ethnicity, Customized Asian | 14.8 percentage of participants | 12.8 percentage of participants | 27.6 percentage of participants |
| Race/Ethnicity, Customized Black | 10.2 percentage of participants | 10.8 percentage of participants | 21 percentage of participants |
| Race/Ethnicity, Customized Hispanic | 13.4 percentage of participants | 10.6 percentage of participants | 24 percentage of participants |
| Race/Ethnicity, Customized Missing | 4.3 percentage of participants | 7.8 percentage of participants | 12.1 percentage of participants |
| Race/Ethnicity, Customized Other | 5.9 percentage of participants | 5.7 percentage of participants | 11.6 percentage of participants |
| Race/Ethnicity, Customized White | 51.3 percentage of participants | 52.3 percentage of participants | 103.6 percentage of participants |
| Renal function at baseline Elevated creatinine | 4.0 percentage of participants | 8.7 percentage of participants | 12.7 percentage of participants |
| Renal function at baseline Missing | 18.6 percentage of participants | 14.1 percentage of participants | 32.7 percentage of participants |
| Renal function at baseline Normal creatinine | 77.4 percentage of participants | 77.1 percentage of participants | 154.5 percentage of participants |
| Sex/Gender, Customized Female | 46.5 percentage of participants | 46.5 percentage of participants | 93 percentage of participants |
| Sex/Gender, Customized Male | 53.5 percentage of participants | 53.5 percentage of participants | 107 percentage of participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Incident Diagnosis of Bladder Cancer (10-year Analysis)
Incident bladder cancers were identified from January 1, 1997 to December 31, 2012.
Time frame: January 1, 1997 to December 31, 2012
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer (10-year Analysis) | 89.8 events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer (10-year Analysis) | 75.9 events per 100,000 person years |
Comparison: Fully adjusted refers to inclusion of all potential confounders in the statistical model from the 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder cancer, renal insufficiency, HbA1c and the interaction with new diagnosis of diabetes, duration of diabetes, and year of cohort entry.95% CI: [0.92, 1.31]
Comparison: Fully adjusted adding the proteinuria testing variable.95% CI: [0.89, 1.26]
Secondary
Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis)
Time frame: January 1, 1997 to December 31, 2012
Population: All participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | 1 - 14000 mg | 69.1 events per 100,000 person years |
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | 14001 - 40000 mg | 96.9 events per 100,000 person years |
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | >40000 mg | 101.4 events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | >40000 mg | NA events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | 1 - 14000 mg | NA events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | 14001 - 40000 mg | NA events per 100,000 person years |
Comparison: Cumulative dose 1-14000 mg. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.69, 1.16]
Comparison: Cumulative dose 14001-40000 mg. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.85, 1.42]
Comparison: Cumulative dose \>40000 mg. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.79, 1.44]
Secondary
Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis)
Time frame: January 1, 1997 to December 31, 2012
Population: All participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | Less than 1.5 years | 67.5 events per 100,000 person years |
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | 1.5 - 4.0 years | 88.4 events per 100,000 person years |
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | More than 4 years | 113.7 events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | Less than 1.5 years | NA events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | 1.5 - 4.0 years | NA events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | More than 4 years | NA events per 100,000 person years |
Comparison: Duration of therapy \<1.5 years. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.68, 1.16]
Comparison: Duration of therapy 1.5-4 years. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.8, 1.33]
Comparison: Duration of therapy \>4 years. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.87, 1.54]
Secondary
Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis)
Time frame: January 1, 1997 to December 31, 2012
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | Less than 4.5 years | 68.2 events per 100,000 person years |
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | 4.5 -8.5 years | 111.6 events per 100,000 person years |
| Pioglitazone Exposed Group | Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | More than 8.0 years | 125.8 events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | Less than 4.5 years | NA events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | 4.5 -8.5 years | NA events per 100,000 person years |
| Pioglitazone Unexposed Group | Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | More than 8.0 years | NA events per 100,000 person years |
Comparison: Time since starting pioglitazone \<4.5 years vs unexposed group. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.71, 1.12]
Comparison: Time since starting pioglitazone 4.5-8 years vs unexposed group. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.93, 1.59]
Comparison: Time since starting pioglitazone \>8 years vs unexposed group. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria.95% CI: [0.83, 1.75]
Secondary
Stage of Bladder Cancer (10 Year Analysis)
Time frame: January 1, 1997 to December 31, 2012
Population: Participants diagnosed with bladder cancer.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pioglitazone Exposed Group | Stage of Bladder Cancer (10 Year Analysis) | In situ | 50 percentage of participants |
| Pioglitazone Exposed Group | Stage of Bladder Cancer (10 Year Analysis) | PUNLMP | 1 percentage of participants |
| Pioglitazone Exposed Group | Stage of Bladder Cancer (10 Year Analysis) | Local | 40 percentage of participants |
| Pioglitazone Exposed Group | Stage of Bladder Cancer (10 Year Analysis) | Regional | 4 percentage of participants |
| Pioglitazone Exposed Group | Stage of Bladder Cancer (10 Year Analysis) | Distant | 2 percentage of participants |
| Pioglitazone Exposed Group | Stage of Bladder Cancer (10 Year Analysis) | Undetermined | 3 percentage of participants |
| Pioglitazone Unexposed Group | Stage of Bladder Cancer (10 Year Analysis) | Distant | 3 percentage of participants |
| Pioglitazone Unexposed Group | Stage of Bladder Cancer (10 Year Analysis) | Regional | 6 percentage of participants |
| Pioglitazone Unexposed Group | Stage of Bladder Cancer (10 Year Analysis) | PUNLMP | 1 percentage of participants |
| Pioglitazone Unexposed Group | Stage of Bladder Cancer (10 Year Analysis) | In situ | 49 percentage of participants |
| Pioglitazone Unexposed Group | Stage of Bladder Cancer (10 Year Analysis) | Undetermined | 3 percentage of participants |
| Pioglitazone Unexposed Group | Stage of Bladder Cancer (10 Year Analysis) | Local | 38 percentage of participants |