Pioglitazone does not affect the risk of kidney cancer in patients with type 2 diabetes Chin-Hsiao Tseng PII: DOI: Reference:
S0026-0495(14)00138-3 doi: 10.1016/j.metabol.2014.04.014 YMETA 53020
To appear in:
Metabolism
Received date: Revised date: Accepted date:
20 December 2013 29 April 2014 30 April 2014
Please cite this article as: Tseng Chin-Hsiao, Pioglitazone does not affect the risk of kidney cancer in patients with type 2 diabetes, Metabolism (2014), doi: 10.1016/j.metabol.2014.04.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pioglitazone does not affect the risk of kidney cancer in patients with type 2 diabetes
Department of Internal Medicine, National Taiwan University College of Medicine,
RI P
1
T
Chin-Hsiao Tseng1,2,3
2
SC
Taipei, Taiwan
Division of Endocrinology and Metabolism, Department of Internal Medicine,
3
MA NU
National Taiwan University Hospital, Taipei, Taiwan
Division of Environmental Health and Occupational Medicine of the National Health
PT
Corresponding author:
ED
Research Institutes, Taipei, Taiwan
Chin-Hsiao Tseng, MD, PhD
CE
Department of Internal Medicine, National Taiwan University Hospital No. 7 Chung-Shan South Road, Taipei (100), Taiwan
AC
Telephone and Fax: 886-2-2388-3578; E-mail: [email protected] Word count of the abstract: 230 Word count of the text: 2629 Number of references: 49; Number of tables: 3; Number of figures: 0 Conflict of interest: None
1
ACCEPTED MANUSCRIPT Abstract
T
Objective: To investigate whether pioglitazone treatment of patients with type 2
RI P
diabetes mellitus was associated with an increased risk of kidney cancer.
SC
Methods: The reimbursement databases of all Taiwanese patients with type 2 diabetes who received oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved
MA NU
from the National Health Insurance. An entry date was set at 1 January 2006, and a total of 1,093,675 patients with type 2 diabetes were followed up for kidney cancer incidence until the end of 2009. The incidences of kidney cancer among patients who
ED
had and had not received pioglitazone, as well as among subgroups of those treated
PT
with pioglitazone (sorted by time since starting pioglitazone, duration of treatment
CE
and cumulative dose) were calculated and hazard ratios (HRs) estimated by Cox
AC
regression analysis.
Results: Of the 1,093,675 patients, 58,172 (5.3%) had and 1,035,503 (94.7%) had not received pioglitazone, with incident kidney cancer developing in 208 (0.36%) and 3304 (0.32%) patients, respectively, and a respective incidence of 97.7 and 90.5 per 100,000 person-years. Pioglitazone and kidney cancer were not significantly associated in unadjusted (HR 1.04; 95% confidence interval (CI), 0.90–1.20), age-sex-adjusted (HR 1.09; 95% CI, 0.95–1.25), and fully adjusted (HR 1.09; 95% CI, 0.94–1.26) models. None of the dose-response parameters showed a significant trend
2
ACCEPTED MANUSCRIPT of risk association, with all P-trends >0.10.
T
Conclusions: Pioglitazone does not affect the risk of kidney cancer.
RI P
Keywords: Asian population, cohort study, epidemiology, insurance database, Taiwan
ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification
MA NU
SC
Abbreviations:
HR: hazard ratio
CI: confidence interval
KPNC: Kaiser Permanente Northern California
NHI: National Health Insurance
PPARγ: peroxisome proliferator-activated receptor-γ
AC
CE
PT
ED
3
ACCEPTED MANUSCRIPT Introduction
T
Kidney cancer is one of the most common cancers in western countries [1].
RI P
Many of these patients are diagnosed incidentally during imaging for unrelated
SC
conditions, with a high proportion (20%–30%) of these patients having metastatic disease at diagnosis [1]. Approximately 90% of patients with kidney cancer have renal
MA NU
cell carcinoma, which is resistant to chemotherapy/radiotherapy, and surgical removal remains the mainstay of treatment [1].
Diabetes mellitus and metabolic syndrome may increase the risk of cancer [2-13],
ED
including kidney cancer [2,10-13]. Although the link between diabetes and cancer
PT
remains unclear, anti-diabetic drugs have been shown to affect this risk [14-19].
CE
Peroxisome proliferator-activated receptor-γ (PPARγ) is highly expressed in human
AC
renal cell carcinoma [20,21]. A phase II clinical trial showed that treatment of metastatic renal cell carcinoma patients with the anti-inflammatory agent pioglitazone plus other agents showed promising effects on overall survival and progression-free survival, with response paralleling a reduction in C-reactive protein concentration [22]. Few observational studies to date have analyzed the association between pioglitazone use and kidney cancer risk, although two recent cohort studies in western countries suggested they were not associated [23,24]. For example, a cohort study
4
ACCEPTED MANUSCRIPT using databases from the Kaiser Permanente Northern California (KPNC) Diabetes
T
Registry in the USA showed that the adjusted hazard ratio (HR) for use versus
RI P
non-use of pioglitazone was 0.7 (95% confidence interval [CI] 0.4–1.1) [23]. The
SC
other cohort analysis, using information from the French insurance system, also suggested a lack of association between pioglitazone use and kidney cancer risk, with
MA NU
an adjusted HR for use versus non-use of pioglitazone of 0.91 (95% CI 0.79–1.06) [24]. A pooled estimate of the HR for kidney cancer associated with pioglitazone derived from these two studies was 0.89 (95% CI 0.76–1.04) [25]. To our knowledge,
ED
the association between pioglitazone use in patients with type 2 diabetes mellitus and
PT
the risk of kidney cancer has not been investigated in Asian populations. The
CE
association between pioglitazone use and bladder cancer risk has been reported to
AC
differ depending upon ethnicity [26]. Therefore, this study was designed to investigate the association between pioglitazone use and kidney cancer in Taiwanese patients with type 2 diabetes mellitus using the reimbursement databases of the National Health Insurance (NHI). Materials and Methods Since March 1995 a compulsory and universal system of health insurance, the NHI, was implemented in Taiwan. All contracted medical institutes must submit computerized and standard claim documents for reimbursement. More than 99% of
5
ACCEPTED MANUSCRIPT Taiwanese citizens are enrolled in the NHI, and >98% of the hospitals nationwide are
T
under contract with the NHI. The average number of annual physician visits per
RI P
capita in Taiwan, 15 in 2009, is one of the highest in countries around the world.
SC
This study was approved by an ethics review board of the National Health Research Institutes with registered approval number 99274.
MA NU
The identification information of the individuals was scrambled to protect privacy. Diabetes was coded 250.1-250.9 and kidney cancer 189, based on the International Classification of Diseases, Ninth Revision, Clinical Modification
ED
(ICD-9-CM).
PT
The databases of all patients who had been diagnosed with type 2 diabetes
CE
mellitus and were treated with either oral anti-diabetic agents or insulin from 1996 to
AC
2009, and who remained enrolled in the NHI after 2006, were retrieved (n=1,446,408). The selected entry date was 1 January 2006. After excluding patients diagnosed with diabetes after 2006 (n=342,351), patients who held a Severe Morbidity Card as having type 1 diabetes (n=7,120, in Taiwan, patients with type 1 diabetes are issued a “Severe Morbidity Card” after certified diagnosis, with most co-payments waived), patients diagnosed with kidney cancer before 2006 (n=10,282), patients who died (n=96,320) or withdrew from the NHI (n=12,502) before entry date, patients with duplicate identification numbers (n=106), and patients with unclear information on date of birth
6
ACCEPTED MANUSCRIPT or sex (n=5,123), a total of 1,093,675 patients diagnosed with type 2 diabetes mellitus
T
and treated with oral anti-diabetic agents or insulin were included.
RI P
Those who had ever been prescribed pioglitazone before the entry date were
SC
defined as users; and those never prescribed pioglitazone before entry date as non-users. To evaluate a possible dose-response relationship between pioglitazone use
MA NU
and kidney cancer, the cutoffs used by the KPNC study [27] were used for analysis; i.e., time since starting pioglitazone in months, duration of therapy in months and cumulative dose in mg; and the tertile cutoffs of these variables calculated from the
ED
databases were also analyzed.
PT
The entry date at the beginning of 2006 was selected for two reasons: (1)
CE
Pioglitazone was approved for clinical use in Taiwan in 2002, making an entry date of
AC
2006 approximately in the middle of the marketing date of pioglitazone in Taiwan and the ending date of the available NHI databases in 2009. Therefore, this entry date would provide a longest exposure of 4 years at entry and a longest follow-up duration of 4 years. (2) The possible association between bladder cancer and pioglitazone use noted in the PROactive trial was published in 2005 [28], and in 2007, another thiazolidinedione, rosiglitazone, was reported associated with a risk of acute myocardial infarction [29]. These findings changed the prescriptions written by physicians, to stop prescribing the thiazolidinediones, including rosiglitazone and
7
ACCEPTED MANUSCRIPT pioglitazone (troglitazone has not been marketed in Taiwan), such that patients
T
prescribed these drugs after 2006 may have stopped taking these drugs. Therefore, a
RI P
later entry date may have made estimates of the duration of therapy and cumulative
SC
dose of pioglitazone less reliable, as well as shortening the follow-up duration for cancer incidence.
MA NU
All comorbidities and covariates were determined as a status/diagnosis before the entry date; the ICD-9-CM codes for these comorbidities have been described elsewhere [30-34]. Medications included sulfonylureas, metformin, acarbose, insulin,
ED
and rosiglitazone. Baseline characteristics between users and non-users of
PT
pioglitazone were compared using Chi-square tests.
CE
The incidence of kidney cancer was calculated for pioglitazone users and
AC
non-users and for different subgroups of pioglitazone users and compared using Chi-square tests.
The numerator for the incidence was the number of patients with incident kidney cancer during the 4-year follow-up, and the denominator was the person-years of follow-up. The follow-up duration for pioglitazone users was censored on the date of kidney cancer diagnosis or, in those without incident kidney cancer, on the date of the last record of reimbursement. Follow-up in users was censored on the date of starting pioglitazone, kidney cancer diagnosis or the last record of reimbursement. This
8
ACCEPTED MANUSCRIPT ensured non-exposure to pioglitazone throughout the entire follow-up in the non-user
T
group.
RI P
Cox proportional hazards regression was performed to estimate the HRs for
SC
kidney cancer for pioglitazone users versus non-users, and for the various subgroups of dose-response parameters. The following three models were created: (1) unadjusted;
MA NU
(2) adjusted for age and sex; and (3) adjusted for all variables compared previously as baseline characteristics between users and non-users (fully adjusted model). Analyses were performed using SAS statistical software, version 9.3 (SAS
ED
Institute, Cary, NC). P
S0026-0495(14)00138-3 doi: 10.1016/j.metabol.2014.04.014 YMETA 53020
To appear in:
Metabolism
Received date: Revised date: Accepted date:
20 December 2013 29 April 2014 30 April 2014
Please cite this article as: Tseng Chin-Hsiao, Pioglitazone does not affect the risk of kidney cancer in patients with type 2 diabetes, Metabolism (2014), doi: 10.1016/j.metabol.2014.04.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pioglitazone does not affect the risk of kidney cancer in patients with type 2 diabetes
Department of Internal Medicine, National Taiwan University College of Medicine,
RI P
1
T
Chin-Hsiao Tseng1,2,3
2
SC
Taipei, Taiwan
Division of Endocrinology and Metabolism, Department of Internal Medicine,
3
MA NU
National Taiwan University Hospital, Taipei, Taiwan
Division of Environmental Health and Occupational Medicine of the National Health
PT
Corresponding author:
ED
Research Institutes, Taipei, Taiwan
Chin-Hsiao Tseng, MD, PhD
CE
Department of Internal Medicine, National Taiwan University Hospital No. 7 Chung-Shan South Road, Taipei (100), Taiwan
AC
Telephone and Fax: 886-2-2388-3578; E-mail: [email protected] Word count of the abstract: 230 Word count of the text: 2629 Number of references: 49; Number of tables: 3; Number of figures: 0 Conflict of interest: None
1
ACCEPTED MANUSCRIPT Abstract
T
Objective: To investigate whether pioglitazone treatment of patients with type 2
RI P
diabetes mellitus was associated with an increased risk of kidney cancer.
SC
Methods: The reimbursement databases of all Taiwanese patients with type 2 diabetes who received oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved
MA NU
from the National Health Insurance. An entry date was set at 1 January 2006, and a total of 1,093,675 patients with type 2 diabetes were followed up for kidney cancer incidence until the end of 2009. The incidences of kidney cancer among patients who
ED
had and had not received pioglitazone, as well as among subgroups of those treated
PT
with pioglitazone (sorted by time since starting pioglitazone, duration of treatment
CE
and cumulative dose) were calculated and hazard ratios (HRs) estimated by Cox
AC
regression analysis.
Results: Of the 1,093,675 patients, 58,172 (5.3%) had and 1,035,503 (94.7%) had not received pioglitazone, with incident kidney cancer developing in 208 (0.36%) and 3304 (0.32%) patients, respectively, and a respective incidence of 97.7 and 90.5 per 100,000 person-years. Pioglitazone and kidney cancer were not significantly associated in unadjusted (HR 1.04; 95% confidence interval (CI), 0.90–1.20), age-sex-adjusted (HR 1.09; 95% CI, 0.95–1.25), and fully adjusted (HR 1.09; 95% CI, 0.94–1.26) models. None of the dose-response parameters showed a significant trend
2
ACCEPTED MANUSCRIPT of risk association, with all P-trends >0.10.
T
Conclusions: Pioglitazone does not affect the risk of kidney cancer.
RI P
Keywords: Asian population, cohort study, epidemiology, insurance database, Taiwan
ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification
MA NU
SC
Abbreviations:
HR: hazard ratio
CI: confidence interval
KPNC: Kaiser Permanente Northern California
NHI: National Health Insurance
PPARγ: peroxisome proliferator-activated receptor-γ
AC
CE
PT
ED
3
ACCEPTED MANUSCRIPT Introduction
T
Kidney cancer is one of the most common cancers in western countries [1].
RI P
Many of these patients are diagnosed incidentally during imaging for unrelated
SC
conditions, with a high proportion (20%–30%) of these patients having metastatic disease at diagnosis [1]. Approximately 90% of patients with kidney cancer have renal
MA NU
cell carcinoma, which is resistant to chemotherapy/radiotherapy, and surgical removal remains the mainstay of treatment [1].
Diabetes mellitus and metabolic syndrome may increase the risk of cancer [2-13],
ED
including kidney cancer [2,10-13]. Although the link between diabetes and cancer
PT
remains unclear, anti-diabetic drugs have been shown to affect this risk [14-19].
CE
Peroxisome proliferator-activated receptor-γ (PPARγ) is highly expressed in human
AC
renal cell carcinoma [20,21]. A phase II clinical trial showed that treatment of metastatic renal cell carcinoma patients with the anti-inflammatory agent pioglitazone plus other agents showed promising effects on overall survival and progression-free survival, with response paralleling a reduction in C-reactive protein concentration [22]. Few observational studies to date have analyzed the association between pioglitazone use and kidney cancer risk, although two recent cohort studies in western countries suggested they were not associated [23,24]. For example, a cohort study
4
ACCEPTED MANUSCRIPT using databases from the Kaiser Permanente Northern California (KPNC) Diabetes
T
Registry in the USA showed that the adjusted hazard ratio (HR) for use versus
RI P
non-use of pioglitazone was 0.7 (95% confidence interval [CI] 0.4–1.1) [23]. The
SC
other cohort analysis, using information from the French insurance system, also suggested a lack of association between pioglitazone use and kidney cancer risk, with
MA NU
an adjusted HR for use versus non-use of pioglitazone of 0.91 (95% CI 0.79–1.06) [24]. A pooled estimate of the HR for kidney cancer associated with pioglitazone derived from these two studies was 0.89 (95% CI 0.76–1.04) [25]. To our knowledge,
ED
the association between pioglitazone use in patients with type 2 diabetes mellitus and
PT
the risk of kidney cancer has not been investigated in Asian populations. The
CE
association between pioglitazone use and bladder cancer risk has been reported to
AC
differ depending upon ethnicity [26]. Therefore, this study was designed to investigate the association between pioglitazone use and kidney cancer in Taiwanese patients with type 2 diabetes mellitus using the reimbursement databases of the National Health Insurance (NHI). Materials and Methods Since March 1995 a compulsory and universal system of health insurance, the NHI, was implemented in Taiwan. All contracted medical institutes must submit computerized and standard claim documents for reimbursement. More than 99% of
5
ACCEPTED MANUSCRIPT Taiwanese citizens are enrolled in the NHI, and >98% of the hospitals nationwide are
T
under contract with the NHI. The average number of annual physician visits per
RI P
capita in Taiwan, 15 in 2009, is one of the highest in countries around the world.
SC
This study was approved by an ethics review board of the National Health Research Institutes with registered approval number 99274.
MA NU
The identification information of the individuals was scrambled to protect privacy. Diabetes was coded 250.1-250.9 and kidney cancer 189, based on the International Classification of Diseases, Ninth Revision, Clinical Modification
ED
(ICD-9-CM).
PT
The databases of all patients who had been diagnosed with type 2 diabetes
CE
mellitus and were treated with either oral anti-diabetic agents or insulin from 1996 to
AC
2009, and who remained enrolled in the NHI after 2006, were retrieved (n=1,446,408). The selected entry date was 1 January 2006. After excluding patients diagnosed with diabetes after 2006 (n=342,351), patients who held a Severe Morbidity Card as having type 1 diabetes (n=7,120, in Taiwan, patients with type 1 diabetes are issued a “Severe Morbidity Card” after certified diagnosis, with most co-payments waived), patients diagnosed with kidney cancer before 2006 (n=10,282), patients who died (n=96,320) or withdrew from the NHI (n=12,502) before entry date, patients with duplicate identification numbers (n=106), and patients with unclear information on date of birth
6
ACCEPTED MANUSCRIPT or sex (n=5,123), a total of 1,093,675 patients diagnosed with type 2 diabetes mellitus
T
and treated with oral anti-diabetic agents or insulin were included.
RI P
Those who had ever been prescribed pioglitazone before the entry date were
SC
defined as users; and those never prescribed pioglitazone before entry date as non-users. To evaluate a possible dose-response relationship between pioglitazone use
MA NU
and kidney cancer, the cutoffs used by the KPNC study [27] were used for analysis; i.e., time since starting pioglitazone in months, duration of therapy in months and cumulative dose in mg; and the tertile cutoffs of these variables calculated from the
ED
databases were also analyzed.
PT
The entry date at the beginning of 2006 was selected for two reasons: (1)
CE
Pioglitazone was approved for clinical use in Taiwan in 2002, making an entry date of
AC
2006 approximately in the middle of the marketing date of pioglitazone in Taiwan and the ending date of the available NHI databases in 2009. Therefore, this entry date would provide a longest exposure of 4 years at entry and a longest follow-up duration of 4 years. (2) The possible association between bladder cancer and pioglitazone use noted in the PROactive trial was published in 2005 [28], and in 2007, another thiazolidinedione, rosiglitazone, was reported associated with a risk of acute myocardial infarction [29]. These findings changed the prescriptions written by physicians, to stop prescribing the thiazolidinediones, including rosiglitazone and
7
ACCEPTED MANUSCRIPT pioglitazone (troglitazone has not been marketed in Taiwan), such that patients
T
prescribed these drugs after 2006 may have stopped taking these drugs. Therefore, a
RI P
later entry date may have made estimates of the duration of therapy and cumulative
SC
dose of pioglitazone less reliable, as well as shortening the follow-up duration for cancer incidence.
MA NU
All comorbidities and covariates were determined as a status/diagnosis before the entry date; the ICD-9-CM codes for these comorbidities have been described elsewhere [30-34]. Medications included sulfonylureas, metformin, acarbose, insulin,
ED
and rosiglitazone. Baseline characteristics between users and non-users of
PT
pioglitazone were compared using Chi-square tests.
CE
The incidence of kidney cancer was calculated for pioglitazone users and
AC
non-users and for different subgroups of pioglitazone users and compared using Chi-square tests.
The numerator for the incidence was the number of patients with incident kidney cancer during the 4-year follow-up, and the denominator was the person-years of follow-up. The follow-up duration for pioglitazone users was censored on the date of kidney cancer diagnosis or, in those without incident kidney cancer, on the date of the last record of reimbursement. Follow-up in users was censored on the date of starting pioglitazone, kidney cancer diagnosis or the last record of reimbursement. This
8
ACCEPTED MANUSCRIPT ensured non-exposure to pioglitazone throughout the entire follow-up in the non-user
T
group.
RI P
Cox proportional hazards regression was performed to estimate the HRs for
SC
kidney cancer for pioglitazone users versus non-users, and for the various subgroups of dose-response parameters. The following three models were created: (1) unadjusted;
MA NU
(2) adjusted for age and sex; and (3) adjusted for all variables compared previously as baseline characteristics between users and non-users (fully adjusted model). Analyses were performed using SAS statistical software, version 9.3 (SAS
ED
Institute, Cary, NC). P
