Risk of Bladder Cancer Among Diabetic Patients Treated With Pioglitazone: Interim report of a longitudinal cohort study

James D. Lewis; Assiamira Ferrara; Tiffany Peng; Monique Hedderson; Warren B. Bilker; Charles P. Quesenberry; David J. Vaughn; Lisa Nessel; Joseph Selby; Brian L. Strom

doi:10.2337/dc10-1068

Original Research

Risk of Bladder Cancer Among Diabetic Patients Treated With Pioglitazone

Interim report of a longitudinal cohort study

James D. Lewis, MD, MSCE¹,²,³ ⇓,
Assiamira Ferrara, MD, PHD⁴,
Tiffany Peng, MA⁴,
Monique Hedderson, PHD⁴,
Warren B. Bilker, PHD¹,²,
Charles P. Quesenberry Jr., PHD⁴,
David J. Vaughn, MD³,
Lisa Nessel, MSS, MLSP¹,
Joseph Selby, MD⁴ and
Brian L. Strom, MD, MPH¹,²,⁵

¹Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania
²Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
³Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
⁴Division of Research, Kaiser Permanente Northern California, Oakland, California
⁵Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania

↵Corresponding author: James D. Lewis, lewisjd{at}mail.med.upenn.edu.

Diabetes Care 2011 Apr; 34(4): 916-922. https://doi.org/10.2337/dc10-1068

Article Figures & Tables

Tables

Table 1

Demographics of the study cohort according to ever use of pioglitazone: the KPNC diabetes registry, 1997–2008

	Ever use of pioglitazone^*	Never use of pioglitazone^*
N	30,173	162,926
Age (years)
40–49	8,612 (28.5)	36,452 (22.4)
50–59	9,945 (33.0)	41,962 (25.8)
60–69	7,799 (25.8)	42,691 (26.2)
≥70	3,817 (12.7)	41,821 (25.7)
Sex (female)	14,157 (46.9)	75,686 (46.5)
Race/ethnicity
White	14,768 (48.9)	80,777 (49.6)
Black	2,823 (9.4)	16,731 (10.3)
Asian	3,834 (12.7)	18,877 (11.6)
Hispanic	3,320 (11.0)	14,430 (8.9)
Other	1,691 (5.6)	8,876 (5.4)
Missing	3,737 (12.4)	23,235 (14.3)
Current smoker	6,052 (20.1)	28,023 (17.2)
Renal function
Normal creatinine	23,174 (76.8)	125,879 (77.3)
Elevated creatinine^†	1248 (4.1)	13,993 (8.6)
Missing	5,751 (19.1)	23,054 (14.2)
Bladder condition^‡	3,686 (12.2)	25,581 (15.7)
Congestive heart failure	969 (3.2)	11,038 (6.8)
Income
Low^§	14,413 (47.8)	82,270 (50.5)
High	12,825 (42.5)	66,133 (40.6)
Missing	2,935 (9.7)	14,523 (8.9)
Baseline A1C (%)
<7	4,873 (16.2)	46,407 (28.5)
7–7.9	5,455 (18.1)	31,517 (19.3)
8–8.9	3,921 (13.0)	17,060 (10.5)
9–9.9	2,979 (9.9)	11,524 (7.1)
≥10	7,330 (24.3)	28,017 (17.2)
Missing	5,615 (18.6)	28,401 (17.4)
Newly diagnosed with diabetes at the start of follow-up^¶	14,687 (48.7)	94,739 (58.1)
Duration of diabetes (years)
0–5	17,363 (57.5)	102,916 (63.2)
5–9	2,983 (9.9)	9,671 (5.9)
≥10	2,956 (9.8)	17,432 (10.7)
Missing	6,871 (22.8)	32,907 (20.2)
Other cancer prior to baseline	1,186 (3.9)	8,762 (5.4)
Other diabetes medications
Other TZDs	2,754 (9.1)	2,470 (1.5)
Metformin	24,797 (82.2)	70,956 (43.6)
Sulfonylureas	26,311 (87.2)	95,429 (58.6)
Other oral hypoglycemic drugs	1,482 (4.9)	1,865 (1.1)
Insulin	13,123 (43.5)	41,337 (25.4)
Pioglitazone use during follow-up
Time since starting pioglitazone (months)	39.5 (1–102)	N/A
<18	7,245 (24.0)	N/A
18–36	6,681 (22.1)	N/A
>36	16,247 (53.8)	N/A
Duration of therapy (months)	24.1 (1–102)	N/A
<12	7,332 (24.3)	N/A
12–24	7,677 (25.4)	N/A
>24	15,164 (50.3)	N/A
Cumulative dose (mg)	17,670 (450–179,000)	N/A
1–10,500	10,281 (34.1)	N/A
10,501–28,000	9,667 (32.0)	N/A
>28,000	10,225 (33.9)	N/A

Data are n (%) or median (range) unless otherwise indicated. N/A, not applicable.
↵*All comparisons have P values <0.01 except female sex (P = 0.46).
↵†Creatinine ≥1.4 mg/dL for women and ≥1.5 mg/dL for men.
↵‡History of urinary tract infections, urolithiasis, incontinence, and other bladder or urethral conditions.
↵§Low income defined as median household income in census block below the cohort average ($59,000).
↵¶Includes newly diagnosed patients and patients who newly enrolled in KPNC with an existing diagnosis of diabetes.

Table 2

Incidence rate and HR of bladder cancer with pioglitazone use: the KPNC diabetes registry, 1997–2008

	Median (range) bladder cancer incidence rate (per 100,000 person-years)	HR (95% CI) adjusted for age and sex	Fully adjusted HR (95% CI)^*
Never use of pioglitazone	68.8 (64.1–73.6)	Ref.	Ref.
Ever use of pioglitazone^†	81.5 (64.7–98.4)	1.2 (0.9–1.5)^‡	1.2 (0.9–1.5)
Time since starting pioglitazone (months)^†
<18	67.1 (41.8–92.4)	1.1 (0.8–1.6)	1.2 (0.8–1.7)
18–36	85.2 (51.8–118.6)	1.3 (0.9–2.0)	1.4 (0.9–2.1)
>36	93.1 (63.5–122.7)	1.3 (0.9–1.8)	1.3 (0.9–1.8)
P_trend	—	0.04	0.07
Duration of therapy (months)^†
<12	48.4 (29.0–67.8)	0.8 (0.5–1.2)	0.8 (0.6–1.3)
12–24	86.7 (52.0–121.4)	1.3 (0.9–2.0)	1.4 (0.9–2.1)
>24	102.8 (71.7–133.8)	1.5 (1.1–2.0)	1.4 (1.03–2.0)
P_trend	—	0.02	0.03
Cumulative dose (mg)^†
1–10,500	59.7 (39.0–80.4)	1.0 (0.7–1.4)	1.0 (0.7–1.5)
10,501–28,000	76.8 (48.3–105.2)	1.1 (0.8–1.6)	1.2 (0.8–1.8)
>2,8000	105.9 (68.0–143.8)	1.5 (1.1–2.2)	1.4 (0.96–2.1)
P_trend	—	0.05	0.08

↵*Includes all potential confounders listed in Table 1 in the statistical model.
↵†Never use of pioglitazone was the reference group for the calculation of the HR associated with ever use of pioglitazone and time, duration, and dose of pioglitazone use.
↵‡Also adjusted for use of other diabetes medications.