Pioglitazone and bladder cancer

Overview

Tuccori M et al.. BMJ 2016 · PMID 27029385 · DOI 10.1136/bmj.i1541

Pioglitazone users had 63% more bladder cancer, about 3 extra cases per 10,000 people per year.

Does the study support the specific claim? Yes · Methodological quality: moderate

Original publication

Plain-language summary

Scientific in-depth review

1. Full reference

Authors

Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L

Journal

BMJ

Year

2016

Identifier

PMID 27029385 DOI 10.1136/bmj.i1541 · PMC4816602

Verification

verified – PubMed E-utilities efetch, 2026-10-25

Retracted

no

Corrections

none

Extent checked

full text

Conflicts of interest and funding

Funded by the Canadian Institutes of Health Research; authors declare no financial relationships with organisations with an interest in the work.

2. Research question

Pioglitazone and bladder cancer

3. Study design and population

Study design

Cohort study – Population-based new-user cohort study in the UK Clinical Practice Research Datalink with time-varying thiazolidinedione exposure lagged by 1 year; competing-risk Cox models; head-to-head comparison with rosiglitazone (incl. high-dimensional propensity score subcohort); nine sensitivity analyses.

Population

Patients aged >=40 newly treated with non-insulin antidiabetic drugs who initiated a new drug class 2000-2013; excluded prior insulin, gestational diabetes, PCOS, prior bladder cancer, <1 year follow-up. Mean age 63.7; 56.8% male.

Country

UK

Period

Cohort entry 1 January 2000 - 31 July 2013; follow-up to 31 July 2014 (mean 4.7 years, up to 14.5).

Sample size

145,806 patients; 689,616 person-years; 622 bladder cancers (54 during pioglitazone exposure, 56 rosiglitazone, 497 no thiazolidinedione).

Inclusion and exclusion criteria

As described in the abstract; details not available in abstract.

4. Methods and endpoints

Exposure / intervention

Pioglitazone (time-varying, 1-year lag); cumulative duration (<1, 1-2, >2 years) and cumulative dose (<=10,500; 10,501-28,000; >28,000 mg).

Comparator

No thiazolidinedione use; rosiglitazone (active comparator / negative control).

Endpoints

Incident bladder cancer (malignant and in situ).

Statistical methods

Time-dependent Cox with Fine-Gray competing risk; adjusted for age, sex, year, BMI, smoking, alcohol disorders, HbA1c, diabetes duration, bladder conditions, prior cancer, urine protein testing, Charlson score; sensitivity: 0/2-year lag, stricter exposure, multiple imputation, censoring at 2010, marginal structural model, other drugs; rule-out method for unmeasured confounding.

5. Actual results

Results

Pioglitazone vs no TZD: 121.0 vs 88.9 per 100,000 person-years, aHR 1.63 (95% CI 1.22-2.19). Duration: <=1 year 1.33 (0.73-2.40), 1-2 years 1.66 (0.97-2.84), >2 years 1.78 (1.21-2.64); P trend <0.01. Dose: <=10,500 mg 1.63 (1.02-2.60), 10,500-28,000 mg 1.58 (0.98-2.55), >28,000 mg 1.70 (1.04-2.78); P trend 0.01. Rosiglitazone: 86.2 vs 88.9, aHR 1.10 (0.83-1.47), no duration/dose trend. Pioglitazone vs rosiglitazone aHR 1.48 (1.01-2.16); hdPS subcohort 1.46 (0.94-2.27). Sensitivity HRs 1.46-1.76 (no lag 1.49, 2-year lag 1.73). An unmeasured confounder would need OR >3.7 with exposure and RR >5.0 with outcome to null the result.

Absolute risks

121.0 vs 88.9 bladder cancers per 100,000 person-years (pioglitazone vs no TZD), i.e. about 32 extra cases per 100,000 person-years (difference calculated).

Authors' conclusion

Pioglitazone is associated with an increased risk of bladder cancer varying with duration and dose; absence of association with rosiglitazone suggests a drug-specific, not class, effect.

6. Strengths

• New-user design with 1-year latency lag and time-varying exposure (avoids immortal-time and prevalent-user bias)
• Active comparator/negative control (rosiglitazone) with same indication and market entry
• Adjustment for smoking, BMI, HbA1c; competing risks; extensive sensitivity analyses and bias quantification
• Independent public funding; no COI

7. Weaknesses

• Observational; residual confounding (occupational exposures, diet, ethnicity) possible
• Only 54 exposed cases; dose-response steps imprecise and nearly flat across dose categories
• Pioglitazone users differed from non-users (diabetes duration 4.2 vs 0.3 years; more prior bladder conditions and urine testing - possible detection bias)
• GP-recorded prescriptions only; specialist initiation missed
• Literature inconsistent (several large null studies; trial evidence imprecise)

8. Risk of bias

Orienting tool

ROBINS-E

Type of assessment

structured assessment based on the full text by a single reviewer (no formal double review)

Full formal assessment

no

Overall risk of bias

some concerns

Rationale

Single-reviewer ROBINS-E-oriented judgement from the full text; formal assessment requires two independent reviewers. Overall unchanged (some_concerns): well-designed pharmacoepidemiological cohort; main residual concerns are small exposed case numbers and possible detection bias.

Full-text review (25 October 2026): Cohort definition, person-years, exposed event counts (54), duration and dose category HRs, head-to-head vs rosiglitazone (1.48), sensitivity range (1.46-1.76) and rule-out analysis added; COI confirmed (CIHR, none declared); ROBINS-E domains added, overall unchanged.

9. Assessment of the statistical interpretation

Moderate relative increase (HR 1.63) with small absolute excess (~3 per 10,000 person-years); duration-response present, dose categories nearly flat. Consistent with a drug-specific signal but not definitive causal proof.

10. Relevance to the specific claim

Supports C-ODD-12, C-ODD-05.

11. Independent contrary findings

Not reviewed.

12. Transferability to Germany and Europe

UK data.

13. Overall methodological judgement

Well-designed cohort supporting a drug-specific association of pioglitazone with bladder cancer (small absolute risk); rosiglitazone not associated. Supports the specific claim 'pioglitazone raises bladder cancer risk by 63%' as a relative association, not as a class effect of all diabetes drugs.

14. Open questions

None beyond those stated.

15. Linked fact checks

• Every major class of glucose-lowering drug (metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists) carries a documented signal of serious harm in the peer-reviewed literature. – Studies supporting the claim
• Pioglitazone (Actos) raises bladder cancer risk by 63%. – Studies supporting the claim

Use by the Tayebat archive

Note: according to the archive, the studies were compiled by the archive operators. Whether Dr. Elawady himself cited this study is not established.

What the archive says about the study

Narrative: BMJ cohort of 145,806 tied pioglitazone to a 63% rise in bladder cancer.

A. What was actually studied?

Pioglitazone and bladder cancer

B. What did the authors find?

aHR 1.63 (1.22-2.19), 121.0 vs 88.9 per 100,000 person-years; >2 years use aHR 1.78; rosiglitazone null (1.10); pioglitazone vs rosiglitazone 1.48.

C. What conclusions do the authors themselves draw?

Pioglitazone associated with increased bladder cancer; drug-specific, not class effect.

D. What does the archive derive from it?

Used as example of class harm.

E. Is this derivation scientifically justified?

Numbers correct; the archive omits the small absolute risk (~32 per 100,000 person-years) and that the authors found no effect for rosiglitazone (drug-specific, not class-wide).

Adequacy of the interpretation (by the archive)

essentially correct but incomplete