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Assessing Bladder Cancer Risk in Type 2 Diabetes Clinical Trials: the Dapagliflozin Drug Development Program as a
Agata Ptaszynska1, Samuel M Cohen2, Edward M Messing3
1Bristol-Myers Squibb, Princeton, NJ, USA. agata.ptaszynska@bms.com.
Introduction:
Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, decreases plasma glucose levels by suppressing renal glucose reabsorption and increasing urinary glucose excretion. Previously published pre-clinical data suggest that dapagliflozin lacks carcinogenic potential. This article reviews data on bladder cancer with dapagliflozin to illustrate the challenges in assessing bladder cancer in drug development programs in patients with type 2 diabetes mellitus (T2DM).
Methods:
Clinical cases of bladder cancer were analyzed in a pooled population of >9000 patients in 21 phase 2b/3 dapagliflozin clinical trials of up to 208 weeks' duration.
Results:
In the 21-study pool, demographic and baseline characteristics were generally consistent between dapagliflozin and comparator groups. The overall incidence of malignancies was also balanced between the treatment groups, with an incidence rate ratio (IRR) of 1.035 [95% confidence interval (CI): 0.724, 1.481]. Nine of 5936 dapagliflozin-treated patients and 1 of 3403 comparator-treated patients reported bladder cancer, with an IRR of 5.168 (95% CI: 0.677, 233.55). All of these patients had clinical attributes typical of bladder cancer in the general population (≥60-year-old males; 8 of the 10 patients were current/former smokers). All cases of bladder cancer were reported within 2 years of starting study treatment. There was an absence of detailed workup of hematuria prior to randomization, and no hematuria workup data were collected proactively in the dapagliflozin trials, which is typical of clinical practice. Failure to exclude bladder cancer prior to randomization increases the chance of recruiting patients with pre-existing bladder cancer in clinical trials and may delay the final diagnosis. Of the nine dapagliflozin-treated patients with bladder cancer, eight had microscopic hematuria prior to start of treatment or within 6 months of initiating study treatment.
Conclusion:
The assessment of bladder cancer data illustrates the challenges of characterizing cancer risk in T2DM drug development programs. The totality of evidence to date does not suggest a causal relationship between dapagliflozin and bladder cancer.
Funding:
AstraZeneca.
Insights
Dapagliflozin, a type 2 diabetes medication, showed no causal link to bladder cancer in clinical trials. Analysis of over 9000 patients revealed similar cancer rates between dapagliflozin and placebo groups.
Area of Science:
- Pharmacology
- Oncology
- Endocrinology
Background:
- Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor used to manage type 2 diabetes mellitus (T2DM).
- Pre-clinical studies indicated dapagliflozin lacks carcinogenic potential.
- This review examines bladder cancer data from dapagliflozin trials to address challenges in drug development.
Purpose of the Study:
- To review and analyze clinical data on bladder cancer incidence in patients treated with dapagliflozin.
- To illustrate the complexities of assessing bladder cancer risk during drug development for T2DM.
Main Methods:
- A pooled analysis of over 9000 patients from 21 phase 2b/3 clinical trials of dapagliflozin (up to 208 weeks).
- Comparison of bladder cancer incidence between dapagliflozin and comparator groups.
Main Results:
- Overall malignancy incidence was balanced between treatment groups (IRR 1.035).
- Nine dapagliflozin-treated patients (5936) and one comparator patient (3403) developed bladder cancer (IRR 5.168).
- Bladder cancer cases were typical of the general population (older males, smokers), occurring within 2 years; 8/9 dapagliflozin patients had prior hematuria.
Conclusions:
- The totality of evidence does not suggest a causal relationship between dapagliflozin and bladder cancer.
- Challenges in assessing bladder cancer risk in T2DM drug development were highlighted, including the impact of pre-existing conditions like hematuria.
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