Assessing Bladder Cancer Risk in Type 2 Diabetes Clinical Trials: the Dapagliflozin Drug Development Program as a 'Case Study' - PubMed (original) (raw)

Assessing Bladder Cancer Risk in Type 2 Diabetes Clinical Trials: the Dapagliflozin Drug Development Program as a 'Case Study'

Agata Ptaszynska et al. Diabetes Ther. 2015 Sep.

Abstract

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.

Keywords: Bladder cancer; Dapagliflozin; Hematuria; SGLT2 inhibitor; Type 2 diabetes mellitus.

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Figures

Fig. 1

Fig. 1

Incident rate ratio of malignant and unspecified tumors by organ category from the dapagliflozin clinical trials. N is the number of treated patients. Only trials with at least one selected event contributed to the analysis. Confidence intervals are based on an exact method. Includes serious and non-serious adverse events on or after the first date/time of double-blind treatment and on or prior to the last day of short-term plus long-term treatment +30 days (or up to follow-up visit whichever was first) or +4 days

Fig. 2

Fig. 2

Kaplan–Meier plot of time to first event of bladder cancer. Includes data after rescue. Week is not scheduled week visit, but actual days from the first dose of double-blind study medication divided by 7. The number of patients at risk is the number of patients at risk in the beginning of the period

Fig. 3

Fig. 3

Relationship between first hematuria event after randomization and time to first bladder cancer event

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