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01-09-2015 | Genitourinary cancers | Article

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

Journal: Diabetes Therapy

Authors: Agata Ptaszynska, Samuel M. Cohen, Edward M. Messing, Timothy P. Reilly, Eva Johnsson, Kristina Johnsson

Publisher: Springer Healthcare

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.
Literature
1.
Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–85.PubMedCentralCrossRefPubMed
2.
Fang H, Yao B, Yan Y, et al. Diabetes mellitus increases the risk of bladder cancer: an updated meta-analysis of observational studies. Diabetes Technol Ther. 2013;15:914–22.PubMedCentralCrossRefPubMed
3.
Zhu Z, Wang X, Shen Z, Lu Y, Zhong S, Xu C. Risk of bladder cancer in patients with diabetes mellitus: an updated meta-analysis of 36 observational studies. BMC Cancer. 2013;13:310.PubMedCentralCrossRefPubMed
4.
Newton CC, Gapstur SM, Campbell PT, Jacobs EJ. Type 2 diabetes mellitus, insulin-use and risk of bladder cancer in a large cohort study. Int J Cancer. 2013;132:2186–91.CrossRefPubMed
5.
MacKenzie T, Zens MS, Ferrara A, Schned A, Karagas MR. Diabetes and risk of bladder cancer: evidence from a case-control study in New England. Cancer. 2011;117:1552–6.PubMedCentralCrossRefPubMed
6.
Suissa S, Azoulay L, Dell’Aniello S, Evans M, Vora J, Pollak M. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia. 2011;54:2254–62.CrossRefPubMed
7.
Hanefeld M, Bramlage P. Insulin use early in the course of type 2 diabetes mellitus: the ORIGIN trial. Curr Diab Rep. 2013;13:342–9.PubMedCentralCrossRefPubMed
8.
Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732–44.PubMedCentralCrossRefPubMed
9.
Ruiter R, Visser LE, van Herk-Sukel MP, et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51–62.PubMedCentralCrossRefPubMed
10.
Macconell L, Brown C, Gurney K, Han J. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials. Diabetes Metab Syndr Obes. 2012;5:29–41.PubMedCentralPubMed
11.
Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials. Diabetes Res Clin Pract. 2014;103:269–75.CrossRefPubMed
12.
Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ. 2014;348:g2366.PubMedCentralCrossRefPubMed
13.
Roy D, Chadwick KD, Tatarkiewicz K, et al. The glucagon-like peptide-1-based therapeutics exenatide and saxagliptin did not cause detrimental effects on the pancreas in mice, rats, dogs and monkeys. Diabetes Obes Metab. 2014;16:910–21.CrossRefPubMed
14.
Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract. 2012;98:271–84.CrossRefPubMed
15.
FDA Drug Safety Communication. Ongoing safety review of actos (pioglitazone) and potential increased risk of bladder cancer after two years exposure [database on the Internet] 2010. Available from: http://​www.​fda.​gov/​drugs/​drugsafety/​ucm226214.​htm. Accessed May 7, 2014.
16.
US Food and Drug Administration. FDA Drug Safety Podcast for Healthcare Professionals: update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer. 2013. Available from: http://​www.​fda.​gov/​Drugs/​DrugSafety/​DrugSafetyPodcas​ts/​ucm259489.​htm. Accessed Aug 2015.
17.
Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34:916–22.PubMedCentralCrossRefPubMed
18.
Takeda Pharmaceuticals International GmbH. Takeda Announces Completion of the Post-Marketing Commitment to Submit Data to the FDA, the EMA and the PMDA for Pioglitazone Containing Medicines Including ACTOS. 2014. Available from: https://​www.​takeda.​com/​news/​2014/​20140829_​6714.​html. Accessed Aug 10, 2015.
19.
Wei L, MacDonald TM, Mackenzie IS. Pioglitazone and bladder cancer: a propensity score matched cohort study. Br J Clin Pharmacol. 2013;75:254–9.PubMedCentralCrossRefPubMed
20.
Balaji V, Seshiah V, Ashtalakshmi G, Ramanan SG, Janarthinakani M. A retrospective study on finding correlation of pioglitazone and incidences of bladder cancer in the Indian population. Indian J Endocrinol Metab. 2014;18:425–7.PubMedCentralCrossRefPubMed
21.
Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:782–90.CrossRefPubMed
22.
Farxiga (dapagliflozin). Highlights of prescribing information. Farxiga (dapagliflozin) tablets, for oral use. Princeton, NJ. 2014. Available from: http://​www.​accessdata.​fda.​gov/​drugsatfda_​docs/​label/​2014/​202293s003lbl.​pdf. Accessed Aug 10, 2015.
23.
European Medicines Agency. EPAR summary for the public. [database on the Internet] 2012. Available from: http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​EPAR_​-_​Summary_​for_​the_​public/​human/​002322/​WC500136025.​pdf. Accessed May 15, 2014.
24.
Prescribing information [database on the Internet] 2014. Available from: http://​www.​azpicentral.​com/​xigduo/​pi_​xigduoxr.​pdf. Accessed Jun 2015.
25.
27.
De Jonghe S, Proctor J, Vinken P, et al. Carcinogenicity in rats of the SGLT2 inhibitor canagliflozin. Chem Biol Interact. 2014;224:1–12.CrossRefPubMed
28.
Taub ME, Ludwig-Schwellinger E, Ishiguro N, et al. Sex-, species-, and tissue-specific metabolism of empagliflozin in male mouse kidney forms an unstable hemiacetal metabolite (M466/2) that degrades to 4-Hydroxycrotonaldehyde, a reactive and cytotoxic species. Chem Res Toxicol. 2015;28:103–15.CrossRef
29.
Abdul-Ghani MA, Norton L, DeFronzo RA. Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Curr Diab Rep. 2012;12:230–8.CrossRefPubMed
30.
Tirmenstein M, Dorr TE, Janovitz EB, et al. Nonclinical toxicology assessments support the chronic safety of dapagliflozin, a first-in-class sodium-glucose cotransporter 2 inhibitor. Int J Toxicol. 2013;32:336–50.CrossRefPubMed
31.
List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–7.PubMedCentralCrossRefPubMed
32.
Center for Drug Evaluation and Research. Pharmacology/Toxicology NDA review and evaluation. 2013. Available from: http://​www.​accessdata.​fda.​gov/​drugsatfda_​docs/​nda/​2014/​202293Orig1s000P​harmR.​pdf. Accessed Aug 10, 2015.
33.
Reilly TP, Graziano MJ, Janovitz EB, et al. Carcinogenicity risk assessment supports the chronic safety of dapagliflozin, an inhibitor of sodium-glucose co-transporter 2, in the treatment of type 2 diabetes mellitus. Diabetes Ther. 2014;5:73–96.PubMedCentralCrossRefPubMed
34.
Clayson DB, Cooper EH. Cancer of the urinary tract. Adv Cancer Res. 1970;13:271–381.CrossRefPubMed
35.
Tian L, Cai T, Pfeffer MA, Piankov N, Cremieux PY, Wei LJ. Exact and efficient inference procedure for meta-analysis and its application to the analysis of independent 2 × 2 tables with all available data but without artificial continuity correction. Biostatistics. 2009;10:275–81.PubMedCentralCrossRefPubMed
36.
Kobayashi H, Kikuchi E, Mikami S, et al. Long term follow-up in patients with initially diagnosed low grade Ta non-muscle invasive bladder tumors: tumor recurrence and worsening progression. BMC Urol. 2014;14:5.PubMedCentralCrossRefPubMed
37.
Crow P, Bayley J, Keeley F Jr. Smoking and urological disease. BJU Int. 2009;103:1317–9.CrossRefPubMed
38.
Baris D, Karagas MR, Verrill C, et al. A case-control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst. 2009;101:1553–61.PubMedCentralCrossRefPubMed
39.
Matanoski GM, Elliott EA. Bladder cancer epidemiology. Epidemiol Rev. 1981;3:203–29.PubMed
40.
Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst. 1995;87:524–30.CrossRefPubMed
41.
Friedman GD, Carroll PR, Cattolica EV, Hiatt RA. Can hematuria be a predictor as well as a symptom or sign of bladder cancer? Cancer Epidemiol Biomarkers Prev. 1996;5:993–6.PubMed
42.
Malone KE. Diethylstilbestrol (DES) and breast cancer. Epidemiol Rev. 1993;15:108–9.PubMed
44.
Waites CR, Dominick MA, Sanderson TP, Schilling BE. Nonclinical safety evaluation of muraglitazar, a novel PPARalpha/gamma agonist. Toxicol Sci. 2007;100:248–58.CrossRefPubMed
45.
Tseng CH, Tseng FH. Peroxisome proliferator-activated receptor agonists and bladder cancer: lessons from animal studies. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2012;30:368–402.CrossRefPubMed
46.
SEER Stat Fact Sheets: Bladder Cancer [database on the Internet] 2011. Available from: http://​seer.​cancer.​gov/​statfacts/​html/​urinb.​html. Accessed Mar 24, 2015.
47.
Shephard EA, Stapley S, Neal RD, Rose P, Walter FM, Hamilton WT. Clinical features of bladder cancer in primary care. Br J Gen Pract. 2012;62:e598–604.PubMedCentralCrossRefPubMed
48.
Vermeulen SH, Hanum N, Grotenhuis AJ, et al. Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study. Br J Cancer. 2015;112:594–600.CrossRefPubMed
49.
Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124:477–84.CrossRefPubMed
50.
Friedlander DF, Resnick MJ, You C, et al. Variation in the intensity of hematuria evaluation: a target for primary care quality improvement. Am J Med. 2014;127:633–40.PubMedCentralCrossRefPubMed
51.
Johnson EK, Daignault S, Zhang Y, Lee CT. Patterns of hematuria referral to urologists: does a gender disparity exist? Urology. 2008;72:498–502 (discussion 502–3).CrossRefPubMed
52.
Nieder AM, Lotan Y, Nuss GR, et al. Are patients with hematuria appropriately referred to Urology? A multi-institutional questionnaire based survey. Urol Oncol. 2010;28:500–3.CrossRefPubMed
53.
Shinagare AB, Silverman SG, Gershanik EF, Chang SL, Khorasani R. Evaluating hematuria: impact of guideline adherence on urologic cancer diagnosis. Am J Med. 2014;127:625–32.CrossRefPubMed
54.
Kaku K, Inoue S, Matsuoka O, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2013;15:432–40.CrossRefPubMed
55.
Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012;35:1473–8.PubMedCentralCrossRefPubMed
56.
Wilding JP, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156:405–15.CrossRefPubMed
57.
Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.PubMedCentralCrossRefPubMed
58.
Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34:2015–22.PubMedCentralCrossRefPubMed
59.
Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62:1252–62.CrossRefPubMed