Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort studyBMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i581 (Published 17 February 2016) Cite this as: BMJ 2016;352:i581
- Laurent Azoulay, assistant professor of oncology1 2,
- Kristian B Filion, assistant professor of medicine1 3,
- Robert W Platt, professor of biostatistics4,
- Matthew Dahl, statistician5,
- Colin R Dormuth, associate professor6,
- Kristin K Clemens, endocrinologist and adjunct professor of medicine7,
- Madeleine Durand, assistant clinical professor of medicine8,
- David N Juurlink, professor and division head9,
- Laura E Targownik, gastroenterologist and associate professor of medicine5 10,
- Tanvir C Turin, assistant professor of family medicine11,
- J Michael Paterson, scientist9 12,
- Pierre Ernst, professor of medicine1 3
- for the Canadian Network for Observational Drug Effect Studies (CNODES) Investigators
- 1Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada
- 2Department of Oncology, McGill University, Montreal, Canada
- 3Department of Medicine, McGill University, Montreal, Canada
- 4Departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health, McGill University, and the Research Institute of the McGill University Health Centre, Montreal, Canada
- 5Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada and Department of Family Medicine, McMaster University, Hamilton, Canada
- 6Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, Canada
- 7Department of Medicine, Western University, London, Canada
- 8Department of Internal Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
- 9Institute for Clinical Evaluative Sciences, Toronto, Canada
- 10Section of Gastroenterology, Division of Internal Medicine, University of Manitoba, Winnipeg, Canada
- 11Department of Family Medicine, University of Calgary, Calgary, Canada
- 12Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto
- Correspondence to: L Azoulay
- Accepted 11 January 2016
Objective To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes.
Design Population based cohort.
Setting Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom.
Participants A cohort of 972 384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014.
Main outcome measures Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models.
Results During 2 024 441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking.
Conclusions In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.
We are grateful for the programming support of Zhihai Ma and Jianguo Zhang(Alberta), Gregory A Carney (US MarketScan), Hui Yin (UK CPRD), Caixia Fangyun Wu and Simon Hollands (Ontario), and Menglan Pang (Quebec). We also thank Corine Mizrahi, Melissa Dahan, and Laura Sang at the Coordinating Center; Héloïse Cardinal for her contribution to the development of the study design; and the important contributions of the CNODES collaborators and assistants at each site. This study was made possible through data sharing agreements between CNODES member research centres and the respective provincial governments of Alberta, Manitoba (HIPC No 2014/2015-08; HREB No H2014:236), Ontario, and Quebec. The opinions, results, and conclusions reported in this paper are those of the authors. No endorsement by the provinces is intended or should be inferred. KBF holds a Canadian Institutes of Health Research new investigator award. RWP is supported by a Chercheur-National Award of the Fonds de Recherche du Quebec-Santé (FRQS; Quebec Foundation for Health Research). MD is supported by a clinical investigator award of the FRQS. DNJ is supported by the Eaton scholar programme, Department of Medicine, University of Toronto.
The Canadian Network for Observational Drug Effect Studies (CNODES) Investigators are: Samy Suissa (principal investigator); Colin R Dormuth (British Columbia); Brenda R Hemmelgarn (Alberta); Gary F Teare (Saskatchewan); Patricia Caetano, and Dan Chateau (Manitoba); David A Henry and J Michael Paterson (Ontario); Jacques LeLorier (Québec); Adrian R Levy (Nova Scotia); Pierre Ernst (UK Clinical Practice Research Datalink (CPRD)); Robert W Platt (Methods); and Ingrid S Sketris (Knowledge Translation). CNODES, a collaborating centre of the Drug Safety and Effectiveness Network (DSEN), is funded by the Canadian Institutes of Health Research (grant No DSE-111845).
Contributors: All authors conceived and designed the study, analysed and interpreted the data, and critically revised the manuscript for important intellectual content. LA, KBF, CRD, MD, LT, TCT, JMP, and PE acquired the data. LA drafted the manuscript. LA, KBF, RWP, MD, CRD, MD, LET, TCT, JMP, and PE carried out the statistical analysis. The Canadian Network for Observational Drug Effect Studies Investigators obtained the funding. LA, KBF, RWP, and PE supervised the study. LA is the guarantor.
Funding: Canadian Network for Observational Drug Effect Studies, a collaborating centre of the Drug Safety and Effectiveness Network, is funded by the Canadian Institutes of Health Research (grant No DSE-111845). The sponsor had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. This study was made possible through data sharing agreements between CNODES member research centres and the respective provincial governments of Alberta, Manitoba, Ontario, and Quebec. The opinions, results, and conclusions reported in this paper are those of the authors. No endorsement by the provinces is intended or should be inferred.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: LET is on the speaker’s panel for Janssen Canada, Takeda Canada, Pfizer Canada, and Shire Canada, has received grant support from Pfizer Canada and Abbvie Canada, and is on advisory boards for Takeda Canada, Abbvie Canada, and Janssen Canada. RWP received consulting fees for work unrelated to this project from Pfizer, Amgen, Abbvie, and Novartis.
Ethical approval: The study protocol was approved by the institutional review boards at all participating sites, and by the Independent Scientific Advisory Committee (ISAC) of the CPRD (protocol number 14_119R). The ISAC protocol was made available to the journal reviewers. The study protocol is registered at www.clinicaltrials.gov (NCT02475499).
Data sharing: No additional data available.
Transparency: The guarantor (LA) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
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