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Original Investigation |

Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis ONLINE FIRST

Laurent Azoulay, PhD1,2; Kristian B. Filion, PhD1,3; Robert W. Platt, PhD4,5; Matthew Dahl, BSc6,7; Colin R. Dormuth, ScD8; Kristin K. Clemens, MD, MSc9; Madeleine Durand, MD, MSc10; Nianping Hu, MD, PhD11; David N. Juurlink, MD, PhD12; J. Michael Paterson, MSc12,13; Laura E. Targownik, MD, MSHS6,13; Tanvir C. Turin, MD, PhD14; Pierre Ernst, MD, MSc1,3 ; and the Canadian Network for Observational Drug Effect Studies (CNODES) Investigators
[+] Author Affiliations
1Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada
2Department of Oncology, McGill University, Montreal, Quebec, Canada
3Department of Medicine, McGill University, Montreal, Quebec, Canada
4Departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
5The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
6Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
7Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada
8Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
9Department of Medicine, Western University, London, Ontario, Canada
10Department of Internal Medicine, University of Montreal Health Centre, Montreal, Quebec, Canada
11Health Quality Council, Saskatoon, Saskatchewan, Canada
12Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
13Institute of Health Policy, Management and Evaluation, University of Toronto, Ontario, Toronto
14Department of Family Medicine, University of Calgary, Calgary, Alberta, Canada
JAMA Intern Med. Published online August 01, 2016. doi:10.1001/jamainternmed.2016.1522
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Importance  The association between incretin-based drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, and acute pancreatitis is controversial.

Objective  To determine whether the use of incretin-based drugs, compared with the use of 2 or more other oral antidiabetic drugs, is associated with an increased risk of acute pancreatitis.

Design, Setting, and Participants  A large, international, multicenter, population-based cohort study was conducted using combined health records from 7 participating sites in Canada, the United States, and the United Kingdom. An overall cohort of 1 532 513 patients with type 2 diabetes initiating the use of antidiabetic drugs between January 1, 2007, and June 30, 2013, was included, with follow-up until June 30, 2014.

Exposures  Current use of incretin-based drugs compared with current use of at least 2 oral antidiabetic drugs.

Main Outcomes and Measures  Nested case-control analyses were conducted including hospitalized patients with acute pancreatitis matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and follow-up duration. Hazard ratios (HRs) and 95% CIs for hospitalized acute pancreatitis were estimated and compared current use of incretin-based drugs with current use of 2 or more oral antidiabetic drugs. Secondary analyses were performed to assess whether the risk varied by class of drug (DPP-4 inhibitors and GLP-1 agonists) or by duration of use. Site-specific HRs were pooled using random-effects models.

Results  Of 1 532 513 patients included in the analysis, 781 567 (51.0%) were male; mean age was 56.6 years. During 3 464 659 person-years of follow-up, 5165 patients were hospitalized for acute pancreatitis (incidence rate, 1.49 per 1000 person-years). Compared with current use of 2 or more oral antidiabetic drugs, current use of incretin-based drugs was not associated with an increased risk of acute pancreatitis (pooled adjusted HR, 1.03; 95% CI, 0.87-1.22). Similarly, the risk did not vary by drug class (DPP-4 inhibitors: pooled adjusted HR, 1.09; 95% CI, 0.86-1.22; GLP-1 agonists: pooled adjusted HR, 1.04; 95% CI, 0.81-1.35) and there was no evidence of a duration-response association.

Conclusions and Relevance  In this large population-based study, use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared with other oral antidiabetic drugs.

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Figure 1.
Construction of the Base and Study Cohorts

HAART indicates highly active antiretroviral therapy; HIV, human immunodeficiency virus.

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Figure 2.
Association Between the Use of Incretin-Based Drugs and the Risk of Acute Pancreatitis Among Patients With Type 2 Diabetes

The reference category was current use of 2 or more oral antidiabetic drugs. The size of the boxes is proportional to the weight of a given participating site in the random-effects meta-analysis. The I2 (percentage of the total variance due to between-study heterogeneity) was 13.6% (P = .33 for heterogeneity). CPRD indicates Clinical Practice Research Datalink; HR, hazard ratio.

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Figure 3.
Sensitivity Analyses for the Association Between the Use of Incretin-Based Drugs and the Incidence of Acute Pancreatitis

HR, hazard ratio; NA, not applicable.

aDefined as current use of incretin-based drugs in combination with at least 1 other antidiabetic drug.

bThe models were adjusted for a composite variable of microvascular complications variable, categorical variables were converted to their continuous counterparts where possible, and insulin, oral antidiabetic drug monotherapy, and not currently exposed were collapsed to a single “other exposure” category.

cThe models included only exposure (current use of incretin-based drugs, current use of oral antidiabetic combinations, and other exposure) and the Deyo version of the Charlson comorbidity index.

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