Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02475499.

Fig 1 Flow of base and study cohorts

Fig 2 Forest plot of association between use of incretin based drugs and risk of pancreatic cancer among patients with type 2 diabetes. Reference category was use of sulfonylureas. Box size is proportional to weight of participating site in random effects meta-analysis (I²=0%)

Fig 3 Sensitivity analyses for association between use of incretin based drugs and incidence of pancreatic cancer. Reference category for all analyses was use of sulfonylureas. Site specific hazard ratios were pooled using random effects meta-analysis. Stricter exposure definition: defined as receiving at least four prescriptions within any 12 month period. *Adjusted for alcohol related disorders, history of acute or chronic pancreatitis, composite variable of microvascular complications of diabetes, number of hospital admissions (continuous), number of unique non-diabetic drugs in previous year (continuous), number of antidiabetic drugs received before entry to study cohort (continuous), and ever use of statins. In CPRD, we further adjusted for body mass index, smoking status, and glycated haemoglobin A1c level (≤7.0% (53 mmol/mol), 7.1-8.0% (54-64 mmol/mol), and >8.0% (64 mmol/mol)). †Adjusted for Deyo version of Charlson comorbidity index and history of acute or chronic pancreatitis