Concerns Over Incretin-Based Drugs, Pancreatic Cancer Risk Addressed in New Study

A total of 972,384 patients were monitored in this large-scale study
A total of 972,384 patients were monitored in this large-scale study

A new international, multicenter study has found that incretin-based drugs, used to treat type 2 diabetes, are not associated with an increased risk of pancreatic cancer. Findings from this study, published in the BMJ, might help allay some of the concerns initially brought to the forefront by the U.S. Food and Drug Administration (FDA) in response to increased reporting of pancreatic cancer in patients taking incretin-based drugs vs. other oral antidiabetic agents (2.9 times higher with exenatide, 2.7 times higher with sitagliptin).

Incretin-based drugs include dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, linagliptin, sitagliptin, vildagliptin, saxagliptin) and glucagon-like peptide-1 receptor agonists (eg, exenatide, liraglutide). Previous studies which noted the pancreatic cancer risk (but which didn't specifically investigate it) were limited in a number of ways including, small sample sizes, low duration time follow-ups and a low number of specific incretin-based drugs. The findings of this new study suggests that when compared to sulfonylureas, incretin-based drugs are not associated with an increased risk of pancreatic cancer.

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In total, 972,384 patients from 6 participating sites in Canada, the U.S., and the United Kingdom, were included. In follow-ups, with the median follow-up time ranging from 1.3 to 2.8 years, 1221 out of the 972,384 were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with use of sulfonylureas, incretin-based drugs were not associated with an increased risk of incident pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23).

Researchers used a nested case-control analyses methodology for each participating site. Cases of pancreatic cancer were matched with up to 20 randomly selected controls matched on sex, age, cohort entry data, duration of treated diabetes, and duration follow-up. Calculations on the crude incidence rate of pancreatic cancer were based on the Poisson distribution with 95% confidence intervals.

Although incretin-based drugs have been linked with positive outcomes including lower risk of hypoglycemia, concern has arisen that their use may increase the risk of pancreatic cancer development. In a secondary analysis where DDP-4 and glucagon-like peptide-1 receptor agonists were stratified, the study also found no independent association of increased risk of pancreatic cancer in the use of incretin-based drugs by class (DPP-4 inhibitors, 1.02, 0.84 to 1.24; glucagon-like peptide-1 receptor agonists, 1.13, 0.38 to 3.38).

In other secondary analyses' the results remained consistent, further disassociating the likelihood of incretin-based drugs as a cause of pancreatic cancer onset. A cumulative duration of less than one year yielded an increased but non-significant pooled hazard ratio (1.53, 0.93 to 2.51), whereas longer durations of use generated pooled hazard ratios close to or below unity (1-1.9 years, 1.07, 0.82 to 1.39; ≥2 years, 0.62, 0.36 to 1.07). The analysis of time since initiation yielded pooled hazard ratios close to the null (1-1.9 years, 1.06, 0.86 to 1.31; ≥2 years, 0.93, 0.60 to 1.45). These findings were similarly observed across each class of incretin-based drug.

The patients in the study were initiated between January 2007 and June 2013, with follow-ups occurring until June 2014, meaning the longest follow-up time was 8 years. Given the latency of the cancer, the full effects of incretin-based drugs needs to be surveilled over longer durations in future studies. However the authors of the study suggest their findings do provide some reassurance to patients and clinicians with concerns of an association between incretin-based drugs and pancreatic cancer. 

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