Dipeptidyl peptidase-4 inhibitors are associated with a 75% increase in the risk of inflammatory bowel disease (IBD) in individuals with type 2 diabetes, a study has found.

Researchers reported the results of an observational cohort study of 141,170 patients with type 2 diabetes newly treated with noninsulin antidiabetic drugs, with 552,413 person years of follow-up. Of these, 30,488 patients (21.6%) received at least one prescription for a dipeptidyl peptidase-4 inhibitor, and median duration of use was 1.6 years.

The report was published March 21 in the BMJ .

The researchers found that dipeptidyl peptidase-4 (DPP-4) inhibitors were associated with a 75% increased risk of IBD, compared with other antidiabetic drugs (53.4 vs. 34.5 per 100,000 per year, 95% confidence interval, 1.22-2.49).

The risk increased with longer duration of use, peaking at a nearly threefold increase in the risk of IBD after 3-4 years of taking DPP-4 inhibitors (hazard ratio 2.9, 95% CI, 1.31-6.41), and declining to a 45% increase in risk with 4 years of use.

“Although the absolute risk is low, physicians should be aware of this possible association and perhaps refrain from prescribing dipeptidyl peptidase-4 inhibitors for people at high risk (that is, those with a family history of disease or with known autoimmune conditions),” wrote Devin Abrahami of McGill University, Montreal, and coauthors. “Moreover, patients presenting with persistent gastrointestinal symptoms such as abdominal pain or diarrhoea should be closely monitored for worsening of symptoms.”

The same pattern was seen with years since initiation of medication, with a peak in the risk of IBD seen at 3-4 years after initiation followed by a decline.

“This gradual increase in the risk is consistent with the hypothesis of a possible delayed effect of the use of dipeptidyl peptidase-4 inhibitors on the incidence of inflammatory bowel disease,” the authors wrote.

When compared directly with insulin, the use of DPP-4 inhibitors was associated with an over twofold increase in the risk of IBD (HR, 2.28, 95% CI, 1.07-4.85).

The use of DPP-4 inhibitors was also associated with a greater than twofold increase in the risk of ulcerative colitis but no significant effect was seen for Crohn’s disease. However, the authors noted that this result was based on relatively few events and should be interpreted with caution.

The research did not find any difference in risk across different DPP-4 inhibitor drugs.

The DPP-4 enzyme is known to be expressed on the surface of cell types involved in immune response, and patients with IBD have been found to have lower serum DPP-4 enzyme concentrations than healthy controls.

Yet the authors said this was the first study to their knowledge that specifically investigated the effect of DPP-4 inhibitor use on the incidence of IBD.

One previous observational study actually found a decreased risk of a composite outcome of several autoimmune disorders – including IBD – with the use of DPP-4 inhibitors, but it did not report on IBD specifically. The authors also noted that DPP-4 may have a different biological function in IBD.

The Canadian Institutes of Health Research funded the study. No conflicts of interest were declared.

SOURCE: Abrahami D et al. BMJ. 2018;360:k872 .