Dipeptidyl Peptidase 4 Inhibitors and Risk of Inflammatory Bowel Disease: Real-world Evidence in U.S. Adults

Abstract

A recent study raises concerns that dipeptidyl peptidase 4 inhibitors (DPP4i) are associated with increased risk of inflammatory bowel disease (IBD). We evaluated the association between new use of DPP4i and IBD risk compared with other secondline antihyperglycemics. RESEARCH DESIGN AND METHODS We implemented an active-comparator, new-user cohort design using two U.S. administrative claims databases for commercially insured (MarketScan) and older adult (Medicare fee-for-service, 20% random sample) patients from January 2007 to December 2016. We identified patients, aged ‡18 years, who initiated DPP4i versus sulfonylureas (SUs) or initiated DPP4i versus thiazolidinediones (TZDs) and were without prior diagnosis, treatment, or procedure for IBD. The primary outcome was incident IBD, defined by IBD diagnosis preceded by colonoscopy and biopsy and followed by IBD treatment. We performed propensity score weighting to control for measured baseline confounding, estimated adjusted hazard ratios (aHRs [95% CI]) using weighted Cox proportional hazards models, and used randomeffects meta-analysis models to pool aHRs across cohorts. RESULTS We identified 895,747 eligible patients initiating DPP4i, SU, or TZD; IBD incidence rates ranged from 11.6 to 32.3/100,000 person-years. Over a median treatment duration of 1.09-1.69 years, DPP4i were not associated with increased IBD risk across comparisons. The pooled aHRs for IBD were 0.82 (95% CI 0.41-1.61) when comparing DPP4i (n 5 161,612) to SU (n 5 310,550) and 0.76 (0.46-1.26) when comparing DPP4i (n 5 205,570) to TZD (n 5 87,543). CONCLUSIONS Our population-based cohort study of U.S. adults with diabetes suggests that shortterm DPP4i treatment does not increase IBD risk. Dipeptidyl peptidase 4 inhibitors (DPP4i), a commonly prescribed second-line glucose-lowering drug (GLD) class, reduce hyperglycemia by increasing the levels of incretin hormones, which in turn increase insulin and decrease glucagon in a glucose-dependent fashion (1). DPP4, also known as CD26, is expressed on leukocytes and can inactivate various cytokines as well as act as a costimulator of T lymphocytes (2), thus raising concerns about potential immunologic effects of DPP4i (3). A recent

Safety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials

“…patients with end-stage renal disease) and the population appeared to be similar to real-world patients. 60 , 61 Therefore, none of the studies was downrated because of concerns of applicability. Most RCTs were performed in Western countries.…”

GLP-1 based therapies and disease course of inflammatory bowel disease

“…Conflicting results exits on the association between DPP-4 inhibitors and risk of IBD with one study showing increased risk of IBD in patients treated with DPP-4 inhibitors [15] and another study showing no association [16] . However, to the best of our knowledge, no previous studies have examined the disease course in IBD patients treated with GLP-1-receptor agonists and/or DPP-4 inhibitors.…”

“…It is unclear which impact treatment with GLP-1 based therapies has on the development of IBD [ 15 , 16 ] and subsequent disease course. We therefore also applied a design, including both prevalent and new users, and here, we observed a similar lower IRR as compared with the main analysis including new users only.…”

“…Although animal studies have shown that treatment with DPP-4 inhibitors and GLP-1 receptor agonists alleviate gut inflammation in mice [ 13 , 14 ], their role in patients with IBD is unclear. Observational studies have examined the association between treatment with DPP-4 inhibitors and risk of incident IBD [ 15 , 16 ], but to our knowledge, no studies have assessed the disease course in IBD patients treated with GLP-1-receptor agonists and/or DPP-4 inhibitors.…”

Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

“…However, the mean follow-up period was only 1.5 years. Wang et al [ 101 ] also evaluated this association in the real-world setting using the insurance databases and compared the risk of IBD between DPP-4i with sulfonylurea and thiazolidinedione users. During a median duration of 1.09–1.69 years, DPP-4i was not found to be associated with a risk of IBD.…”