DPP-4 inhibitors associated with risk of cholecystitis, meta-analysis finds

Patients with type 2 diabetes who were randomized to receive dipeptidyl peptidase-4 (DPP-4) inhibitors had higher rates of gallbladder disease than those who got placebo or nonincretin drugs, but no difference in risk of cholelithiasis or biliary diseases.

Dipeptidyl peptidase-4 (DPP-4) inhibitors may increase risk of cholecystitis, according to a new systematic review of randomized controlled trials.

The pairwise meta-analysis included randomized controlled trials in which DPP-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors were compared with placebo or other diabetes drugs in 104,833 adults with type 2 diabetes. The main outcomes were a composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. Results were published by The BMJ on June 28.

In 82 trials that compared DPP-4 inhibitors with placebo or nonincretin drugs, DPP-4s were significantly associated with increased risk of the composite outcome of gallbladder or biliary disease (odds ratio [OR], 1.22 [95% CI, 1.04 to 1.43]; risk difference, 11 more events per 10,000 person-years) and cholecystitis (OR, 1.43 [95% CI, 1.14 to 1.79]; risk difference, 15 more events per 10,000 person-years). DPP-4 inhibitors were not associated with any increase in risk of cholelithiasis and biliary diseases. In the study's network meta-analysis of 184 trials, DPP-4 inhibitors increased the risk of gallbladder or biliary diseases and cholecystitis compared with SGLT-2 inhibitors but not compared with GLP-1 receptor agonists.

The study authors noted that the association between DPP-4 inhibitors and gallbladder or biliary diseases was more common in patients taking the drugs for a longer period; since the duration of therapy “is usually longer in routine practice than in clinical trials, awareness of the role of treatment duration might be of great clinical importance,” they said. The authors suggested that the observed effects might be due to the roles of GLP-1 and glucose-dependent insulinotropic polypeptide, which could suggest that the findings may extend to related drug classes.

“This study highlights the importance and raises awareness of the risks of cholecystitis with dipeptidyl peptidase-4 inhibitors for physicians and should encourage researchers to make them predefined safety endpoints,” said the authors, who also noted that the absolute risk was small and should be weighed against the benefits of DPP-4 inhibitor treatment.