In July 2022, a team from the Department of Endocrinology at Peking Union Medical College Hospital published their research findings in a treatise in one of the four major international general medical journals. The team evaluated the relationship between oral hypoglycemics dipeptidyl peptidase-4 (DPP-4) inhibitors and the incidence of gallbladder or biliary disease through a meta-analysis. The results showed that DPP-4 inhibitors may be associated with an increased risk of cholecystitis.

The world’s first DPP-4 inhibitor was launched in 2006; now DPP-4 inhibitors have become a major class of oral medications for patients with type 2 diabetes because they enable better glycemic control, do not affect body weight, do not increase cardiovascular risk, and pose a low risk of hypoglycemia. There are about 120 million type 2 diabetic patients in China, hence the large base of the population taking DPP-4 inhibitors. Drug safety risk identification of new drugs that have been marketed can reveal safety risks that have not been identified in clinical trials or whose effects are insignificant over the short term, thus of great significance to clinical practices.

Adopting the traditional meta-analysis, the study conducted a comprehensive assessment of DPP-4 inhibitors by including 82 randomized controlled trials with 104,833 patients worldwide. The analysis found that the administration of DPP-4 inhibitors, compared placebo or non-incretin-based drugs, was associated with the increased risk of cholecystitis, especially in the population with prolonged medication use. The study did not find an association between the administration of DPP-4 inhibitors and cholelithiasis or biliary disease.

The study also included 184 randomized controlled trials with 267,676 patients worldwide to conduct a network meta-analysis of the correlation between the use of DPP-4 inhibitors, sodium-glucose co-transporter protein 2 (SGLT-2) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) and gallbladder or biliary disease. The study found that DPP-4 inhibitors were associated with a higher risk of cholecystitis than SGLT-2 inhibitors, and that DPP-4 inhibitors were associated with a similar risk of cholecystitis compared with GLP-1 receptor agonists.

Overall, the absolute risk of cholecystitis associated with DPP-4 inhibitors is small, with only 1.5 additional cholecystitis events per 1,000 persons at a one-year follow-up. The mechanism for the increase in cholecystitis events is unclear for the time being. The study suggests that clinicians and patients, especially those taking these drugs for long periods of time, need to carefully weigh the benefit-to-risk balance of DPP-4 inhibitor use and make rational decisions.

The professor who is the Associate Editor-in-Chief of NEJM Journal Watch spoke highly of the value of the study in informing clinical medication: “Gallbladder and biliary disease are uncommon in this population with or without the use of DPP-4 inhibitors. However, given the widespread use of DPP-4 inhibitors and GLP-1 receptor agonists, the small increase in risk of gallbladder and biliary disease is still of concern and should probably be discussed with patients, especially those on long-term use of these drugs.”

With funding from the Major Program of the National Natural Science Foundation of China, among others, the endocrinology research team of PUMCH stays committed to the research on post-marketing adverse reactions of endocrine drugs based on multiple data sources (including electronic medical records and online databases) combined with AI. Their previous relevant research results were published in top journals and served as basis for the FDA to revise the corresponding drug instructions.

Written by: The Department of Endocrinology and Gan Dingzhu

Translator: Liu Haiyan

Editor: Yang Hongbo and Wang Yao