“Do Not Use” Type 2 Diabetes Gliptin Drugs Also Raise Risk of Gallbladder Inflammation

Gliptins, or dipeptidyl peptidase 4 (DPP-4) inhibitors, are a family of drugs that are used to treat type 2 diabetes.[1] These drugs, a subset of medications called incretin-based drugs, are taken orally and include alogliptin (NESINA), linagliptin (TRADJENTA), saxagliptin (ONGLYZA) and sitagliptin (JANUVIA). Public Citizen’s Health Research Group has classified all drugs in this family as Do Not Use drugs because their limited benefits in reducing blood sugar levels do not outweigh their substantial risks, which include severe joint pain, acute pancreatitis, heart failure and severe skin reactions.[2]

A new study published in June 2022 in BMJ[3] showed that, compared with other diabetes drugs, gliptins put patients at a higher relative risk of a range of gallbladder or biliary diseases, such as gallstones (cholelithiasis) and gallbladder inflammation (cholecystitis, a condition that often requires surgical removal of the gallbladder). Although the absolute risk of these adverse events was relatively low with about 11 additional cases per 10,000 person years, these come in addition to the many already known risks of these drugs.

The drug families included in the study

When patients with type 2 diabetes cannot maintain their target blood sugar level with diet and exercise alone, physicians may prescribe one or more diabetes medications.

There are a number of drug classes that all work in different ways to reduce blood sugar levels.

The new study compared gliptins with several other diabetes drug families in two separate meta-analyses (studies that analyze pooled data from multiple other studies).[4] One meta-analysis included 82 trials that compared gliptins with non-incretin–based drugs or placebo. In another meta-analysis, the researchers included 184 studies that compared gliptins with two other diabetes drug classes (glucagon-like peptide 1 receptor agonists and flozins) or with standard care, other types of diabetes drugs or placebo.

Glucagon-like peptide 1 receptor agonists

Glucagon-like peptide 1 receptor agonists (also called incretin mimetics) are, like gliptins, incretin-based, although nearly all drugs in this class have to be injected. Incretin mimetics include dulaglutide (TRULICITY), exenatide (BYDUREON BCISE, BYETTA), liraglutide (SAXENDA, VICTOZA), lixisenatide (ADLYXIN) and semaglutide (OZEMPIC, RYBELSUS, WEGOVY). Drugs in this family also have been designated as Do Not Use by Public Citizen’s Health Research Group because the limited benefits of these drugs do not outweigh the serious adverse effects, including cardiovascular risks, pancreatitis, and pancreatic and thyroid cancer.[5]

Flozins

Unlike gliptins and incretin mimetics, “flozins,” or sodium-glucose cotransporter 2 (SGLT-2) inhibitors are non-incretin diabetes drugs. Flozins are taken orally and include canagliflozin (INVOKANA), dapagliflozin (FARXIGA), empagliflozin (JARDIANCE) and ertugliflozin (STEGLATRO).

The results of the new study[6]

The set of studies that compared gliptins, flozins and incretin mimetics with each other, with placebo or with other anti-diabetic drugs demonstrated that patients with type 2 diabetes were at an increased risk of developing gallbladder or biliary diseases when they were taking one of the two incretin-based drugs, gliptins or incretin mimetics compared with patients taking flozins, other diabetes drugs or placebo.

For example, compared with patients taking flozins, those who were taking gliptins had a 55% higher relative risk of developing gallbladder inflammation, and those taking incretin mimetics had a 46% higher relative risk. Patients taking gliptins or incretin mimetics were 31% and 46% more likely to develop gallstones, respectively, than those who were taking flozins.

In the other set of trials that compared gliptins with non-incretin drugs or placebo, gliptins again increased the relative risk of gallbladder inflammation compared with the other treatments. For example, patients taking gliptins had a 43% higher relative risk of developing gallbladder inflammation than those in the control group, a risk that increased to 51% when patients were taking gliptins for 26 weeks or longer. However, the study also showed that the gliptins only minimally increased patients’ relative risk of gallstones and did not lead to a higher risk of biliary diseases compared with non-incretin drugs or placebo.

The higher risks associated with longer-term treatment are particularly worrisome, because patients tend to take this type of drug for a longer period than the limited period covered in clinical trials. This might mean that patients’ risk of gallbladder and biliary diseases are even higher than indicated in this study.

What You Can Do

Do not use any of the gliptin or incretin mimetic drugs discussed in this article because there is no convincing evidence that they offer greater benefit to patients than other diabetes drugs, but they are associated with significant adverse events. If you are currently taking any of the drugs described above, talk to your doctor to discuss switching to another, safer diabetes drug. Do not stop taking any drug before seeing your doctor.

If you are taking gliptins or incretin mimetic drugs and you experience symptoms related to gallbladder inflammation (including severe pain in the right upper abdomen, often following a high-fat meal, along with nausea, vomiting and fever), ask your doctor to consider whether it could be drug-related.

Report all serious adverse events related to gliptins or other medications to the FDA’s MedWatch adverse event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] A Review of the ‘Gliptin’ Diabetes Drugs. Worst Pills, Best Pills News. March 2012. https://www.worstpills.org/newsletters/view/784. Accessed December 19, 2022.

[2] Food and Drug Administration Warns of Severe Joint Pain with Diabetes Drug. Worst Pills, Best Pills News. September 2015. https://www.worstpills.org/e-alerts/view/116. Accessed December 19, 2022.

[3] He L, Wang J, Ping F, et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials. BMJ. 2022;377:e068882

[4] He L, Wang J, Ping F, et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials. BMJ. 2022;377:e068882

[5] Incretin-Mimetic Drugs: Do Not Use to Treat Diabetes. Worst Pills, Best Pills News. August 2016. https://www.worstpills.org/newsletters/view/1047. Accessed December 6, 2022.

[6] He L, Wang J, Ping F, et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network under meta-analysis of randomised controlled trials. BMJ. 2022;377:e068882