“We expected DPP-4 (dipeptidyl peptidase-4) inhibitors’ antifibrotic effects shown in animal experiments to lead to clinical benefits. Unfortunately, they did not. In diabetes treatment, drugs that have proved various additional benefits, including cardiovascular benefits, appear one after another. Some patients may need colorless and odorless DPP-4 inhibitors, but physicians will need to naturally shift their prescription patterns to other drugs.”

Professor Lee Dae-ho of the Department of Endocrine Metabolism at Gachon Gil University Medical Center said so while explaining his study on DPP-4 inhibitors’ non-cardiovascular safety published in the Journal of Clinical Endocrinology & Metabolism recently.

On Sept. 15, Professor Lee’s team presented a paper titled “Association Between DPP4 Inhibitor Use and the Incidence of Cirrhosis, ESRD, and Some Cancers in Patients with Diabetes.”

Noting the scarcity of data on long-term, non-cardiovascular clinical results of DPP-4 inhibitors, Lee’s team conducted a study on DPP-4 inhibitors’ non-cardiovascular effects compared to other treatments, using data at the National Health Insurance Service (NHIS)’s database.

“DPP-4 inhibitors demonstrated non-inferiority in cardiovascular events compared to placebo through past studies,” Professor Lee said. “However, if there's no difference in cardiovascular safety compared to placebo despite lowering blood sugar, shouldn’t we judge that it increased the risk?”

For similar reasons, Lee brushed aside some researchers’ emphasizing non-inferiority in the cardiovascular outcome trial (CVOT), saying, “It’s nothing but a play on words.” He then explained the background of the study, recalling that experts had looked forward to the antifibrotic effects of DPP-4 inhibitors in past animal experiments."

Researchers carried out three pairwise comparison studies concerning metformin-combined anti-diabetic therapy in adult diabetics using the NHIS data from 2007 to 2018. They compared the DPP-4 inhibitor group with all other oral diabetes drug groups, sulfonylurea/glinide group, and Thiazolidinedione (TZD). They set liver cirrhosis, end-stage renal disease, liver cancer, kidney cancer, and pancreatic cancer as the primary evaluation variables.

As a result, DPP-4 inhibitor treatment was associated with a higher risk for liver cirrhosis, end-stage renal disease, liver cancer, and pancreatic cancer compared with TZD treatment. In addition, DPP-4 inhibitors showed higher risk and relevance in the occurrence of end-stage renal disease, liver cancer, kidney cancer, and pancreatic cancer, except for cirrhosis, compared to all other treatments. These results were more pronounced in the analysis of patients exposed to DPP-4 inhibitors for a long time (additional adjustment risk associated with using DPP-4 inhibitors).

However, Professor Lee asked not to expand interpretation beyond academic evaluation concerning this result. Although researchers set insurance codes least subject to bias, such as cirrhosis, end-stage renal disease, liver cancer, kidney cancer, and pancreatic cancer, as assessment variables, the research had the limitation of retrospective evaluation, he added.

“Clinically, one should not overstretch its meaning to DPP-4 inhibitors increasing the risk of end-stage renal disease, liver cancer, kidney disease, and pancreatic cancer compared to other diabetes treatment clinically,” he said.

Nevertheless, Professor Lee expressed a negative opinion on the current broad use of DPP-4 inhibitors. At a time when a series of drugs that have proved additional benefits, including cardiovascular benefits, such as SLGT-2 inhibitors and GLP-1 analogs, are appearing and recommended in guidelines, there are few good reasons to stick to DPP-4 inhibitors like now.

“DPP-4 inhibitors are colorless, odorless drugs,” he said. “Physicians may use DPP-4 inhibitors to control blood sugar levels of patients leaving the hospital after surgery without worrying about any side effects. However, when drugs with various proven benefits are used, they should not necessarily adhere to DPP-4 inhibitors.”

According to the analysis of diabetes treatment prescription patterns by ingredient in the 2022 diabetes fact sheet released by the Korea Diabetes Association recently, DPP-4 inhibitors accounted for 63.9 percent of prescription ingredients in 2019.