Association Between DPP4 Inhibitor Use and the Incidence of Cirrhosis, ESRD, and Some Cancers in Patients With Diabetes

J Clin Endocrinol Metab. 2022 Nov 23;107(11):3022-3034. doi: 10.1210/clinem/dgac540.


Context: There are relatively few data on noncardiovascular (non-CV) long-term clinical outcomes of dipeptidyl peptidase 4 inhibitor (DPP4i) treatment.

Objective: We aimed to evaluate some non-CV effects of DPP4is in patients with diabetes.

Methods: Based on data from the National Health Insurance Service database in Korea (2007-2018), we conducted 3 pairwise comparisons of metformin-combined antidiabetic therapies in adult patients with diabetes: DPP4is vs (1) all other oral antidiabetic agents, (2) sulfonylureas/glinides, and (3) thiazolidinediones (TZDs). Major outcomes were liver cirrhosis, end-stage renal disease (ESRD), and cancers in the liver, kidney, and pancreas. Adjusted hazard ratios (HRs) and 95% CIs for the outcomes were estimated using an adjusted Cox model.

Results: Of the 747 124 patients included, 628 217 had received DPP4i therapy for a mean duration of 33.8 ± 25.0 months. Compared with TZD therapy, DPP4i therapy was associated with higher adjusted HRs [95% CIs] for liver cirrhosis (1.267 [1.108-1.449]), ESRD (1.596 [1.139-2.236]), liver cancer (1.117 [1.011-1.235]), and pancreatic cancer (1.158 [1.040-1.290]). Furthermore, apart from liver cirrhosis, a higher risk of each of these outcomes was associated with DPP4i use than with non-DPP4i use. The higher adjusted HRs associated with DPP4i use further increased when patients with long-term exposure to DPP4is were analyzed.

Conclusion: DPP4i therapy in patients with diabetes was associated with a higher risk of liver cirrhosis and cancer, ESRD, and pancreatic cancer than TZD therapy and, except for liver cirrhosis, the risk of these outcomes was greater with DPP4i treatment than with non-DPP4i treatment.

Keywords: big data; cancers; diabetes mellitus; dipeptidyl peptidase 4 inhibitors; end stage renal disease; liver cirrhosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / epidemiology
  • Dipeptidyl Peptidase 4
  • Dipeptidyl-Peptidase IV Inhibitors* / adverse effects
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Incidence
  • Kidney Failure, Chronic* / epidemiology
  • Kidney Failure, Chronic* / etiology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / epidemiology
  • Pancreatic Neoplasms* / complications


  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4