DPP-4 Inhibitors: How They Work for Diabetes and What Else They Might Treat

What the researchers found

DPP-4 is a widely expressed enzyme that clips dipeptides from the N-terminus of peptides containing proline or alanine at position 2. Its most clinically relevant targets are the incretin hormones GLP-1 and GIP, which regulate blood glucose. Several families of DPP-4 inhibitors have been developed, and multiple gliptins are now approved for type 2 diabetes based on their ability to preserve incretin activity and improve glycemic control.

Beyond diabetes, this review highlights that DPP-4 has many other peptide substrates involved in immune regulation, inflammation, and cell signaling — suggesting gliptins could potentially be repurposed for other therapeutic areas.

Why it matters

DPP-4 inhibitors were one of the first peptide-based therapeutic strategies to achieve widespread clinical use in diabetes. Understanding how these drugs protect incretins from enzymatic degradation provides a foundation for understanding the newer GLP-1 receptor agonists (like semaglutide and tirzepatide) that took a different approach to the same problem. The review also flags the broader biological significance of DPP-4, which remains relevant as researchers explore incretin biology beyond blood sugar control.

How the study worked

This is a Perspective article published in the Journal of Medicinal Chemistry. It reviews the biological functions of DPP-4, the structure-activity relationships of various DPP-4 inhibitor families, their clinical development for type 2 diabetes, and emerging evidence for non-diabetic applications. It synthesizes data from preclinical models and clinical trials.

What this study cannot tell us

As a review/perspective article, this does not present new experimental data. The discussion of non-diabetic applications is largely based on preclinical evidence and mechanistic reasoning rather than clinical trials. The field has advanced considerably since 2014, and some predictions about future applications may not have panned out.

How to read the evidence

This is a review/perspective article that synthesizes existing literature rather than presenting original clinical data. While published in a high-impact journal and authored by an expert, it provides indirect evidence through aggregation of other studies' findings.

When this study was published

Published in 2014, this review predates the obesity drug revolution driven by semaglutide and tirzepatide. The core DPP-4 biology remains accurate, but the therapeutic landscape has shifted significantly since publication.

The bigger picture

DPP-4 inhibitors represent an important chapter in incretin-based medicine. While GLP-1 receptor agonists have since overtaken gliptins in terms of efficacy for both diabetes and obesity, understanding DPP-4's role in peptide metabolism remains foundational. This review connects the enzyme's broad substrate specificity to potential therapeutic applications in immunology, oncology, and inflammation — areas still being explored over a decade later.

Questions still open

• Have any non-diabetic applications of DPP-4 inhibitors been clinically validated since this review was published?
• How does the broad substrate specificity of DPP-4 affect the long-term safety profile of gliptins?
• Why did GLP-1 receptor agonists ultimately prove more effective than DPP-4 inhibitors for both diabetes and weight loss?

Common questions

Read the original research

Dipeptidyl peptidase IV and its inhibitors: therapeutics for type 2 diabetes and what else?

Journal of medicinal chemistry, 57(6), 2197-212

Citation

Juillerat-Jeanneret, Lucienne. (2014). Dipeptidyl peptidase IV and its inhibitors: therapeutics for type 2 diabetes and what else?. Journal of medicinal chemistry, 57(6), 2197-212. https://doi.org/10.1021/jm400658e