DPP-4

Dipeptidyl peptidase-4 (DPP-4), also known as the T-cell antigen CD26, is a serine protease found on the surface of many cell types and as a soluble form circulating in plasma. It removes N-terminal dipeptides from peptides whose second residue is proline or alanine. GLP-1(7-36)amide (His-Ala) and GIP (Tyr-Ala) are among its best-established physiological substrates; cleavage produces truncated metabolites, GLP-1(9-36)amide and GIP(3-42), that no longer act effectively at their receptors. Inhibiting DPP-4 raises levels of the intact incretins, which is the basis of the DPP-4 inhibitor (gliptin) class of oral diabetes medicines.

Human studies show that GLP-1 given under the skin or into a vein is rapidly degraded from its N-terminus, leaving only a small fraction intact. Two drug strategies grew from this: DPP-4 inhibitors such as sitagliptin and vildagliptin, which protect the body's own incretins, and DPP-4-resistant GLP-1 receptor agonists. Semaglutide, for example, replaces the alanine at position 8 with the unnatural amino acid Aib, which prevents DPP-4 cleavage.

DPP-4 is the main reason natural GLP-1 cannot be used as a long-acting medicine. Laboratory work in the early 1990s showed that the enzyme cuts GLP-1 and GIP at their second amino acid, and human studies soon confirmed that injected GLP-1 is degraded within minutes. Because an intact N-terminus is needed for these hormones to activate their receptors, a single cut is enough to switch them off. Much of incretin drug development has been shaped by the need to work around this one enzyme.

Two separate drug classes came from that insight. DPP-4 inhibitors, taken by mouth, slow the breakdown of the body's own GLP-1 and GIP, giving modest glucose lowering with a low risk of hypoglycemia and no weight gain. GLP-1 receptor agonists take the opposite route, using molecules engineered to resist DPP-4 so that they act far longer than the natural hormone. The two approaches are related but not interchangeable, and they differ in effect size, side effects and route of administration.

DPP-4 also matters when judging claims about other peptides. The enzyme can cleave many peptides in the test tube, but only a few, including GLP-1, have been shown to be true physiological substrates in people. Any peptide with proline or alanine in the second position is a potential target, so a claim that an unapproved peptide is stable in the body needs measured human pharmacokinetic data rather than an assumption.

“DPP-4 inhibitors and GLP-1 receptor agonists are the same kind of drug”

Both act on the incretin system, but differently. DPP-4 inhibitors protect the body's own GLP-1 and GIP from breakdown, so their effect is limited by how much hormone is released. GLP-1 receptor agonists directly stimulate the receptor at higher, sustained levels. In clinical studies the agonists generally produce larger reductions in glucose and body weight.

“DPP-4 only acts on GLP-1”

DPP-4 also inactivates GIP and can cleave a range of other peptides with proline or alanine in the second position. It has non-enzymatic roles too, including functions in the immune system as the CD26 antigen. Only a small number of its in-vitro substrates have been confirmed as physiological targets in humans.

“Every GLP-1 drug is a DPP-4 inhibitor”

Semaglutide, liraglutide and other GLP-1 receptor agonists are not DPP-4 inhibitors. They are modified versions of GLP-1, or related peptides such as exenatide, that resist DPP-4 cleavage. DPP-4 inhibitors such as sitagliptin are small molecules that block the enzyme itself.

What does DPP-4 do in the body?

DPP-4 is an enzyme on cell surfaces and in plasma that removes two amino acids from the front of certain peptides. Its best-characterized job is inactivating the incretin hormones GLP-1 and GIP after a meal. It also works as a binding protein and as the immune-cell marker CD26, and its wider role in metabolism is still being studied.

How do DPP-4 inhibitors work?

DPP-4 inhibitors, often called gliptins, block the enzyme so that the body's own GLP-1 and GIP stay active for longer. Higher levels of intact incretins increase glucose-dependent insulin release and reduce glucagon. Early clinical studies of sitagliptin and vildagliptin showed modest HbA1c reductions with few adverse events and no weight gain.

How does semaglutide resist DPP-4?

Semaglutide differs from human GLP-1 at position 8, where alanine is replaced by aminoisobutyric acid (Aib), an unnatural amino acid that DPP-4 cannot cleave efficiently. Together with a fatty acid side chain that binds albumin, this change underpins its long half-life of about a week in people, compared with minutes for native GLP-1.