DPP4 Inhibitor Mechanism of Action

Physiology of the DPP4 enzyme in glucose metabolism

Dipeptidyl peptidase-4 (DPP4) is a multifunctional enzyme expressed on the surface of a variety of cell types, including immune, epithelial, and endothelial cells. DPP4 plays a significant role in numerous physiological processes, such as glucose metabolism, immune regulation, and inflammation.

DPP4 is crucial in the process of glucose metabolism process, where it modulates insulin secretion by cleaving incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP are hormones secreted from the intestine in response to food consumption, and stimulate insulin secretion while decreasing glucagon secretion, resulting in increased glycemic control. The cleaving action of DPP4 on these hormones attenuates their activity and potentially contributes to impaired insulin secretion.

Mechanism of action of DPP4 inhibitors

The action mechanism of Dipeptidyl peptidase-4 (DPP4) inhibitors revolves around inhibiting the activity of DPP4, the enzyme responsible for degrading incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). As explained previously, these incretin hormones are secreted from the gut after food intake, and they stimulate insulin secretion while reducing glucagon secretion, leading to improved glycemic control.

mechanism of action of DPP4 inhibitors

By impeding the degradation of GLP-1 and GIP by DPP4, DPP4 inhibitors lead to elevated levels of these hormones in the blood. As a result, incretins can exert their physiological effects of boosting insulin secretion and reducing glucagon secretion, which ultimately leads to lower blood glucose levels.

Practice Guide for DPP4 Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors display structural heterogeneity, leading to differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties between this class of drugs.

For example, sitagliptin is primarily eliminated unchanged through the urinary system, while Vildagliptin is metabolized in the kidneys in an inactive metabolites, with about a quarter of it being excreted unchanged in the urine. On the other hand, saxagliptin undergoes substantial metabolism in the liver, producing an active metabolite that is subsequently eliminated via the urinary route.

Uniquely, Linagliptin is the sole DPP-4 inhibitor completely expelled through the biliary system. This distinctive elimination pathway positions Linagliptin as the DPP-4 inhibitor of choice for patients with all stages of kidney failure, as it does not require dose adjustments.

Table. Pharmacologic properties of various DPP4 inhibitors

Drug Name (Trade name)Dose RangeMaximum Daily DoseFrequencyOnset of ActionDuration of Action
Sitagliptin (Januvia)25–100 mg daily100 mgOnce daily1 to 4 hours24 hours
Linagliptin (Tradjenta)5 mg daily5 mgOnce daily1.5 hours24 hours
Saxagliptin (Onglyza)2.5–5 mg daily5 mgOnce daily2 hours24 hours
Alogliptin (Nesina)12.5–25 mg daily25 mgOnce daily2-3 hours24 hours


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