What is the mode of action of Dipeptidyl Peptidase-4 (DPP4) inhibitors?

Mode of Action of DPP-4 Inhibitors

DPP-4 inhibitors work by preventing the degradation of incretin hormones, thereby increasing insulin secretion and reducing glucagon secretion in a glucose-dependent manner, which improves glycemic control without causing hypoglycemia or weight gain.

Primary Mechanism of Action

DPP-4 inhibitors target the enzyme dipeptidyl peptidase-4, which is responsible for the rapid degradation of incretin hormones. Their mechanism involves:

• Incretin hormone preservation: DPP-4 inhibitors prevent the breakdown of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), extending their half-life and biological activity 1, 2

• Glucose-dependent insulin secretion: By increasing active GLP-1 and GIP levels, DPP-4 inhibitors stimulate insulin biosynthesis and secretion from pancreatic beta cells, but only in the presence of elevated blood glucose 2

• Glucagon suppression: GLP-1 reduces glucagon secretion from pancreatic alpha cells, resulting in decreased hepatic glucose production 2

Physiological Sites of Action

DPP-4 inhibitors work at multiple sites throughout the body:

1. Systemic circulation: Inhibition of DPP-4 in plasma prevents inactivation of circulating incretin hormones 3

2. Intestinal action:

   • DPP-4 is highly expressed on intestinal epithelial cells
   • Local inhibition of intestinal DPP-4 prevents immediate degradation of newly released GLP-1 4
   • This intestinal action may activate the gut-to-pancreas neural axis via the vagus nerve 4

3. Pancreatic islets:

   • DPP-4 inhibition in islets prevents local inactivation of GLP-1
   • This enhances insulin secretion and inhibits glucagon secretion 5
   • May also have anti-inflammatory effects on islet cells 5

Pharmacological Characteristics

• Glucose dependency: Unlike sulfonylureas, DPP-4 inhibitors stimulate insulin secretion only when blood glucose is elevated, minimizing hypoglycemia risk 3, 6

• Weight neutrality: DPP-4 inhibitors do not cause weight gain, unlike some other antidiabetic medications 6

• Selectivity: DPP-4 inhibitors selectively bind to and inhibit DPP-4 but not closely related enzymes like DPP-8 or DPP-9 1, 2

Additional Mechanisms and Effects

• Prevention of bioactive dipeptide formation: DPP-4 inhibitors prevent the formation of dipeptides (His-Ala from GLP-1 and Tyr-Ala from GIP) that may have negative effects on glucose tolerance 4

• Protection of other substrates: Beyond incretins, DPP-4 inhibitors may preserve other bioactive peptides such as stromal-derived factor-1α and pituitary adenylate cyclase-activating polypeptide, which could contribute to their effects 5

• Potential beta-cell preservation: Some evidence suggests DPP-4 inhibitors may inhibit beta-cell apoptosis and potentially favor regeneration and differentiation 7

Clinical Implications

• Moderate efficacy: DPP-4 inhibitors provide moderate HbA1c reduction (0.4-0.9%), less potent than GLP-1 receptor agonists but with better tolerability 6

• Low hypoglycemia risk: When used as monotherapy, DPP-4 inhibitors have minimal risk of hypoglycemia 3

• Cardiovascular considerations: Cardiovascular outcomes trials have demonstrated cardiovascular safety but no cardiovascular benefit for sitagliptin, saxagliptin, and alogliptin 3, 6

• Caution in heart failure: Saxagliptin and alogliptin have been associated with a potential increased risk of heart failure hospitalization 3

DPP-4 inhibitors represent a unique approach to diabetes management by enhancing the body's natural incretin system rather than directly stimulating insulin secretion or improving insulin sensitivity, making them particularly suitable for earlier stages of type 2 diabetes when significant endogenous insulin production remains.