“Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i), exert their actions through potentiation of incretin receptor signaling. Incretins are gut-derived hormones, principally GLP-1 and glucose-dependent insulinotropic peptide (GIP), that are secreted at low basal levels in the fasting state. Circulating levels increase rapidly and transiently following food ingestion. As native GLP-1 displays a very short circulating half-life due to renal clearance and NH2-terminal degradation by the enzyme DPP-4, degradation-resistant GLP-1R agonists have been developed.” Diabetes Care. 2010
Insulin Secretagogues and Incretin-Based Medications
Both insulin secretagogues and incretin-based medications have MOAs that lead to increased insulin secretion by the beta cells of the pancreas. The secretagogues cause direct Beta cell insulin secretion while the GLP1-receptor agonists and DPP-4 inhibitors do it indirectly through incretins by mimicking them (GLP-1R agonists) or preventing their degradation (DPP-4i). *** Incretins only stimulate glucose-dependent insulin secretion — i.e. insulin secretion with meals that have glucose.
GLP-1 Receptor Agonists (mimick incretins)
GLP–1 Receptor Agonists. GLP-1 and GIP are examples of incretins, a group of hormones that stimulate the pancreas to make insulin. Incretin receptor agonists (also called incretin mimetics) mimick incretins and act on incretin receptors stimulating the pancreas to make insulin. The incretin mimetics currently being used are GLP-1 receptor agonists. They work by activating the GLP-1 receptors, which increases insulin secretion, decreases glucagon secretion, slows or delays gastric emptying, and increases satiety. Because these drugs increase satiety, they are associated with weight loss. Their names end in -tide (peptide). Exenatide (Byetta). Liraglutide (Victoza). GLP-1 analogs. Liraglutide (Victoza) is an injectable drug.
–Associated w/ weight loss. Associated with pancreatitis. Need to adjust the dose in CKD.
GLP-1 agonists are contraindicated in patients with medullary thyroid cancer or multiple endocrine neoplasm syndrome, or with a family history of these conditions.
GLP-1 agonists are resistant to degradation by DPP4 and have a long half-life.
*Agonist=analog. GLP-1 receptor agonist=Glucagon-like Peptide-1 receptors agonists.
Dipeptidyl Peptidase-4 (DPP-4 ) inhibitors (Block degradation of incretins)
Dipeptidyl Peptidase-4 (DPP-4 ) inhibitors —also called Gliptins — block degradation of incretins (GLP-1 & GIP). Incretins stimulate the pancreas to make insulin. Dipeptidyl Peptidase-4 breaks down incretins as a control mechanism. By blocking the degradation of incretins, DPP-4 inhibitors increase incretin levels (GLP-1, GIP), and as such increase insulin secretion.
They work through a mechanism similar to the SSRIs. GLP-4 inhibitor’s names end in gliptin. E.g. Sitagliptin (Januvia)
-They are weight neutral. Associated with pancreatitis. Need to adjust the dose in CKD.
Further Reading
Diabetes Care. 2010;33(2):428-433. Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits.
J Fam Pract. 2010 Sep;59(9 Suppl 1): S20-7. Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies.
dtc.ucsf.edu/types-of-diabetes/type2/treatment-of-type-2-diabetes/medications-and-therapies/type-2-non-insulin-therapies/incretin-based-treatments/