GLP-1 receptor agonists (glucagon-like peptide-1 receptor agonists) are medications that mimic the action of an endogenous incretin hormone, GLP-1. Originally developed to treat type 2 diabetes mellitus, these metabolic signaling analogs have become widely known for their highly effective role in chronic weight management and in reducing cardiovascular risk.
In humans, native GLP-1 is secreted by intestinal L-cells in response to nutrient ingestion. Still, it is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), giving it a half-life of only a few minutes. GLP-1 drugs are structurally engineered peptides designed to resist DPP-4 degradation, allowing for prolonged therapeutic activity. They exert their metabolic effects by binding to the G-protein-coupled GLP-1 receptor, triggering downstream intracellular signaling:
In the pancreas, GLP-1 drugs stimulate glucose-dependent insulin secretion from pancreatic beta cells and suppress inappropriate glucagon secretion from alpha cells. Because this mechanism is glucose-dependent, the risk of hypoglycemia is low.
GLP-1 drugs slow gastric emptying, thereby delaying postprandial glucose absorption and prolonging satiety.
In the Central Nervous System, GLP-1 drugs cross the blood-brain barrier to act directly on the hypothalamus and hindbrain, signaling fullness, decreasing appetite, and reducing food cravings.
“P-1 reduces blood glucose levels by acting on different pancreatic cell types.
In β cells, GLP-1(7–36) activates the GLP-1 receptor (GLP‑1R), increasing intracellular cAMP levels and subsequently activating PKA and CREB, leading to enhanced insulin secretion. The PI3K/Akt pathway further increases glucose sensitivity in β cells and promotes insulin secretion. This pathway also supports β‑cell survival and proliferation, helping maintain sufficient β‑cell mass to sustain normal insulin output. Overall, these signaling cascades increase insulin gene expression, enhance protein synthesis, improve cell survival, and reduce apoptosis. Additional metabolic effects include stimulation of fatty acid oxidation, inhibition of gluconeogenesis, and increased energy expenditure.
In α cells, GLP‑1(7–36) primarily regulates function through indirect mechanisms. Because GLP‑1R expression is lower in α cells than in β and δ cells, the direct effects of GLP‑1 on α cells are relatively limited. Through paracrine signaling from β cells, GLP‑1 enhances insulin secretion, which in turn suppresses glucagon release from α cells. GLP‑1 also stimulates somatostatin secretion from δ cells, further inhibiting glucagon secretion. GLP‑1(7–36) can directly suppress glucagon secretion in α cells by increasing cAMP, activating PKA and EPAC, reducing intracellular calcium levels, and thereby decreasing glucagon release. GLP‑1(9–36) inhibits glucagon secretion through a GCGR‑dependent mechanism by activating inhibitory G proteins (Gi/o) and suppressing PKA activity. By promoting the undocking of secretory granules, GLP‑1(9–36) reduces the number of granules available for exocytosis, further limiting glucagon release.
δ cells primarily secrete somatostatin. GLP‑1(7–36) regulates somatostatin secretion by modulating calcium channels and influencing changes in membrane potential. The effects of GLP‑1(7–36) on δ cells may also be indirect, mediated through insulin and glucagon released by β and α cells, respectively, which can alter somatostatin secretion. Additionally, somatostatin inhibits gastrointestinal activity, reducing pancreatic enzyme secretion and gastric acid secretion, thereby indirectly decreasing glucagon demand.
Figure modified from Zheng et al (2024), an open access publication. glp1_cellular_moa. {Zheng Z, et al. (2024): Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy. 9:234. PMC}"
GLP-1 drugs include pure GLP-1 single agonists as well as newer multi-receptor agonists (twincretins or triagonists) that target complementary metabolic pathways, such as GIP (glucose-dependent insulinotropic polypeptide) or glucagon receptors.
Table: FDA-approved GLP-1 (glucagon-like peptide-1) receptor agonist drugs
| Molecule | Type/Target | Common Brand Names | Primary Clinical Indications |
| Semaglutide | Pure GLP-1R agonist | Ozempic, Wegovy, Rybelsus | Type 2 Diabetes, Weight Managment, MACE reduction |
| Tirzepatide | Dual GIP/GLP-1R agonist | Monjaro, Zepbound | Type 2 Diabetes, Weight Management |
| Liraglutide | Pure GLP-1R agonist | Victoza, Saxenda | Type 2 Diabetes, Weight Management (daily) |
| Dulaglutide | Pure GLP-1R agonist | Trulicity | Type 2 Diabetes |
Half-life extension of the drugs is possible via structural engineering
To move from daily or continuous administration to weekly dosing, molecular modifications are made to the peptide backbone:
Fatty Acid Acylation: In molecules like semaglutide and tirzepatide, a hydrophobic fatty acid chain is conjugated via a linker to a specific amino acid residue. Fatty acid acylation enables reversible binding to serum albumin, shielding the peptide from renal clearance and enzymatic breakdown.
Sequence Substitution: Amino acid substitutions, such as replacing alanine with alpha-aminobutyric acid or synthetic analogs at position 2, directly prevent DPP-4 recognition and cleavage.