GLP-1 (Glucagon-Like Peptide-1)

GLP-1 (glucagon-like peptide-1) is a 30- or 31-amino-acid peptide hormone produced primarily by enteroendocrine L-cells in the ileum and colon. It belongs to the incretin family — hormones released in response to nutrient ingestion that amplify insulin secretion in a glucose-dependent manner.

Biological functions

GLP-1 has four principal actions relevant to metabolic health:

1. Insulin secretion — GLP-1 binds its receptor on pancreatic beta cells and potentiates glucose-dependent insulin release. The glucose-dependent part is critical: unlike sulfonylureas, GLP-1 signaling doesn't cause insulin secretion at low blood sugar, dramatically reducing hypoglycemia risk.
2. Glucagon suppression — GLP-1 inhibits alpha-cell glucagon secretion, reducing hepatic glucose output. This complements the insulin effect to lower postprandial blood sugar.
3. Gastric emptying — GLP-1 slows gastric emptying (the rate at which food leaves the stomach), contributing to earlier satiety and reduced postprandial glucose spikes.
4. Appetite regulation — GLP-1 receptors in the hypothalamus and brainstem mediate central appetite suppression. This is the mechanism behind the dramatic weight-loss effects of GLP-1 receptor agonists.

The half-life problem

Native GLP-1 has a plasma half-life of approximately 2 minutes. The enzyme DPP-4 (dipeptidyl peptidase-4) rapidly cleaves GLP-1 at position 2, inactivating it. This extreme brevity makes native GLP-1 therapeutically impractical.

Two drug-design strategies emerged:

• DPP-4 inhibitors (sitagliptin, saxagliptin) — block the enzyme that degrades GLP-1, raising endogenous levels by 2-3x. Modest efficacy.
• GLP-1 receptor agonists — synthetic peptides modified to resist DPP-4 cleavage and bind albumin for extended half-life. This is where semaglutide (half-life ~7 days), liraglutide (~13 hours), and tirzepatide (~5 days) sit.

GLP-1 receptor agonists

The progression of GLP-1 drug development:

Exenatide (Byetta, 2005) — derived from Gila monster venom (exendin-4). Twice-daily injection. The first approved GLP-1 RA.

Liraglutide (Victoza/Saxenda, 2010/2014) — acylated human GLP-1 analog. Daily injection. First GLP-1 RA approved for obesity (Saxenda).

Semaglutide (Ozempic/Wegovy/Rybelsus, 2017-2021) — further-modified with albumin-binding fatty acid chain. Weekly injection or daily oral. The STEP trials demonstrated 14.9% weight loss; SELECT showed 20% cardiovascular event reduction.

Tirzepatide (Mounjaro/Zepbound, 2022-2023) — dual GIP/GLP-1 agonist. Weekly injection. SURMOUNT-1 showed 22.5% weight loss — the highest of any approved drug.

Retatrutide (Phase 2, 2023) — triple GLP-1/GIP/glucagon agonist. Phase 2 showed up to 24% weight loss at 48 weeks. Phase 3 trials ongoing.

Beyond metabolic disease

GLP-1 receptor agonists are being investigated for conditions beyond diabetes and obesity:

• Cardiovascular disease — SELECT trial demonstrated 20% MACE reduction with semaglutide
• NASH/MAFLD — semaglutide reduced liver fibrosis markers in Phase 2 trials
• Alzheimer's disease — GLP-1 receptors in the brain; early clinical trials underway
• Addiction — preclinical and observational data suggest reduced alcohol and substance use
• Sleep apnea — SURMOUNT-OSA trial showed tirzepatide reduced apnea severity

The expansion of GLP-1 RA indications beyond metabolic disease is one of the most active areas in clinical medicine.

Related entries

• Semaglutide — the most widely prescribed GLP-1 RA
• Tirzepatide — the dual GIP/GLP-1 agonist
• What Are Peptides? — foundational reference