GLP-1 Agonists in Research

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L-cells in response to nutrient intake. It potentiates glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying, and reduces appetite via central GLP-1 receptors. Native GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) with a plasma half-life of roughly 2 minutes, which drove decades of work to engineer stable, long-acting receptor agonists.

Exendin-4 (Exenatide)

Exendin-4 is a 39-amino-acid peptide originally isolated from the saliva of Heloderma suspectum (Gila monster). It shares ~53% homology with human GLP-1 but resists DPP-4 cleavage, giving it a half-life near 2.4 hours. It was the first GLP-1 receptor agonist approved for type 2 diabetes (Eng et al., J Biol Chem, 1992) and remains a benchmark mono-agonist in receptor research.

Semaglutide

Semaglutide is a long-acting GLP-1 analog with two amino-acid substitutions and a C18 fatty-acid chain attached via a linker, enabling reversible albumin binding. Its terminal half-life is approximately 165 hours (~7 days), supporting once-weekly dosing. The STEP and SUSTAIN clinical programs established its effects on HbA1c and body weight (Wilding et al., N Engl J Med, 2021).

Tirzepatide

Tirzepatide is a synthetic 39-amino-acid peptide engineered as a dual GIP and GLP-1 receptor agonist. It is biased toward GIP receptor activation while retaining GLP-1 agonism, with a half-life around 5 days. The SURPASS and SURMOUNT trials demonstrated greater HbA1c and body-weight reductions than GLP-1 monotherapy in head-to-head studies (Frías et al., N Engl J Med, 2021; Jastreboff et al., NEJM, 2022).

Retatrutide

Retatrutide is a triple agonist at the GIP, GLP-1, and glucagon receptors. Glucagon receptor activation is hypothesized to add energy-expenditure effects on top of the appetite and insulinotropic actions of GIP/GLP-1. Phase 2 data reported mean weight reductions of up to ~24% at 48 weeks in adults with obesity (Jastreboff et al., N Engl J Med, 2023). It remains investigational.

Receptor Selectivity at a Glance

• Exendin-4 / Semaglutide: GLP-1R selective mono-agonists.
• Tirzepatide: GIP-R + GLP-1R dual agonist.
• Retatrutide: GIP-R + GLP-1R + glucagon-R triple agonist.

References

• Eng J, et al. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. J Biol Chem. 1992;267(11):7402–7405.
• Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989–1002.
• Frías JP, et al. Tirzepatide versus semaglutide once weekly in type 2 diabetes. N Engl J Med. 2021;385:503–515.
• Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity. N Engl J Med. 2023;389:514–526.