GLP-1 agonists in the literature: semaglutide, tirzepatide, cagrilintide, retatrutide

What are GLP-1 agonists?

GLP-1 (glucagon-like peptide-1) is an endogenous hormone of the incretin family, secreted by the L-cells of the intestine after food intake. The literature describes it as acting through the GLP-1 receptor (GLP-1R) and associates it with:

• glucose-dependent insulin secretion
• inhibition of glucagon secretion
• slowing of gastric emptying
• activation of the GLP-1 receptor in central pathways (hypothalamus, brainstem)

Endogenous GLP-1 is broken down within minutes by the enzyme DPP-4. GLP-1 agonists (GLP-1RAs) are synthetic analogs with modifications such as amino-acid substitutions and the attachment of a fatty-acid chain that binds to albumin. These modifications increase resistance to degradation and extend the half-life. Newer compounds combine activity at the GLP-1 receptor with activity at other receptors: GIP, glucagon or amylin.

The main compounds in published studies

The percentages below are mean changes in body weight from baseline, as published in the respective randomized, placebo-controlled trials. Each trial had a different population, duration and design, so the results cannot be compared directly with one another.

Semaglutide

• Mono-agonist of the GLP-1 receptor, with a fatty-acid chain that binds to albumin; half-life about 7 days.
• In published studies such as the phase 3 STEP 1 trial (1,961 adults with overweight or obesity, 68 weeks), the mean change in body weight was −14.9% versus −2.4% with placebo.
• HbA1c and other metabolic markers are recorded as separate endpoints in several trials of the STEP program.

Tirzepatide

• Dual agonist of the GIP and GLP-1 receptors; a 39-amino-acid peptide with a C20 fatty-acid chain and a half-life of about 5 days.
• In the phase 3 SURMOUNT-1 trial (2,539 adults without diabetes, 72 weeks), the mean change in body weight ranged from −15.0% to −20.9%, depending on the study group, versus −3.1% with placebo.
• In the literature, the additional activity at the GIP receptor is described as the key feature that distinguishes tirzepatide from GLP-1 mono-agonists.

Cagrilintide and its combination with semaglutide

• Cagrilintide is a long-acting amylin analog that acts at the amylin (AMY) and calcitonin (CTR) receptors. Endogenous amylin is co-secreted with insulin by the beta cells of the pancreas.
• In the phase 3 REDEFINE 1 trial (3,417 adults with overweight or obesity, 68 weeks), the combination of cagrilintide and semaglutide was associated with a mean change in body weight of −20.4%, versus −14.9% with semaglutide alone, −11.5% with cagrilintide alone and −3.0% with placebo.
• In the phase 3 REDEFINE 2 trial, in adults with overweight or obesity and type 2 diabetes, the mean change in body weight was −13.7% versus −3.4% with placebo. The change in HbA1c is reported separately in the publication.
• In the Peptology catalog the combination is available as CS10 (cagrilintide + semaglutide).

Retatrutide

• Triple agonist of the GLP-1, GIP and glucagon (GCGR) receptors; a 39-amino-acid peptide with a half-life of about 6 days.
• In the phase 2 trial (338 adults with obesity or overweight, 48 weeks), the mean change in body weight in the highest-dose group studied was −24.2%, versus −2.1% with placebo.
• That trial compared retatrutide with placebo, not with semaglutide or tirzepatide. Comparisons between the available compounds come from meta-analyses of different trials (indirect comparisons), not from head-to-head trials.
• The phase 3 TRIUMPH program is ongoing.

New directions in GLP-1 research

• Non-peptide agonists: small molecules such as orforglipron are being studied as oral GLP-1 receptor agonists without a peptide structure; the first phase 2 data were published in 2023.
• Multi-agonists: after dual (GLP-1/GIP) and triple (GLP-1/GIP/glucagon) agonists, combinations with amylin analogs such as cagrilintide are being studied.
• Extended-release formulations: formulations that release the substance over weeks or months are under investigation.

Mechanisms beyond metabolism

GLP-1 receptors have also been found outside the pancreas: in the heart, the blood vessels, the kidney and the central nervous system. For this reason GLP-1 signaling is also studied in cardiovascular, renal and neurobiological research models. In many of these fields the data are preliminary and do not support conclusions beyond the design of each study.

Conclusion

GLP-1 agonists are among the most extensively studied classes of peptides in metabolic research. The literature describes a stepwise progression: from the mono-agonist (semaglutide) to the dual agonist (tirzepatide), to the combination with an amylin analog (cagrilintide) and to the triple agonist (retatrutide). Each molecule was studied in a different program, with different populations and durations. The published percentages therefore describe each study on its own and do not constitute a ranking of the molecules.

The Peptology products mentioned in this article are intended exclusively for laboratory research and not for human use.

References

1. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metabolism, 2018.
2. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine, 2021.
3. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). New England Journal of Medicine, 2022.
4. Jastreboff AM, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine, 2023.
5. Garvey WT, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). New England Journal of Medicine, 2025.
6. Davies MJ, et al. Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2). New England Journal of Medicine, 2025.
7. Wharton S, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. New England Journal of Medicine, 2023.