Semaglutide

Overview

Semaglutide is a synthetic analogue of glucagon-like peptide-1 (GLP-1), a hormone the gut releases after a meal. Native GLP-1 is degraded within minutes by the enzyme DPP-4; semaglutide is engineered both to resist that degradation and to remain in circulation for days.

Three modifications make the difference: a non-natural amino acid (Aib) at position 8 protects against DPP-4 cleavage, a C18 diacid on Lys26 binds serum albumin, and Arg34 stabilises the molecule. This extends the half-life to about one week: weekly dosing.

Semaglutide is the compound behind several approved medicines (Ozempic, Rybelsus, Wegovy). That regulatory status is a fact about the respective authorities. At Peptalis, semaglutide is available strictly for research use only: in-vitro laboratory research, not for human or animal use.

Mechanism of action

Semaglutide activates the GLP-1 receptor on pancreatic beta cells and in brain regions regulating hunger and satiety. The response is glucose-dependent.

GLP-1 receptor activation

• In the pancreas semaglutide enhances insulin release, but only when blood glucose is elevated (glucose-dependent), limiting the risk of hypoglycaemia.
• It suppresses glucagon (which drives hepatic glucose production), slows gastric emptying and reduces appetite via central brain regions.

Albumin-bound pharmacokinetics

• The C18 diacid tail binds serum albumin reversibly, keeping the molecule in circulation for days.
• A single weekly dose thus sustains receptor activation rather than a brief peak (Lau 2015; Knudsen & Lau 2019).

Research findings

• Preclinical: selected as a GLP-1 analogue with weekly duration, retained receptor potency (Lau 2015)
• SUSTAIN-6 (n=3,297, T2D): primary cardiovascular endpoint 6.6% vs 8.9% placebo, hazard ratio 0.74 (Marso 2016)
• STEP 1 (n=1,961, obesity without diabetes): mean weight change −14.9% vs −2.4% over 68 weeks (Wilding 2021)
• SELECT (n=17,604, CVD without diabetes): primary cardiovascular endpoint 6.5% vs 8.0%, hazard ratio 0.80 (Lincoff 2023)

Preclinical evidence

• Semaglutide was selected as a GLP-1 analogue in which the combination of Aib8 and the C18 diacid linker produced a weekly half-life with retained GLP-1 receptor potency (Lau 2015).
• In animal models of glucose regulation and food intake, semaglutide consistently lowered blood glucose and food intake.

Human studies

• SUSTAIN-6 (Marso 2016): 3,297 people with type 2 diabetes at high cardiovascular risk received 0.5 or 1.0 mg per week; the primary cardiovascular endpoint was 6.6% vs 8.9% (hazard ratio 0.74).
• STEP 1 (Wilding 2021): 1,961 adults without diabetes received 2.4 mg per week; mean weight change −14.9% vs −2.4% over 68 weeks.
• SELECT (Lincoff 2023): 17,604 people with cardiovascular disease without diabetes received 2.4 mg per week; primary cardiovascular endpoint 6.5% vs 8.0% (hazard ratio 0.80).

Research context

This profile describes what has been done and found in research. Regulatory and clinical facts are facts about the respective trials and authorities, not claims about a Peptalis product; the compound is for in-vitro laboratory research only (RUO).

Open questions

• Very-long-term effects over many years and weight regain after discontinuation are still being mapped.
• Direct head-to-head comparison with other incretin agonists is limited; for the dual/triple agonists the field partly relies on indirect data.
• The mechanistic fine structure of the weight and cardiovascular effects remains an active area of research.

Research outlook

Semaglutide is a well-characterized reference molecule for research into GLP-1 receptor signalling and incretin pharmacology.

Albumin-based half-life extension remains a fruitful design principle for further research.

Scientific interest

Reference GLP-1 agonist: the weekly second generation after liraglutide.

Glucose-dependent insulin release, a mechanism with low hypoglycaemia risk.

Large, internationally replicated human dossier including cardiovascular outcome trials.

Specifications

References

1. Glucagon-like peptide-1 7-36: a physiological incretin in man. · Kreymann B, et al · Lancet · 1987
2. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. · Nauck MA, et al · Diabetologia · 1993
3. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. · Willms B, et al · J Clin Endocrinol Metab · 1996
4. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. · Flint A, et al · J Clin Invest · 1998
5. The physiology of glucagon-like peptide 1. · Holst JJ · Physiol Rev · 2007
6. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide · Lau J, et al. · J Med Chem · 2015
7. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes · Marso SP, et al. · N Engl J Med · 2016
8. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. · Drucker DJ · Cell Metab · 2018
9. The Discovery and Development of Liraglutide and Semaglutide · Knudsen LB, Lau J · Front Endocrinol (Lausanne) · 2019
10. Semaglutide lowers body weight in rodents via distributed neural pathways. · Gabery S, et al · JCI Insight · 2020
11. Once-Weekly Semaglutide in Adults with Overweight or Obesity · Wilding JPH, et al. · N Engl J Med · 2021
12. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. · Wilding JPH, et al · Diabetes Obes Metab · 2022
13. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes · Lincoff AM, et al. · N Engl J Med · 2023

Availability

Not in catalogue · Profile complete · verification and sourcing not yet finished