DRPSHP

Scientific Reference

Semaglutide

Evidence profile: Human Phase 3 evidence

Semaglutide is best understood as human GLP-1 re-engineered so that it lasts. The native hormone is a 31-residue peptide destroyed in the bloodstream within a couple of minutes; semaglutide keeps the 31-residue frame but swaps in three changes, referenced to native numbering. Position 8 carries aminoisobutyric acid (Aib) so that dipeptidyl peptidase-4 cannot clip it, position 34 holds arginine instead of lysine, and the lysine at position 26 bears an 18-carbon diacid chain on a short spacer that lets the molecule ride on albumin. Receptor pharmacology, rodent models and a very extensive human trial record in metabolic disease all exist. A live question is how an albumin-bound molecule of this size reaches the brain regions where the receptor sits.

Mechanism of Action

The receptor is GLP-1R, a class B GPCR using Gs and cyclic AMP. In pancreatic beta cells the effect described is glucose-dependent insulin secretion; in alpha cells, lower glucagon output; in the stomach, slower gastric emptying. Receptors in hypothalamus and hindbrain have been mapped in rodents as part of the circuitry governing appetite. Pharmacokinetically, reversible albumin binding through the fatty diacid slows kidney filtration, while the Aib substitution blocks DPP-4, which together account for the long circulating half-life.

Molecular Information

  • Type: GLP-1 receptor agonist
  • Molecular weight: 4114 g/mol
  • Molecular formula: C187H291N45O59
  • CAS: 910463-68-2

Pharmacokinetics

Compared to native GLP-1, semaglutide has a prolonged half-life of around 1 week making it suitable for once weekly subcutaneous administration." and, under Elimination: "With an elimination half-life of approximately 1 week, semaglutide… Maximum concentration was reached 1 to 3 days post dose. Steady state exposure was achieved following 4-5 weeks of once weekly administration. ... Absolute bioavailability of subcutaneous semaglutide was 89%.

Published Research

  • SELECT

    Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

    Lincoff AM et al. · The New England journal of medicine · 2023 · Clinical

    PMID 37952131 — View on PubMed

  • STEP 1

    Once-Weekly Semaglutide in Adults with Overweight or Obesity

    Wilding JPH et al. · The New England journal of medicine · 2021 · Clinical

    PMID 33567185 — View on PubMed

  • Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial

    Marx N et al. · Circulation · 2025 · Clinical

    PMID 40156843 — View on PubMed

  • Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial

    Kadowaki T et al. · The lancet. Diabetes & endocrinology · 2022 · Clinical

    PMID 35131037 — View on PubMed

  • Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial

    Davies M et al. · Lancet (London, England) · 2021 · Clinical

    PMID 33667417 — View on PubMed

  • Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

    Husain M et al. · The New England journal of medicine · 2019 · Clinical

    PMID 31185157 — View on PubMed