Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes
Open accessAbstract
Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [68 Ga]Ga-DO3A-Tuna-2 and [68 Ga]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 ± 14.4% (SD) in N = 5 patients and a GLP1R occupancy of 49.9 ± 13.3%. Fasting Plasma Glucose levels (− 3.30 ± 1.14 mmol/L) and body weight (− 3.87 ± 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.
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The diabetogenic effects of GcgR agonism need to be offset by the insulinotropic effects of GLP-1, typically steering the molecular design of such co-agonists toward greater GLP-1R potency than GcgR potency by reducing the relative GcgR potency by as much as 10-fold.
“the diabetogenic effects of GcgR agonism need to be offset by the insulinotropic effects of GLP-1, typically steering the molecular design of such co-agonists toward greater GLP-1R potency than GcgR potency by virtue of reducing the relative GcgR potency by as much as 10-fold [[26], [27], [28]]”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [26]
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- Authors
- Eriksson, O., Haack, T., Hijazi, Y., Teichert, L., Tavernier, V., Laitinen, I., Berglund, J. E., Antoni, G., Velikyan, I., Johansson, L., Pierrou, S., Wagner, M., & Tillner, J.
- Affiliations
- Uppsala University (SE)
- Sanofi (Germany) (DE)
- Sanofi (France) (FR)
- CTC Clinical Trial Consultants AB (Sweden) (SE)
- Antaros Medical (Sweden) (SE)
- Corresponding author
- Eriksson, Olof
- Tillner, Joachim
- Venue
- Scientific Reports
- Published
- 2020-10-07
- Volume
- 10
- Issue
- 1
- Pages
- 16758-16758
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7542159
- OpenAlex
- W3092613060
- Cited by
- 46
- References
- 0
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 11 · 2023: 5 · 2022: 5 · 2021: 14 · 2020: 2
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- Funders
- Uppsala University
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- GLP-1 receptor, glucagon receptor, receptor occupancy, target engagement, type 2 diabetes, PET radiotracer, pancreas, liver, fasting blood glucose, body weight
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Positron Emission Tomography Computed Tomography, Glucagon-Like Peptide-1 Receptor Agonists, Aged, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemic Agents, Liver, Male, Middle Aged, Pancreas, Receptors, Glucagon
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