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GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management
Open accessAbstract
The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15–25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy. Holst reflects on the development of GLP-1-based drugs for the therapy of obesity, from early observations to remarkable results in more recent clinical trials, discussing physiological, pharmacological and clinical considerations related to their use.
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Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J. F. E., Nauck, M. A., Nissen, S. E., Pocock, S., Poulter, N. R., Ravn, L. S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1603827 · Cited by 7,629 · cited 1×
“https://doi.org/10.1038/s42255-024-01113-9 trial) body weight reduction was maintained for up to 5 years with no upward inflection 218 , and a similar finding was made in the detailed report of the SELECT trial, in which weight loss was recorded for 40 months in 17,600 individuals with obesity and…”
InfluentialSemaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A., Lingvay, I., Rosenstock, J., Seufert, J., Warren, M. L., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1607141 · Cited by 6,900 · cited 2×
“%) were studied for 2 years 124 .”
Once-Weekly Semaglutide in Adults with Overweight or Obesity
Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2032183 · Cited by 5,205
Tirzepatide Once Weekly for the Treatment of Obesity
Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2206038 · Cited by 3,838 · cited 1×
“Recently, even a triple agonist has been developed: retatrutide from Eli Lilly, in which GIP, glucagon and GLP-1 agonism is combined 204 .”
The Physiology of Glucagon-like Peptide 1
Holst, J. J. (2007) · Physiological Reviews · doi:10.1152/physrev.00034.2006 · Cited by 3,371
Self-citationSemaglutide and Cardiovascular Outcomes in Obesity without Diabetes
Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Esbjerg, S., Hardt-Lindberg, S., Hovingh, G. K., Kahn, S. E., Kushner, R. F., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2307563 · Cited by 3,236
A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management
Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., Lau, D. C. W., le Roux, C. W., Violante Ortiz, R., Jensen, C. B., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1411892 · Cited by 2,724
Armstrong, M. J., Gaunt, P., Aithal, G. P., Barton, D., Hull, D., Parker, R., Hazlehurst, J. M., Guo, K., Abouda, G., Aldersley, M. A., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(15)00803-x · Cited by 2,203
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes
Frías, J. P., Davies, M. J., Rosenstock, J., Pérez Manghi, F. C., Fernández Landó, L., Bergman, B. K., Liu, B., Cui, X., & Brown, K. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2107519 · Cited by 2,096 · cited 1×
“In subsequent phase 3 studies, tirzepatide showed even better results and, for instance, in the SURPASS-2 trial, demonstrated reductions in HgbA1c to less than 5.7% in more than 50% of patients with type 2 diabetes accompanied by a weight loss of 12.4% in 40 weeks 164 .”
InfluentialLean, M. E., Leslie, W. S., Barnes, A. C., Brosnahan, N., Thom, G., McCombie, L., Peters, C., Zhyzhneuskaya, S., Al-Mrabeh, A., Hollingsworth, K. G., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(17)33102-1 · Cited by 2,095 · cited 1×
“The importance of the weight-loss results with Wegovy were put in perspective by studies showing that weight losses of this order of magnitude would greatly decrease the risk of developing type 2 diabetes and might even cause remission 130 .”
Research works printed but not linked: 6
- Larsen, J., Hylleberg, B., Ng, K. & Damsbo, P. Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes Care 24, 1416–1421 (2001).
- Kjems, L. L., Holst, J. J., Volund, A. & Madsbad, S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52, 380–386 (2003). · DOI · Paper page
- Frias, J. P. et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care 44, 765–773 (2021).
- Larger, E. et al. Pancreatic alpha-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation. Endocrinol. Diabetes Metab. Case Rep. 2016, 16-0081 (2016).
- Sandhu S & Jialal I. Glucagonoma syndrome. In: StatPearls https://www.ncbi.nlm.nih.gov/books/NBK519500/ (StatPearls, 2024).
- Kuhre, R. E., Wewer Albrechtsen, N. J., Hartmann, B., Deacon, C. F. & Holst, J. J. Measurement of the incretin hormones: glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. J. Diabetes Complications 29, 445–450 (2014).
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Thomsen, R. W., Mailhac, A., Løhde, J. B., & Pottegård, A. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16364 · Cited by 207
GLP-1 and the Neurobiology of Eating Control: Recent Advances
Jones, L. A., & Brierley, D. I. (2025) · Endocrinology · doi:10.1210/endocr/bqae167 · Cited by 43
Recent progress in the pharmacotherapy for obesity
Lu, J., Liu, P., Cai, M., Lv, T., Zhang, M., Yin, K., Cheng, J., & Zhang, G. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177850 · Cited by 17
GLP-1 agonists and exercise: the future of lifestyle prioritization
Codella, R., Senesi, P., & Luzi, L. (2025) · Frontiers in Clinical Diabetes and Healthcare · doi:10.3389/fcdhc.2025.1720794 · Cited by 16
GLP-1 receptor agonists induce loss of lean mass: So does caloric restriction
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Metadata
- Authors
- Holst, J. J.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Holst, Jens Juul
- ORCID
- Holst, Jens Juul
- Venue
- Nature Metabolism
- Published
- 2024-08-19
- Volume
- 6
- Issue
- 10
- Pages
- 1866-1885
- ISSN
- 2522-5812 (ISSN-L)
- OpenAlex
- W4401702015
- Semantic Scholar
- d66c5ddf6ff3374ac09aae6e0892b35bdcf7403a
- Cited by
- 125
- References
- 241
- Citations by year
- 2026: 68 · 2025: 49 · 2024: 8
- FWCI
- 7.34
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- glucagon-like peptide-1, GLP-1 receptor agonists, obesity, weight management, semaglutide, tirzepatide, type 2 diabetes, GLP-1 receptor, sensory afferents, cardiovascular risk reduction, oral GLP-1 receptor agonists, maintenance therapy
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Animals, Diabetes Mellitus, Type 2, Humans, Obesity, Anti-Obesity Agents, Glucagon-Like Peptide 1, Incretins
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