The DOI matches its Crossref record; 241 of the 241 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The text we found for this paper looks like another document, so the self-check wasn’t run.
Citations
Cites
Items 201–241 of 241
Asmar, A., Cramon, P. K., Simonsen, L., Asmar, M., Sorensen, C. M., Madsbad, S., Moro, C., Hartmann, B., Jensen, B. L., Holst, J. J., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00004 · Cited by 56
Self-citationGao, W., Liu, L., Huh, E., Gbahou, F., Cecon, E., Oshima, M., Houzé, L., Katsonis, P., Hegron, A., Fan, Z., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00889-6 · Cited by 56
Patterson, J. T., Ottaway, N., Gelfanov, V. M., Smiley, D. L., Pérez–Tilve, D., Pfluger, P. T., Tschöp, M. H., & DiMarchi, R. D. (2010) · ACS Chemical Biology · doi:10.1021/cb1002015 · Cited by 54
Andersen, D. B., Grunddal, K. V., Pedersen, J., Kuhre, R. E., Lund, M. L., Holst, J. J., & Ørskov, C. (2021) · Endocrinology · doi:10.1210/endocr/bqaa246 · Cited by 54
Self-citationRipa, R. S., Zobel, E. H., von Scholten, B. J., Jensen, J. K., Binderup, T., Díaz, L. J., Curovic, V. R., Hansen, T. W., Rossing, P. R., & Kjær, A. (2021) · Circulation Cardiovascular Imaging · doi:10.1161/circimaging.120.012174 · Cited by 53
Parker, V. E. R., Robertson, D., Erazo-Tapia, E., Havekes, B., Phielix, E., de Ligt, M., Roumans, K. H. M., Mevenkamp, J., Sjoberg, F., Schrauwen-Hinderling, V. B., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00938-0 · Cited by 53
Effect of Glucagon-like Peptide-1 Receptor Antagonism on Appetite and Food Intake in Healthy Men
Steinert, R. E., Schirra, J., Meyer-Gerspach, A. C., Kienle, P., Fischer, H., Schulte, F., Goeke, B., & Beglinger, C. (2014) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.083246 · Cited by 52
Kizilkaya, H. S., Sørensen, K. V., Kibsgaard, C. J., Gasbjerg, L. S., Hauser, A. S., Sparre-Ulrich, A. H., Grarup, N., & Rosenkilde, M. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.749607 · Cited by 52
Jepsen, S. L., Grunddal, K. V., Albrechtsen, N. J. W., Engelstoft, M. S., Gabe, M. B. N., Jensen, E. P., Ørskov, C., Poulsen, S. S., ROSENKILDE, M. M., Pedersen, J., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00239.2019 · Cited by 50
Self-citationSharma, A., Ambrosy, A. P., DeVore, A. D., Margulies, K. B., McNulty, S. E., Mentz, R. J., Hernandez, A. F., Felker, G. M., Cooper, L. B., Lala, A., et al. (2018) · ESC Heart Failure · doi:10.1002/ehf2.12334 · Cited by 46
Jensen, P. B., Blume, N., Mikkelsen, J. D., Larsen, P. J., Jensen, H. I., Holst, J. J., & Madsen, O. D. (1998) · Journal of Clinical Investigation · doi:10.1172/jci275 · Cited by 45
Self-citationSaxena, A. R., Frias, J. P., Gorman, D. N., Lopez, R. N., Andrawis, N., Tsamandouras, N., & Birnbaum, M. J. (2023) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.15168 · Cited by 45
Gasbjerg, L. S., ROSENKILDE, M. M., Meier, J. J., Holst, J. J., & Knop, F. K. (2023) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15216 · Cited by 43
Self-citationGlucagon-Like Peptide-1 Receptor Regulates Thromboxane-Induced Human Platelet Activation
Cahill, K. N., Amin, T., Boutaud, O. G., Printz, R. L., Newcomb, D. C., Foer, D., Hodson, D. J., Broichhagen, J., Beckman, J. A., Yu, C., et al. (2022) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2022.04.004 · Cited by 41
KAZDA, C. M., Frías, J. P., Foga, I., Cui, X., Guzmán, C. B., Garhyan, P., Heilmann, C. R., Yang, J., & Hardy, T. A. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12904 · Cited by 39
Kuhre, R. E., Christiansen, C. B., Saltiel, M. Y., Albrechtsen, N. J. W., & Holst, J. J. (2017) · Physiological Reports · doi:10.14814/phy2.13507 · Cited by 39
Self-citationGrunddal, K. V., Jensen, E. P., Ørskov, C., Andersen, D. B., Windeløv, J. A., Poulsen, S. S., ROSENKILDE, M. M., Knudsen, L. B., Pyke, C., & Holst, J. J. (2021) · Endocrinology · doi:10.1210/endocr/bqab216 · Cited by 34
Self-citationGogineni, P., Melson, E., Papamargaritis, D., & Davies, M. (2024) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2024.2356254 · Cited by 32
Karhunen, V., Daghlas, I., Zuber, V., Vujkovic, M., Olsen, A. K., Knudsen, L. B., Haynes, W. G., Howson, J. M. M., & Gill, D. (2021) · Diabetologia · doi:10.1007/s00125-021-05564-7 · Cited by 28
Molecular and in vivo phenotyping of missense variants of the human glucagon receptor
van der Velden, W. J. C., Lindquist, P., Madsen, J. S., Stassen, R., Albrechtsen, N. J. W., Holst, J. J., Hauser, A. S., & ROSENKILDE, M. M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101413 · Cited by 26
Self-citationMartinussen, C., Bojsen-Møller, K. N., Dirksen, C., Svane, M. S., Kristiansen, V. B., Hartmann, B., Holst, J. J., & Madsbad, S. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02661 · Cited by 25
Self-citationBowker, N., Hansford, R., Burgess, S., Foley, C. N., Auyeung, V. P. W., Erzurumluoglu, A. M., Stewart, I. D., Wheeler, E., Pietzner, M., Gribble, F. M., et al. (2021) · Diabetes · doi:10.2337/db21-0103 · Cited by 25
Pratley, R. E., Catarig, A., Lingvay, I., Viljoen, A., Paine, A., Lawson, J., Chubb, B., Gorst‐Rasmussen, A., & Miresashvili, N. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14497 · Cited by 24
The amino acid sequence of porcine glicentin
Thim, L., & Moody, A. (1981) · Peptides · doi:10.1016/0196-9781(81)90007-3 · Cited by 23
Melhorn, S. J., Tyagi, V., Smeraglio, A., Roth, C. L., & Schur, E. A. (2014) · Appetite · doi:10.1016/j.appet.2014.07.009 · Cited by 21
Watkins, J. D., Carter, S., Atkinson, G., Koumanov, F., Betts, J. A., Holst, J. J., & Gonzalez, J. T. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155375 · Cited by 20
Self-citationKurtzhals, P., Kreiner, F. F., & Bindra, R. S. (2023) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2023.110881 · Cited by 20
Glucagon and the Control of Appetite
Geary, N. (1996) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-61150-6_14 · Cited by 19
Melchiorsen, J. U., Sørensen, K. V., Bork‐Jensen, J., Kizilkaya, H. S., Gasbjerg, L. S., Hauser, A. S., Rungby, J., Sørensen, H. T., Vaag, A. A., Nielsen, J. S., et al. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad290 · Cited by 18
Self-citationPratt, E. J. (2023) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15372 · Cited by 18
Fatima, H., Rangwala, H. S., Mustafa, M. S., Shafique, M. A., Abbas, S. R., Rizwan, A., Ahmad, T. K. F., & Arshad, A. (2023) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s439587 · Cited by 17
Christiansen, C. B., Veedfald, S., Hartmann, B., Gauguin, A. M., Møller, S., Möritz, T., Madsbad, S., & Holst, J. J. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab666 · Cited by 15
Self-citationMarco, J., HEDO, J. A., Villanueva, M. L., et al. (1977) · Diabetologia · doi:10.1007/bf00745140 · Cited by 14
Østergaard, L., Frandsen, C. S., Dejgaard, T. F., & Madsbad, S. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1313109 · Cited by 13
Bojsen-Møller, K. N., Svane, M. S., Martinussen, C., Dirksen, C., Jørgensen, N. B., Jensen, J.-E. B., Jensen, C. Z., Torekov, S. S., Kristiansen, V. B., Rehfeld, J. F., et al. (2023) · International Journal of Obesity · doi:10.1038/s41366-023-01372-8 · Cited by 13
Self-citationHunt, J. E., Holst, J. J., & Jepsen, S. L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.884501 · Cited by 10
Self-citationAssociation of GLP1R Polymorphisms With the Incretin Response
Dorsey-Treviño, E. G., Kaur, V., Mercader, J. M., Florez, J. C., & Leong, A. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac374 · Cited by 10
Ambrosy, A. P., Sharma, A., McNulty, S., et al. (2017) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(17)34073-1 · Cited by 9
GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior
Samms, R. J., Cosgrove, R., Snider, B. M., Furber, E. C., Droz, B. A., Briere, D. A., Dunbar, J. D., Dogra, M., Alsina‐Fernandez, J., Borner, T., et al. (2022) · doi:10.2337/figshare.19601518.v1 · Cited by 7
Gerstenberg, M. K., Andersen, D. B., Torz, L., Castorena, C. M., Bookout, A. L., Hartmann, B., Rehfeld, J. F., Petersen, N., Holst, J. J., & Kuhre, R. E. (2023) · Acta Physiologica · doi:10.1111/apha.13947 · Cited by 5
Self-citationBowker, N., Hansford, R., Burgess, S., Foley, C. N., Auyeung, V. P. W., Erzurumluoglu, A. M., Stewart, I. D., Wheeler, E., Pietzner, M., Gribble, F. M., et al. (2021) · doi:10.2337/figshare.15175518.v2 · Cited by 2
Flagged first, then by citations
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).
Cited by
Sorted by citations
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
Mocciaro, G., Capodici, A., & De Amicis, R. (2025) · BMJ Nutrition, Prevention & Health · doi:10.1136/bmjnph-2025-001206 · Cited by 9
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
