GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management

Holst, Jens Juul

doi:10.1038/s42255-024-01113-9

Cited by 125Diabetes Treatment and ManagementPharmacology and Obesity TreatmentRegulation of Appetite and Obesity

GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management

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Holst, Jens Juul·2024·Nature Metabolism

DOI 10.1038/s42255-024-01113-9

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Abstract

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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The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon
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Effect of Truncated Glucagon-Like Peptide-1 [Proglucagon-(78–107) amide] on Endocrine Secretion from Pig Pancreas, Antrum, and Nonantral Stomach
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Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect
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Effect on Glycemic Control of Exenatide (Synthetic Exendin-4) Additive to Existing Metformin and/or Sulfonylurea Treatment in Patients With Type 2 Diabetes
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A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings
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Complete Sequences of Glucagon-like Peptide-1 from Human and Pig Small Intestine
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Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7?36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships
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GIP Does Not Potentiate the Antidiabetic Effects of GLP-1 in Hyperglycemic Patients With Type 2 Diabetes
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Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow
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The Liver–α-Cell Axis and Type 2 Diabetes
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Effects of PYY3–36 and GLP-1 on energy intake, energy expenditure, and appetite in overweight men
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The effect of glucagon-like peptide 1 on cardiovascular risk
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The physiological role of GLP-1 in human: incretin, ileal brake or more?
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Inhibitory effect of glucagon-like peptide-1 on small bowel motility. Fasting but not fed motility inhibited via nitric oxide independently of insulin and somatostatin.
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Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial
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Glucagon-like Peptide 1 (GLP-1): An Intestinal Hormone, Signalling Nutritional Abundance, with an Unusual Therapeutic Potential
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Glucagon antagonism as a potential therapeutic target in type 2 diabetes
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The Biology of Glucagon and the Consequences of Hyperglucagonemia
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Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from guinea pig pancreas. Identification of a mammalian analogue of the reptilian peptide exendin-4.
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The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans
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Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss
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A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
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What Is Weight Loss After Bariatric Surgery Expressed in Percentage Total Weight Loss (%TWL)? A Systematic Review
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Insulinotropic Properties of Synthetic Human Gastric Inhibitory Polypeptide in Man: Interactions with Glucose, Phenylalanine, and Cholecystokinin-8
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Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice
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Renal extraction and acute effects of glucagon-like peptide-1 on central and renal hemodynamics in healthy men
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Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6
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The Liver–α-Cell Axis in Health and in Disease
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Oxyntomodulin: actions and role in diabetes
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The therapeutic potential of glucagon-like peptide-1 for persons with addictions based on findings from preclinical and clinical studies
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Naturally occurring products of proglucagon 111-160 in the porcine and human small intestine.
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Physiology of the Incretin Hormones, GIP and GLP ‐1—Regulation of Release and Posttranslational Modifications
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Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents
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GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior
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GLP-1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance
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Orforglipron ( <scp>LY3502970</scp> ), a novel, oral non‐peptide glucagon‐like peptide‐1 receptor agonist: A Phase 1b, multicentre, blinded, placebo‐controlled, randomized, multiple‐ascending‐dose study in people with type 2 diabetes
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Creating the amylin story
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Real‐world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer <scp>GLP</scp> ‐ <scp>1RA</scp> ‐based weight‐loss therapies
Thomsen, R. W., Mailhac, A., Løhde, J. B., & Pottegård, A. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16364 · Cited by 207 · see citing works
GLP-1 and the Neurobiology of Eating Control: Recent Advances
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Codella, R., Senesi, P., & Luzi, L. (2025) · Frontiers in Clinical Diabetes and Healthcare · doi:10.3389/fcdhc.2025.1720794 · Cited by 16 · see citing works
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Mocciaro, G., Capodici, A., & De Amicis, R. (2025) · BMJ Nutrition, Prevention & Health · doi:10.1136/bmjnph-2025-001206 · Cited by 9 · see citing works

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No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect
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Self-citation
Incretin therapies for type 2 diabetes: what nurses need to know
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Authors: Holst, J. J.
Affiliations: University of Copenhagen (DK)
Corresponding author: Holst, Jens Juul
ORCID: Holst, Jens Juul
Venue: Nature Metabolism
Publisher: Springer Science and Business Media LLC
Published: 2024-08-19
Volume: 6
Issue: 10
Pages: 1866-1885
ISSN: 2522-5812 (ISSN-L)
DOI: 10.1038/s42255-024-01113-9
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: green
researchprofiles.ku.dk
Licence: cc-by
www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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 › 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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GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management

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