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

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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

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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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Complete Sequences of Glucagon-like Peptide-1 from Human and Pig Small Intestine
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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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Separate and combined glucometabolic effects of endogenous glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 in healthy individuals.
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Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial
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Brain GLP-1 and the regulation of food intake: GLP-1 action in the brain and its implications for GLP-1 receptor agonists in obesity treatment
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An Analysis of Cosecretion and Coexpression of Gut Hormones From Male Rat Proximal and Distal Small Intestine
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The physiological role of GLP-1 in human: incretin, ileal brake or more?
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The effect of glucagon-like peptide 1 on cardiovascular risk
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Amylin - its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity
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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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The Biology of Glucagon and the Consequences of Hyperglucagonemia
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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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Radio-immunoassays for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2)
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Glucagon antagonism as a potential therapeutic target in type 2 diabetes
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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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Effect of obesity and major weight reduction on gastric emptying
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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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Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice
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Glucagon‐like peptide‐2 inhibits antral emptying in man, but is not as potent as glucagon‐like peptide‐1
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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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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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Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating
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Pancreatic glucagon signals postprandial satiety
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Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes
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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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Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic versus hepatic actions of semaglutide
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Glucagon-like Peptide-1 receptor Tie2+ cells are essential for the cardioprotective actions of liraglutide in mice with experimental myocardial infarction
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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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Glucagon receptor antagonism induces increased cholesterol absorption
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Physiology of the Incretin Hormones, GIP and GLP ‐1—Regulation of Release and Posttranslational Modifications
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Mediators of Amylin Action in Metabolic Control
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GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior
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Transfer of liraglutide from blood to cerebrospinal fluid is minimal in patients with type 2 diabetes
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Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor
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Exendin-3, a novel peptide from Heloderma horridum venom, interacts with vasoactive intestinal peptide receptors and a newly described receptor on dispersed acini from guinea pig pancreas. Description of exendin-3(9-39) amide, a specific exendin receptor antagonist.
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Orforglipron ( LY3502970 ), 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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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 (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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GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management

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