The year 2023 brought reports of highly effective glucagon-like peptide 1 (GLP1) mono-agonists or combinations with amylin receptor agonists. Results for monomolecular co-agonists that added glucagon receptor and/or glucose-dependent insulinotropic polypeptide (GIP) receptor agonism to GLP1 receptor activation were also published in 2023. Interestingly, antagonistic GIP receptor antibodies conjugated with a GLP1 agonist were also shown to be effective.
Key advances
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Of particular interest are the SURMOUNT trials from 2023 of the GLP1–GIP co-agonist tirzepatide, which have shown weight loss of up to 25% of body weight in people with obesity4.
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A phase II trial with retatrutide, a GIP–GLP1–glucagon triple agonist, resulted in weight loss of 25% in patients with obesity3.
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A new long-acting amylin-based agonist, cagrilintide, has shown good efficacy in obesity, especially in combination with the highly effective GLP1 receptor agonist semaglutide, with potential for weight loss exceeding 20%5.
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Promising results of a small-molecule GLP1 receptor agonist (orforglipron)10 suggest that an orally active, effective agent will soon be made available, which is of huge interest in countries where injectable therapies are not immediately acceptable; positive results have also been reported for oral semaglutide2.
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AMG 133 combines GLP1 agonism with GIP antagonism, and has shown promising results7.
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References
Lincoff, A. M. et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2307563 (2023).
Knop, F. K. et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 402, 705–719 (2023).
Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).
Wadden, T. A. et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat. Med. 29, 2909–2918 (2023).
Frias, J. P. et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet 402, 720–730 (2023).
Kizilkaya, H. S. et al. Loss of function glucose-dependent insulinotropic polypeptide receptor variants are associated with alterations in BMI, bone strength and cardiovascular outcomes. Front. Cell Dev. Biol. 9, 749607 (2021).
Strande, J. L. et al. A phase 1, randomized, double-blind, placebo-controlled single and multipleascending dose study of AMG 133 in subjects with obesity. Metabolism 142 (Suppl.), 155433 (2023).
Killion, E. A. et al. Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism. Nat. Commun. 11, 4981 (2020).
Willard, F. S. et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 5, e140532 (2020).
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M.M.R. is co-founder of Antag Therapeutics, Bainan Biotech and Synklino and serves as a board member of Bainan Biotech and Synklino.
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Rosenkilde, M.M. Advances in incretin-based therapeutics for obesity. Nat Rev Endocrinol 20, 67–68 (2024). https://doi.org/10.1038/s41574-023-00938-w
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DOI: https://doi.org/10.1038/s41574-023-00938-w