Glucagon-like peptide 1 (GLP1) analogues are licensed options for obesity, but new treatments are required to obtain better weight loss and to directly address other co-morbidities, such as non-alcoholic fatty liver disease. Research published in 2022 shows that co-agonist combinations of GLP1 with other hormones provide clinically important advances.
Key advances
-
In the SURMOUNT-1 trial for obesity, adults with overweight or obesity without type 2 diabetes mellitus achieved placebo-subtracted weight loss of up to 20% after 72 weeks of the GLP1–GIP receptor co-agonist tirzepatide, with a similar safety profile to high-dose semaglutide5.
-
Findings published in a preprint from a phase I clinical trial on the GLP1–glucagon receptor co-agonist NN1177 in adults with overweight or obesity have raised problems with deterioration of glucose tolerance and other safety concerns, despite inducing weight loss, which illustrates the difficulties in getting the agonist balance right during the preclinical development of co-agonist therapies6,7.
-
Preclinical and phase I clinical trial data for a triple GLP1–GIP–glucagon receptor co-agonist therapy (LY3437943) suggest that it is effective at inducing weight loss, without inducing adverse effects that would require discontinuation; adverse effects were gastrointestinal in nature, similar to GLP1 receptor agonists9.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Garvey, W. T. et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat. Med. 28, 2083–2091 (2022).
Newsome, P. N. et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2021).
Clemmensen, C. et al. Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases. Nat. Rev. Endocrinol. 15, 90–104 (2019).
Frías, J. P. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021).
Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).
Friedrichsen, M. et al. Glucagon/GLP-1 receptor co-agonist NNC9204–1177 reduced body weight in adults with overweight or obesity but was associated with safety issues. Preprint at medRxiv https://doi.org/10.1101/2022.06.02.22275920 (2022).
Simonsen, L. et al. Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: Translational difficulties and pitfalls. PLoS One 17, e0264974 (2022).
Nahra, R. et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 44, 1433–1442 (2021).
Coskun, T. et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 34, 1234–1247.e9 (2022).
Enebo, L. B. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet 397, 1736–1748 (2021).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
T.M.-M.T. declares that she is a shareholder and consultant for Zihipp Ltd, an Imperial College spinout company that is developing gut hormone-based analogues for obesity.
Rights and permissions
About this article
Cite this article
Tan, T.MM. Co-agonist therapeutics come of age for obesity. Nat Rev Endocrinol 19, 66–67 (2023). https://doi.org/10.1038/s41574-022-00788-y
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41574-022-00788-y
This article is cited by
-
Targeting the incretin system in obesity and type 2 diabetes mellitus
Nature Reviews Endocrinology (2024)