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Targeting the incretin system in obesity and type 2 diabetes mellitus

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

Obesity and type 2 diabetes mellitus (T2DM) are widespread, non-communicable diseases that are responsible for considerable levels of morbidity and mortality globally, primarily in the form of cardiovascular disease (CVD). Changes to lifestyle and behaviour have insufficient long-term efficacy in most patients with these diseases; metabolic surgery, although effective, is not practically deliverable on the scale that is required. Over the past two decades, therapies based on incretin hormones, spearheaded by glucagon-like peptide 1 (GLP1) receptor agonists (GLP1RAs), have become the treatment of choice for obesity and T2DM, and clinical evidence now suggests that these agents have benefits for CVD. We review the latest advances in incretin-based pharmacotherapy. These include ‘GLP1 plus’ agents, which combine the known advantages of GLP1RAs with the activity of additional hormones, such as glucose-dependent insulinotropic peptide, glucagon and amylin, to achieve desired therapeutic goals. Second-generation non-peptidic oral GLP1RAs promise to extend the benefits of GLP1 therapy to those who do not want, or cannot have, subcutaneous injection therapy. We conclude with a discussion of the knowledge gaps that must be addressed before incretin-based therapies can be properly deployed for maximum benefit in the treatment of obesity and T2DM.

Key points

  • The incretins glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) and related hormones such as glucagon and amylin regulate metabolism, gastrointestinal motility, appetite and body weight.

  • GLP1 receptor agonists (GLP1RAs) are established treatments for type 2 diabetes mellitus (T2DM) and obesity, with data that support positive effects on hard clinical end points such as cardiovascular events and renal outcomes.

  • ‘GLP1 plus’ treatments go beyond GLP1RAs by combining GLP1 activity with complementary activities such as those of GIP, glucagon and amylin; these treatments are beginning to reach clinical practice.

  • People with T2DM and obesity have varying presentations with differing metabolic and organ involvement, so ‘GLP1 plus’ treatments might offer differential advantages, depending on the clinical picture.

  • Oral GLP1RAs are also beginning to reach clinical practice, and will open up access for those who do not want, or cannot have, injections; oral GLP1RAs can also be made at lower cost.

  • Evidence on the duration of treatment for obesity, on the treatment of children <12 years of age and women of reproductive age, on rare adverse effects and on how we can target treatment to subgroups needs to be developed.

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Fig. 1: Therapies based on incretin hormones.

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Authors and Affiliations

  1. Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK

    Saleem Ansari & Tricia Tan

  2. Department of Endocrinology, Division of Medicine, Royal Free Campus, University College London, London, UK

    Bernard Khoo

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All authors researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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T.T. is a shareholder and consultant for Zihipp Ltd., an Imperial College spinout company developing gut hormone-based analogues for obesity. The other authors declare no competing interests.

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Ansari, S., Khoo, B. & Tan, T. Targeting the incretin system in obesity and type 2 diabetes mellitus. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00979-9

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