Abstract

In healthy individuals, the incretin hormone glucagon-like peptide 1 (GLP1) potentiates insulin release and suppresses glucagon secretion in response to the ingestion of nutrients. GLP1 also delays gastric emptying and increases satiety. In patients with type 2 diabetes mellitus (T2DM), supraphysiological doses of GLP1 normalize the endogenous insulin response during a hyperglycaemic clamp. Owing to the short plasma half-life of native GLP1, several GLP1 receptor agonists (GLP1RAs) with longer half-lives have been developed for the treatment of T2DM. These compounds vary in chemical structure, pharmacokinetics and size, which results in different clinical effects on hyperglycaemia and body weight loss; these variations might also explain the difference in cardiovascular effect observed in large-scale cardiovascular outcome trials, in which certain GLP1RAs were shown to have a positive effect on cardiovascular outcomes. Owing to their metabolic effects, GLP1RAs are also considered for the treatment of several other lifestyle-induced conditions, such as obesity, prediabetes and liver disease. This Review provides insights into the physiology of GLP1 and its involvement in the pathophysiology of T2DM and an overview of the currently available and emerging GLP1RAs. Furthermore, we review the results from the currently available large-scale cardiovascular outcome trials and the use of GLP1RAs for other indications.

Key points

  • The incretin hormone glucagon-like peptide 1 (GLP1) promotes satiety and potentiates insulin release and suppression of glucagon release in response to the ingestion of nutrients.

  • Owing to the short plasma half-life of GLP1, several GLP1 receptor agonists (GLP1RAs) were developed with different chemical structures and pharmacokinetic profiles for type 2 diabetes mellitus (T2DM) treatment.

  • GLP1RAs can be categorized as short-acting or long-acting according to their time–action profile.

  • Both short-acting and long-acting GLP1RAs reduce body weight, whereas short-acting GLP1RAs have a greater effect on postprandial plasma levels of glucose and long-acting GLP1RAs predominantly lower fasting plasma concentrations of glucose.

  • Some GLP1RAs (liraglutide and semaglutide) have proved to have positive effects on cardiovascular outcomes in T2DM.

  • The effects of GLP1RAs are sought to be exploited in the treatment of several other conditions, including prediabetes, T1DM, obesity and liver disease.

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Nature Reviews Endocrinology thanks M. Nauck and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Author information

Affiliations

  1. Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark

    • Andreas Andersen
    • , Asger Lund
    • , Filip K. Knop
    •  & Tina Vilsbøll
  2. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Filip K. Knop
    •  & Tina Vilsbøll
  3. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Filip K. Knop

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Contributions

A.A. researched data for the article and wrote the first draft. A.A., A.L., F.K.K. and T.V. contributed substantially to the discussion of content and reviewed and/or edited the article before submission.

Competing interests

A.A. and A.L. have no competing interests. Until 2018, T.V. served on scientific advisory panels and/or speakers’ bureaus and served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi. Thereafter, she has no competing interests. F.K.K. has served on scientific advisory panels and/or speaker's bureaus and served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, Gubra, Merck Sharp & Dohme, Novo Nordisk, Sanofi and Zealand Pharma.

Corresponding author

Correspondence to Tina Vilsbøll.

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DOI

https://doi.org/10.1038/s41574-018-0016-2