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GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes

Nature Reviews Nephrology volume 13, pages 605–628 (2017)Cite this article

Subjects

Key Points

  • The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gut-derived hormones that potentiate insulin secretion and contribute to glucose metabolism through a wide range of physiological actions

  • Inhibitors of the incretin-inactivating enzyme dipeptidyl peptidase 4 (DPP-4) and DPP-4-resistant injectable GLP-1 receptor agonists have been developed for the treatment of hyperglycaemia in type 2 diabetes mellitus (T2DM)

  • GLP-1 and other gut-derived hormones might directly and/or indirectly regulate electrolyte and fluid homeostasis by influencing feeding and drinking behaviour as well as electrolyte transport in the kidneys and gastrointestinal tract

  • GLP-1 receptor (GLP-1R) agonists and DPP-4 inhibitors increase natriuresis in T2DM, possibly through overlapping and distinct mechanisms, and might slightly improve renal haemodynamics in the setting of diabetes-related glomerular hyperfiltration

  • Incretin-based therapies seem to directly influence renal physiology and have indirect metabolic and haemodynamic actions that might reduce renal risk in T2DM; considerable interest exists in identifying these glucose-independent renoprotective actions

  • Data from clinical trials suggest that GLP-1R agonists and, to a lesser extent, DPP-4 inhibitors marginally improve surrogate renal end points, plausibly beyond the effects of improved glycaemic control

Abstract

The gastrointestinal tract — the largest endocrine network in human physiology — orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies — GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors — for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut–renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut–renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM.

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Figure 1: The sensory and secretory function of the L cell.
Figure 2: Evidence for the incretin effect and the putative gastrointestinal regulation of urinary sodium excretion.
Figure 3: Putative actions of glucagon-like peptide 1 (GLP-1).
Figure 4: Effects of glucagon-like peptide 1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs) on renal haemodynamics in diabetes mellitus.
Figure 5: Risk factor control in the intensive treatment group of the Steno-2 trial in patients with type 2 diabetes mellitus and microalbuminuria151.
Figure 6: Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin-based therapies in patients with type 2 diabetes mellitus at high risk of cardiac events.

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  1. Marcel H. A. Muskiet and Lennart Tonneijck: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Diabetes Center, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands

    Marcel H. A. Muskiet, Lennart Tonneijck, Mark M. Smits, Michaël J.B. van Baar, Mark H. H. Kramer & Daniël H. van Raalte

  2. Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, Netherlands

    Ewout J. Hoorn

  3. Department of Nephrology and Hypertension, University Medical Centre, Heidelberglaan 100, 3584 CX, Utrecht, Netherlands

    Jaap A. Joles

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Contributions

M.H.A.M., L.T., M.M.S., J.A.J. and D.H.vR. researched the data, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission. M.J.B.vB., M.H.H.K. and E.J.H. made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission. M.H.A.M. and L.T. contributed equally to this Review.

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Correspondence to Marcel H. A. Muskiet.

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Competing interests

Through M.H.H.K., the VU University Medical Center has received research grants from AstraZeneca, Boehringer Ingelheim, Novo Nordisk and Sanofi. M.H.A.M. and L.T. consulted for Eli Lilly & Co., and D.H.vR. serves on advisory boards of Sanofi Aventis and Merck Sharp & Dohme (all honoraria paid to employer). The other authors declare no competing interests.

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Muskiet, M., Tonneijck, L., Smits, M. et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol 13, 605–628 (2017). https://doi.org/10.1038/nrneph.2017.123

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