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  • Review Article
  • Published:

The gut–renal axis: do incretin-based agents confer renoprotection in diabetes?

Nature Reviews Nephrology volume 10, pages 88–103 (2014)Cite this article

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An Addendum to this article was published on 02 May 2014

This article has been updated

Key Points

  • Incretin-based therapies—glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors—improve glycaemic control by ameliorating multiple phenotypic defects associated with type 2 diabetes mellitus

  • GLP-1R agonists reduce body weight, whereas DPP-4 inhibitors do not affect body weight; both are generally well-tolerated by patients

  • Evidence from animal and human studies indicates that incretin-based therapies might prevent the onset and progression of diabetic nephropathy, as measured by clinical and histological improvements

  • Incretin-based therapies might positively influence haemodynamic variables (hyperfiltration, glomerular capillary hydraulic pressure, and systemic blood pressure), metabolic factors (glycaemia, dyslipidaemia, oxidative stress) and inflammatory pathways in the pathogenesis of diabetic nephropathy

  • Inhibitors of DPP-4 block the degradation of endogenous GLP-1 and might also influence circulating levels and activity of other vasoactive peptides that could act on the kidney

Abstract

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, and is associated with a high risk of cardiovascular morbidity and mortality. Intensive control of glucose levels and blood pressure is currently the mainstay of both prevention and treatment of diabetic nephropathy. However, this strategy cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need remains for additional novel therapies. The incretin-based agents—agonists of glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades glucagon-like peptide 1—are novel blood-glucose-lowering drugs used in the treatment of type 2 diabetes mellitus (T2DM). Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic effects that ameliorate various phenotypic defects of T2DM that are beyond glucose control. Agonists of GLP-1R and inhibitors of DPP-4 reduce blood pressure, dyslipidaemia and inflammation, although only GLP-1R agonists decrease body weight. Both types of incretin-based agents inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in rodents and humans. In rodents, incretin-based therapies also prevent onset of the morphological abnormalities of diabetic nephropathy.

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Figure 1: Pathogenesis of kidney disease in patients with diabetes.
Figure 2: The gut–renal axis.
Figure 3: Effects of incretin-based therapies on renal risk factors in T2DM.
Figure 4: Potential GLP-1-independent effects of DPP-4 inhibitors on renal outcome.

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Change history

  • 02 May 2014

    It is with regret that Nature Review Nephrology informs readers that Professor Michaela Diamant passed away on 9 April 2014. Future correspondence for this article should be addressed to Marcel H. A. Muskiet (ma.muskiet@vumc.nl).

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Authors and Affiliations

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

    Marcel H. A. Muskiet, Mark M. Smits, Linde M. Morsink & Michaela Diamant

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M. Diamant, M. H. A. Muskiet and M. M. Smits researched the data for the article, made a substantial contribution to discussions of the content, wrote the article, and reviewed and/or edited the manuscript before submission. L. M. Morsink made a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Marcel H. A. Muskiet.

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M. Diamant is a consultant for Abbott, Astra Zeneca, Boehringer–Ingelheim, Bristol-Myers Squibb, Eli Lilly, GI Dynamics, Merck Sharp & Dohme, Novo Nordisk, Poxel Pharma and Sanofi. She is also a speaker for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Novo Nordisk and Sanofi. Through M. Diamant, the VU University Medical Centre receives research grants from Abbott, Astra Zeneca, Boehringer–Ingelheim, Bristol-Myers Squibb, Eli Lilly, Medtronic, Merck Sharp & Dohme, Novo Nordisk and Sanofi. M. Diamant receives no personal payments in connection to the above-mentioned activities: all funds are directly transferred to the Diabetes Centre's nonprofit Research Foundation. The other authors declare no competing interests.

Supplementary information

Supplementary Table 1

Evidence of renoprotective effects of established glucose lowering agents in patients with T2DM (DOC 61 kb)

Supplementary Table 2

Evidence of renoprotective effects of established blood pressure lowering agents in patients with T2DM (DOC 116 kb)

Supplementary Table 3

Evidence of renoprotective effects of an established multifactorial intervention in patients with T2DM (DOC 41 kb)

Supplementary Table 4

Renal effects of GLP-1R agonists and DPP-4 inhibitors in preclinical studies (DOC 75 kb)

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Muskiet, M., Smits, M., Morsink, L. et al. The gut–renal axis: do incretin-based agents confer renoprotection in diabetes?. Nat Rev Nephrol 10, 88–103 (2014). https://doi.org/10.1038/nrneph.2013.272

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