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Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence

Nature Reviews Nephrology volume 17, pages 227–244 (2021)Cite this article

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Abstract

As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents — sodium–glucose cotransporter 2 inhibitors and incretin therapies — has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.

Key points

  • Glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors reduce the onset and progression of albuminuria in patients with type 2 diabetes mellitus (T2DM).

  • GLP1R agonists have been shown to delay the decline of estimated glomerular filtration rate in patients with T2DM, including those with or without moderate-to-severe chronic kidney disease. DPP4 inhibitors demonstrate only modest improvement in albuminuria, with no effect on glomerular filtration rate.

  • The kidney-protective effects of GLP1R agonists might be at least partly independent of their effects on glycaemic control.

  • In addition to improved glycaemic control, GLP1R agonists demonstrate a direct effect on the reduction of both systemic and local inflammation, which is a plausible mechanism underpinning kidney protection.

  • Experimental data show that incretin-based therapies block inflammatory cell infiltration and reduce the expression of anti-fibrotic and anti-inflammatory mediators in the diabetic kidney.

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Fig. 1: GLP1 secretion from enteroendocrine L cells and glucagon secretion from pancreatic α-cells.
Fig. 2: Proposed incretin signalling pathways in kidney cells.
Fig. 3: Incretin effects on structural kidney damage observed in diabetic kidney disease.

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Acknowledgements

K.R.T. is supported by four NIDDK/NIH grants, one NCATS/NIH grant, one NIMHD/NIH grant, and a CDC contract, all from the US government, as well as a research grant from Goldfinch Bio.

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Authors and Affiliations

  1. Providence Medical Research Center, Providence Health Care, Spokane, WA, USA

    Radica Z. Alicic, Emily J. Cox & Katherine R. Tuttle

  2. Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, WA, USA

    Radica Z. Alicic

  3. Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA

    Joshua J. Neumiller

  4. Nephrology Division, Kidney Research Institute and Institute of Translational Health Sciences, University of Washington, Spokane and Seattle, WA, USA

    Katherine R. Tuttle

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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the manuscript, and reviewed or edited the manuscript before submission.

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Correspondence to Katherine R. Tuttle.

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Competing interests

K.R.T. has received consulting fees for diabetes and CKD from Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca, Gilead, Goldfinch Bio, Novo Nordisk and Bayer. J.J.N. has received consulting fees from Novo Nordisk. R.Z.A. has received consulting fees from Boehringer Ingelheim. E.J.C. declares no competing interests.

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Glossary

Anorexigenic gut peptides

Appetite-reducing peptides.

Tachyphylaxis

Rapid loss or downregulation of a response to a drug.

Volume of distribution

The volume required to dilute a drug to its observed concentration in plasma.

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Alicic, R.Z., Cox, E.J., Neumiller, J.J. et al. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol 17, 227–244 (2021). https://doi.org/10.1038/s41581-020-00367-2

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