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Review
. 2023 Jul 1;32(4):377-385.
doi: 10.1097/MNH.0000000000000894. Epub 2023 May 4.

Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease

Radica Z Alicic  1   2 , Joshua J Neumiller  1   3 , Katherine R Tuttle  1   2   4
Affiliations
Review

Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease

Radica Z Alicic et al. Curr Opin Nephrol Hypertens. .

Abstract

Purpose of review: Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Development of DKD increases risks for cardiovascular events and death. Glucagon-like peptide-1 (GLP-1) receptor agonist have demonstrated improved cardiovascular and kidney outcomes in large-scale clinical trials.

Recent finding: GLP-1 and dual GLP-1/glucose-depending insulinotropic polypeptide (GIP) receptor agonists have robust glucose-lowering efficacy with low risk of hypoglycemia even in advanced stages of DKD. Initially approved as antihyperglycemic therapies, these agents also reduce blood pressure and body weight. Cardiovascular outcome and glycemic lowering trials have reported decreased risks of development and progression of DKD and atherosclerotic cardiovascular events for GLP-1 receptor agonists. Kidney and cardiovascular protection is mediated partly, but not entirely, by lowering of glycemia, body weight, and blood pressure. Experimental data have identified modulation of the innate immune response as a biologically plausible mechanism underpinning kidney and cardiovascular effects.

Summary: An influx of incretin-based therapies has changed the landscape of DKD treatment. GLP-1 receptor agonist use is endorsed by all major guideline forming organizations. Ongoing clinical trials and mechanistic studies with GLP-1 and dual GLP-1/GIP receptor agonists will further define the roles and pathways for these agents in the treatment of DKD.

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Conflict of interest statement

RZA reports support from NIH research grants 3U24TR001608-05S4, 1OT2OD032581, OT2HL161847, CDC project number 75D301-21-P-12254, grants from Bayer AG, and personal fees and other support from Boehringer Ingelheim outside the submitted work. JJN reports personal fees and other support from Bayer AG, Sanofi, Novo Nordisk, and Dexcom outside the submitted work. KRT is supported by NIH research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568 and CDC project number 75D301-21-P-12254; and reports other support from Eli Lilly; personal fees and other support from Boehringer Ingelheim; personal fees and other support from AstraZeneca; grants, personal fees and other support from Bayer AG; grants, personal fees and other support from Novo Nordisk; grants and other support from Goldfinch Bio; other support from Gilead; and grants from Travere outside the submitted work.

Figures

Box 1
Box 1
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FIGURE 1
FIGURE 1
Tissue distribution of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors and proposed biological actions. VSCM, vascular smooth muscle cells [26▪,27].
FIGURE 2
FIGURE 2
Incretin effects on structural changes observed in diabetic kidney disease. A. Histological manifestations of diabetic kidney disease include glomerular hypertrophy with expansion of the mesangium by matrix and mesangial cells; mesangial matrix accumulation with the formation of nodules (Kimmelstiel–Wilson nodules) and focal to global glomerulosclerosis; thickening of the glomerular basement membrane (GBM); podocyte foot process fusion, effacement and loss; tubular basement membrane thickening with interstitial inflammation, fibrosis and immune cell infiltration (including macrophages, lymphocytes and polymorphonuclear leukocytes); and arteriolar hyalinosis. B. Treatment with incretin-based therapies can ameliorate the structural changes in the kidney that are induced by diabetes, at least in part, through anti-inflammatory and antifibrotic effects. ECM, extracellular matrix. Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol 2021; 17(4):227-244.
See this image and copyright information in PMC

References

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MeSH terms