Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapieJun 18, 2023

How well incretin-based drugs may work for diabetic kidney disease

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

The novel dual GIP and GLP-1 receptor agonist tirzepatide has recently been launched.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease.
Incretin-based therapies, including GLP-1 receptor agonists and DPP-4 inhibitors, may have vasotropic actions that could help reduce DKD.
GIP, another incretin, has been considered unsuitable for treating type 2 diabetes due to diminished insulin action post-secretion.
Recent findings suggest that resistance to GIP can be reversed with improved glycemic control.
Novel dual- or triple-receptor agonists targeting GLP-1, GIP, and glucagon receptors aim to address multiple metabolic pathways.
The long-term effects of tirzepatide on kidney function require further investigation.

Simplified

Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease (CKD), leading end-stage renal disease. Thus, DKD is one of the most important diabetic complications. Incretin-based therapeutic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonizts and dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to elicit vasotropic actions, suggesting a potential for effecting reduction in DKD. Glucose-dependent insulinotropic polypeptide (GIP) is also classified as an incretin. However, the insulin action after GIP secretion is known to be drastically reduced in patients with type 2 diabetes. Therefore, GIP has been formally considered unsuitable as a treatment for type 2 diabetes in the past. This concept is changing as it has been reported that resistance to GIP can be reversed and its effect restored with improved glycemic control. The development of novel dual- or triple- receptor agonizts that can bind to the receptors, not only for GLP-1 but also to GIP and glucagon receptors, is intended to simultaneously address several metabolic pathways including protein, lipid, and carbohydrate metabolism. These led to the development of GIP receptor agonist-based drugs for type 2 diabetes. The possibility of combined GIP/GLP-1 receptor agonist was also explored. The novel dual GIP and GLP-1 receptor agonist tirzepatide has recently been launched (Mounjaro®, Lilly). We have revealed precise mechanisms of the renoprotective effect of GLP-1 receptor agonizts or DPP-4 inhibitors, while the long-term effect of tirzepatide will need to be determined and its potential effects on kidneys should be properly tested.

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Competing interests

Declaration of Competing Interest Akira Mima received a speaker honorarium from Kyowa Kirin, Mitsubishi Tanabe, Kowa, Bayer, Eli Lilly, Mochida, Sumitomo Pharma, Astra Zeneca, and Boehringer Ingelheim. Akira Mima also received research grants from Kyowa Kirin, Sumitomo Pharma, Otsuka, Torii, Mochida, Boehringer Ingelheim, and Eli Lilly.

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How well incretin-based drugs may work for diabetic kidney disease

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