Renal Effects of Incretin-Based Diabetes Therapies: Pre-clinical Predictions and Clinical Trial Outcomes
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Purpose of Review
The purpose of this review is to correlate predictions based on pre-clinical data with outcomes from clinical trials that examine the effects of incretin-based diabetes treatments on the kidney. The incretin-based treatments include agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of the enzyme, dipeptidyl peptidase-4 (DPP-4). In addition, what is known about the incretin-based therapies will be compared to what is known about the renal effects of SGLT2 inhibitors.
Large-scale clinical trials have shown that SGLT2 inhibitors reduce albuminuria and preserve estimated glomerular filtration rate (eGFR) in patients with diabetic nephropathy. A concise and plausible hemodynamic mechanism is supported by pre-clinical research on the physiology and pharmacology of SGLT2. Large-scale clinical trials have shown that incretin-based therapies mitigate albuminuria but have not shown beneficial effects on eGFR. Research on the incretin-based therapies has yielded a diverse array of direct effects throughout the body, which fuels speculation as to how these drugs might benefit the diabetic kidney and affect its function(s). But in vivo experiments have yet to confirm that the proposed mechanisms underlying emergent phenomena, such as proximal tubular fluid reabsorption, are the ones predicted by cell and molecular experiments.
There may be salutary effects of incretin-based treatments on the diabetic kidney, but the system is complex and not amenable to simple explanation or prior prediction. This contrasts with the renal effects of SGLT2 inhibitors, which can be explained concisely.
KeywordsDPP-4 GLP-1 SGLT2 Glomerular filtration Tubular reabsorption Albuminuria
The authors work was supported by the National Institutes of Health (R01DK56248, R01DK112042, R01DK106102, P30DK079337), the Department of Veterans Affairs, and investigator-initiated research grants by Bristol-Myers Squibb, Merck, and Boehringer Ingelheim.
Compliance with Ethical Standards
Conflict of Interest
Dr. Thomson has received research support from Merck and Pfizer. Dr. Vallon has served as a consultant and received honoraria from Boehringer Ingelheim, Intarcia Therapeutics, Janssen Pharmaceutical, Eli Lilly, and Merck, and received grant support for investigator-initiated research from Boehringer Ingelheim, Astra-Zeneca, Fresenius, Janssen, and Bayer.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
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