Potential kidney protection with liraglutide and semaglutide: Exploratory mediation analysis
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Abstract Aims To investigate whether effects on chronic kidney disease risk factors could explain the apparent reduction in kidney outcomes (composite of macroalbuminuria, doubling of serum creatinine, renal replacement therapy, or renal death), primarily driven by changes in albuminuria, after treatment with the glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) liraglutide and semaglutide in patients with type 2 diabetes in the LEADER and SUSTAIN 6 trials. Materials and Methods We evaluated the mediation effect of glycated haemoglobin (HbA1c), systolic blood pressure (BP), and body weight on the kidney effects of GLP‐1RAs. Diastolic BP, haemoglobin, heart rate, low‐density lipoprotein and total cholesterol, and white blood cell count were also investigated. The mediation effect was estimated by the novel Vansteelandt statistical method. Subgroups with estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m 2 were examined in LEADER. Results We observed that HbA1c mediated 25% (95% confidence interval [CI] −7.1; 67.3) and 26% (95% CI noncalculable), and systolic BP 9% (95% CI 2.8; 22.7) and 22% (95% CI noncalculable) of kidney effects of GLP‐1RAs in LEADER and SUSTAIN 6, respectively. Small or no mediation was observed for the other parameters; for example, body weight mediated 9% (95% CI −7.9; 35.5) in the former and did not mediate effects in the latter study. Mediation by HbA1c was greater in patients with eGFR ≥60 mL/min/1.73 m 2 (57%) versus those with eGFR <60 mL/min/1.73 m 2 (no mediation). Conclusions Our results suggest that HbA1c and systolic BP may moderately mediate kidney benefits of liraglutide and semaglutide, with all other variables having a small to no effect. Potential kidney benefits may be driven by other mediators or potentially by direct mechanisms.
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Statistical correction for changes in body weight did not attenuate the albuminuria-lowering effects of GLP-1 receptor agonists in the cardiovascular outcome trials.
“Moreover, statistical correction for changes in body weight did not attenuate the albuminuria-lowering effects of GLP-1 receptor agonists in the CVOTs (23).”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [23]
The Results report that body weight mediated 9% of the composite kidney benefit in LEADER and none in SUSTAIN 6; the Discussion concludes that body weight was not an important mediator in either trial. The Methods define that outcome as including, but not limited to, new-onset macroalbuminuria. The paper therefore supports the broad point about kidney benefit, but it does not report a weight-corrected analysis of albuminuria lowering specifically, and the claim’s unqualified ‘did not attenuate’ overlooks the 9% estimate in LEADER. (LLM, conf=0.86)
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“The first clinical evidence for beneficial effects of GLP-1 receptor agonists came from the cardiovascular outcome trials (CVOTs) that were conducted with these agents, where kidney endpoints were collected as secondary or exploratory endpoints.”
- Authors
- Mann, J. F. E., Buse, J. B., Idorn, T., Leiter, L. A., Pratley, R. E., Rasmussen, S., Vilsbøll, T., Wolthers, B., & Perkovic, V.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of North Carolina at Chapel Hill (US)
- Novo Nordisk (Denmark) (DK)
- St. Michael's Hospital (CA)
- AdventHealth Orlando (US)
- University of Copenhagen (DK)
- UNSW Sydney (AU)
- Corresponding author
- Mann, Johannes F. E.
- ORCID
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2021-06
- Volume
- 23
- Issue
- 9
- Pages
- 2058-2066
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- PMC
- PMC8453827
- OpenAlex
- W3163402894
- Cited by
- 120
- References
- 11
- Citations by year
- 2026: 31 · 2025: 31 · 2024: 23 · 2023: 23 · 2022: 10 · 2021: 2
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Obesity and Metabolism (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
- Funders
- Novo Nordisk
- National Institutes of Health (UL1TR002489)
- Canadian Institutes of Health Research
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK124723)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- liraglutide, semaglutide, GLP-1 receptor agonists, type 2 diabetes, chronic kidney disease, renal protection, mediation analysis, HbA1c, systolic blood pressure, body weight, albuminuria, estimated glomerular filtration rate, LEADER trial, SUSTAIN 6 trial
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Mediation Analysis, Semaglutide, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Humans, Hypoglycemic Agents, Kidney
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