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. 2025 Oct 30;40(11):2182-2192.
doi: 10.1093/ndt/gfaf114.

Rationale, design and baseline characteristics of REMODEL, a mechanism-of-action trial with semaglutide in people with type 2 diabetes and chronic kidney disease

David Z I Cherney  1 , Nicolas Belmar  2 , Petter Bjornstad  3   4 , Milenta M Chacko  5 , Thomas P Gunnarsson  2 , Jeffrey B Hodgin  6 , Matthias Kretzler  7 , Menno Pruijm  8 , Philip A Schytz  2 , Katherine R Tuttle  9   10
Affiliations

Rationale, design and baseline characteristics of REMODEL, a mechanism-of-action trial with semaglutide in people with type 2 diabetes and chronic kidney disease

David Z I Cherney et al. Nephrol Dial Transplant. .

Abstract

Background: Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD) and kidney failure globally. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces the risk of major kidney, cardiovascular and mortality outcomes in people with T2D and CKD, but the mechanism of action remains unclear.

Methods: The REMODEL trial (NCT04865770) is a 52-week placebo-controlled, double-blind, parallel-group, randomized trial in adults with T2D and CKD. Inclusion criteria include haemoglobin A1c (HbA1c) ≤9%, estimated glomerular filtration rate (eGFR) ≥30-≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) ≥20-<5000 mg/g. The co-primary outcomes were magnetic resonance imaging (MRI) based, including change in kidney oxygenation, perfusion and inflammation. Secondary outcomes include change from baseline in creatine clearance rate, urinary sodium excretion, albumin excretion rate and kidney fibrosis and blood flow parameters measured by MRI. A subgroup had kidney biopsies at baseline and at the end of the treatment for tissue-based interrogation, including single nucleus and spatial transcriptomics, pathology and advanced histological assessment.

Results: Across eight countries, 106 participants (n = 33, biopsy subgroup) were enrolled. The mean age was 65.3 years [standard deviation (SD) 9.9] at baseline with HbA1c of 7.1% (SD 0.9), creatinine-based eGFR of 51.1 ml/min/1.73 m2 (SD 10.4) and median UACR of 187.3 mg/g (interquartile range 60.5-546.4). Renin-angiotensin system inhibitor use was 98.1% and sodium-glucose co-transporter 2 inhibitor use was 38.7%. In the kidney biopsy subgroup, baseline characteristics were like those of the full population. Histological analysis of kidney tissues revealed 17 participants with primarily diabetic nephropathy, 6 participants with primarily vascular features, 9 with mixed diabetic nephropathy and vascular characteristics and 1 with membranous nephropathy.

Conclusion: The REMODEL trial leverages multipronged approaches to investigate the kidney-specific effects and underlying mechanisms of semaglutide in a representative population of people with T2D and CKD, which supports the generalizability and clinical relevance of the findings.

Keywords: functional magnetic resonance imaging; gene expression; incretin therapy; kidney; nutrient-stimulated hormone (NuSH) therapy.

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Conflict of interest statement

D.Z.I.C. has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK and Novo Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo Nordisk. N.B., T.P.G. and P.A.S. are employees and stockholders of Novo Nordisk A/S. P.B. is a consultant and advisory board or steering committee member for Lilly, Novo Nordisk, AstraZeneca, Boehringer Ingelheim and Horizon Pharma/Amgen; DMC chair for Bayer; and received research funding from Lilly, Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Horizon Pharma/Amgen and Merck. MMC: Employee and Stockholder of Novo Nordisk A/S. J.B.H. is a consultant for Sygnamap. M.K. is a consultant or receives funding all via the University of Michigan from Boehringer Ingelheim, Certa, Travere, Maze Therapeutics, Roche, AstraZeneca, Novo Nordisk, Moderna, Chinook, Angion Pharmaceuticals, RenalytixAI, Lilly, Gilead, Sanofi, Regeneron, Janssen, Vera Therapeutics and Dimerix. M.P. has served on advisory boards for GSK, Boehringer Ingelheim, Baxter, Novo Nordisk and Bayer; was a speaker for AstraZeneca, Astellas, Vifor, Baxter and Braun and received investigator-initiated grant support from Nephrospec. K.T. has received investigator-initiated grant support from Travere and Bayer to Providence Inland Northwest Health outside of the submitted work and consultancy fees from AstraZeneca, Boehringer Ingelheim, Bayer, Lilly, Novo Nordisk, Travere and Pfizer.

Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
Proposed mechanisms by which GLP-1RAs may have direct effects on the kidney in people with T2D and CKD. ECM: extracellular matrix; PKA: protein kinase A.
Figure 2:
Figure 2:
Summary of the REMODEL trial design. OW: once weekly; s.c.: subcutaneous.
Figure 3:
Figure 3:
Kidney function assessments. (A) Baseline creatinine-based eGFR intervals in the full population and biopsy subgroup. (B) Baseline distribution of UACR in the full population and biopsy subgroup.
Figure 4:
Figure 4:
Histopathological analysis of biopsy subgroup samples from the REMODEL trial. (A) Proportional histopathological predominant characteristics. (B) Representative images of diabetic nephropathy and vascular biopsy samples. *One biopsy was diagnosed as membranous nephropathy and was therefore excluded from this analysis.
See this image and copyright information in PMC

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