Effects of semaglutide on kidney disease in type 2 diabetes: a randomized placebo-controlled trial

IF 52.5 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature Medicine Pub Date : 2026-10-01 DOI:10.1038/s41591-026-04674-2

Katherine R. Tuttle, Petter Bjornstad, Cathy Smith, Menno Pruijm, Phillip J. McCown, Jeffrey B. Hodgin, David Z. I. Cherney, Nicolas Belmar, Milenta Mariam Chacko, Vivek Das, Thomas P. Gunnarsson, Thomas Idorn, Philip A. Schytz, Amaya Zaratiegui, Matthias Kretzler

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Abstract

The GLP-1 receptor agonist semaglutide preserves kidney function in people with type 2 diabetes and chronic kidney disease, but the underlying mechanisms are unclear. Here we report a 52-week randomized trial of subcutaneous semaglutide 1 mg once weekly versus placebo (n = 106 (n = 25 women, n = 81 men)) in participants with type 2 diabetes and chronic kidney disease. To identify kidney-specific mechanisms of action for semaglutide, we performed integrated multiparametric magnetic resonance imaging of the kidney and biopsy for histology (n = 33), alongside single-nucleus (n = 22) and spatial transcriptomics (n = 13) on paired samples with before- and after-treatment measurements. Coprimary magnetic resonance imaging outcomes (oxygenation by R2*, global perfusion and tissue inflammation by T1 mapping) were not significantly altered by semaglutide versus placebo treatment. Secondary outcomes revealed that semaglutide treatment, as compared to placebo, was associated with a significantly reduced renal artery resistive index and stabilization of the apparent diffusion coefficient, indicating prevention of fibrosis progression. Moreover, secondary transcriptomic outcomes revealed pronounced effects of semaglutide on glomerular endothelial cells, consistent with the results of spatial analyses indicating reduced numbers of immune cells in the proximity of these endothelial cells. The results from this trial indicate that mechanisms of kidney protection by semaglutide may include reduced vascular resistance, prevention of fibrosis and improved underlying molecular programs promoting endothelial cell health. ClinicalTrials.gov identifier: NCT04865770.

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西马鲁肽对2型糖尿病肾病的影响：一项随机安慰剂对照试验

GLP-1受体激动剂semaglutide可保护2型糖尿病和慢性肾病患者的肾功能，但其潜在机制尚不清楚。在这里，我们报告了一项为期52周的随机试验，在2型糖尿病和慢性肾病患者中，皮下注射西马鲁肽1mg，每周1次，与安慰剂相比（n = 106 （n = 25女性，n = 81男性））。为了确定西马鲁肽的肾脏特异性作用机制，我们对配对样本进行了多参数肾脏磁共振成像和组织学活检（n = 33），以及单核（n = 22）和空间转录组学（n = 13），并进行了治疗前后的测量。与安慰剂治疗相比，西马鲁肽治疗的主要磁共振成像结果（R2*的氧合，T1定位的整体灌注和组织炎症）没有显著改变。次要结果显示，与安慰剂相比，semaglutide治疗与肾动脉阻力指数显著降低和表观扩散系数稳定相关，表明可以预防纤维化进展。此外，次级转录组学结果显示，semaglutide对肾小球内皮细胞有明显的影响，这与空间分析结果一致，表明这些内皮细胞附近的免疫细胞数量减少。本试验结果表明，西马鲁肽保护肾脏的机制可能包括降低血管阻力、预防纤维化和改善促进内皮细胞健康的潜在分子程序。ClinicalTrials.gov识别码：NCT04865770。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Medicine 医学-生化与分子生物学

CiteScore

100.90

自引率

0.70%

发文量

525

审稿时长

1 months

期刊介绍： Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.