Semaglutide lowers kidney fat, improves glomerular haemodynamic in T2D patients with CKD

Treatment with semaglutide helps reduce kidney fat and enhance glomerular haemodynamic in adult patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), as shown in the REMODEL trial.

Furthermore, semaglutide improves endothelial injury by mitigating inflammation and fibrosis and via metabolic reprogramming.

“Semaglutide, a glucagon-like peptide-1 receptor agonist, reduces the risk of major kidney, cardiovascular, and mortality outcomes in people with T2D and CKD,” said lead author Dr Katherine R Tuttle, Kidney Research Institute and Nephrology Division, University of Washington School of Medicine, Seattle, Washington, US. [N Engl J Med 2024;391:109-121]

However, “[t]he mechanism-of-action for the kidney protective effects of semaglutide is unclear with a number of pathways implicated,” she added.

In the REMODEL trial, Tuttle and her team randomized 106 adults (mean age 65 years) with T2D (HbA1c <9.0 percent) and CKD (estimated glomerular filtration rate [eGFR], ≥30 to ≤75 mL/min/1.73 m²; urine albumin-creatinine ratio [UACR] ≥20 to <5,000 mg/g) 2:1 to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo for 52 weeks.

Additionally, a subgroup of patients (n=33) underwent paired kidney biopsy for histology, single-nuclear, and spatial transcriptomics. Of the participants, 25 (24 percent) were female. At baseline, their mean eGFR was 51 mL/min/1.73 m² and median UACR was 187 mg/g.

The mean estimated treatment effects for semaglutide at 52 weeks included a 40-percent lower UACR (estimated treatment ratio [ETR], 0.60, 95 percent confidence interval [CI], 0.41‒0.88; p=0.008) and 12-mL/min higher creatinine clearance (estimated treatment difference [ETD], 12.0, 95 percent CI, 0.7‒23.3; p=0.038) than placebo. [ASN 2025, abstract FR-OR089]

Kidney fat

Semaglutide also reduced perirenal fat volume by 25 percent (ETR, 0.75, 95 percent CI, 0.58‒0.97; p=0.027) and sinus fat volume by 13 percent (ETR, 0.87, 95 percent CI, 0.78‒0.97; p=0.012). Moreover, an increase was noted in cortical apparent diffusion coefficient (ADC; ETR, 1.05, 95 percent CI, 1.01‒1.09; p=0.005).

The use of semaglutide likewise reduced the renal arterial resistive index (RARI; ETR, 0.96, 95 percent CI, 0.93‒0.99; p=0.008). On the other hand, cortical oxygenation (ETR, 0.98, 95 percent CI, 0.96‒1.01; p=0.13) and perfusion showed an increasing trend (ETR, 1.10, 95 percent CI, 0.98‒1.24; p=0.0.96).

“Increases in kidney oxygenation or global kidney perfusion did not reach statistical significance,” said Tuttle, adding that reduced RARI was indicative of lower renal vascular resistance, whereas “no decrease in cortical ADC [reflects] stabilized fibrosis in the kidney cortex.”

In subgroup analysis, a 10-percent decrease was observed in the arteriolar intimal area of the most diseased vessel. Additionally, glomerular endothelial-cell transcriptomes revealed that semaglutide resulted in the downregulation of genes in metabolic, inflammatory, and fibrotic pathways.

“T2D is the leading cause of kidney failure globally, with 40 percent of people with T2D also living with CKD,” Tuttle noted. [Clin J Am Soc Nephrol 2017;12:2032-2045; N Engl J Med 2022;387:1430-1431; Kidney Int Suppl (2011) 2022;12:7-11]