Effects of Semaglutide on Body Composition and Glomerular Filtration Rate: A Prespecified Analysis of the SMART Trial

Background: The glucagon-like peptide 1 receptor agonist semaglutide reduces HbA1c, body weight, blood pressure, and glomerular filtration rate (GFR) decline. Semaglutide may influence serum creatinine and cystatin C levels via non-kidney related mechanisms and thereby affect estimated GFR. We studied the relationship between changes in body composition, estimated and measured GFR, and blood pressure during semaglutide treatment. Methods: We performed a prespecified analysis of a randomized placebo-controlled double blind clinical trial in 101 adults with chronic kidney disease (CKD) with overweight status or obesity and without type 2 diabetes. Participants were randomized to 24-weeks semaglutide 2.4 mg/week subcutaneous or matched placebo treatment. We measured GFR with iohexol-clearance, estimated GFR with creatinine and cystatin C, and used bio-impedance spectroscopy to determine lean body mass, fat mass, and extracellular water. Results: After 24 weeks treatment, semaglutide compared to placebo changed total body weight, lean body mass, and fat mass by -9.1 (95% Confidence Interval [CI] -11.0, -7.2) kg, -2.5 (95%CI -6.6, 1.6) kg, and -3.9 (95%CI -7.8, 0.0) kg, respectively. No correlations were present between changes in total body weight, lean body mass, and fat mass with changes in estimated (creatinine or cystatin C) or measured GFR during semaglutide treatment, (all Spearman correlation coefficients <0.23). Similar results were observed in multivariable adjusted analyses. Semaglutide compared to placebo changed extracellular water and systolic blood pressure by -0.9 (95%CI -1.6, -0.1) L and -6.3 (95%CI -10.9, -1.7) mmHg, respectively. Systolic blood pressure changes during semaglutide treatment correlated with extracellular water changes (Spearman correlation 0.40; p=0.005),. Conclusion: Semaglutide reduced lean body mass and fat mass in patients with CKD with overweight status or obesity. These changes did not correlate with changes in creatinine or cystatin C eGFR or mGFR, suggesting that body weight reductions of 10% with semaglutide does not influence GFR estimates.