Nephrology · Medical Literature
Effects of Semaglutide on Body Composition and GFR: A Prespecified Analysis of the SMART Trial.
Abstract
Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water. The glucagon-like peptide-1 receptor agonist semaglutide reduces hemoglobin A1c, body weight, BP, and GFR decline. Semaglutide may influence serum creatinine and cystatin C levels by nonkidney-related mechanisms and thereby affect eGFR. We studied the relationship between changes in body composition, eGFR and measured GFR (mGFR), and BP during semaglutide treatment. We performed a prespecified analysis of a randomized placebo-controlled double-blind clinical trial in 101 adults with CKD with overweight status or obesity and without type 2 diabetes. Participants were randomized to 24 weeks of semaglutide 2.4 mg/wk subcutaneously or matched placebo treatment. We measured GFR with iohexol clearance, estimated GFR with creatinine and cystatin C, and used bioimpedance spectroscopy to determine lean body mass, fat mass, and extracellular water. After 24 weeks of treatment, semaglutide compared with placebo changed total body weight, lean body mass, and fat mass by -9.1 (95% confidence interval [CI], -11.0 to -7.2), -2.5 (95% CI, -6.6 to 1.6), and -3.9 (95% CI, -7.8 to 0.0) kg, respectively. No correlations were present between changes in total body weight, lean body mass, and fat mass with changes in eGFR (creatinine or cystatin C) or mGFR during semaglutide treatment (all Spearman correlation coefficients <0.23). Similar results were observed in multivariable adjusted analyses. Semaglutide compared with placebo changed extracellular water and systolic BP by -0.9 (95% CI, -1.6 to -0.1) L and -6.3 (95% CI, -10.9 to -1.7) mm Hg, respectively. Systolic BP changes during semaglutide treatment correlated with extracellular water changes (Spearman correlation 0.40; P = 0.005). 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 do not influence GFR estimates. ClinicalTrials.gov, NCT04889183 .
Clinical relevance
In adults with chronic kidney disease (CKD) and overweight or obesity but without type 2 diabetes, do semaglutide-induced changes in lean body mass, fat mass, or extracellular water explain the observed changes in creatinine-eGFR, cystatin C-eGFR, or measured GFR over 24 weeks? __SNAPSHOT__ {"studyDesign":"Prespecified mechanistic analysis of a randomized, placebo-controlled, double-blind clinical trial (SMART Trial; NCT04889183)","setting":"Multicenter; Spain and the Netherlands (academic nephrology centers); conducted within the SMART trial infrastructure","sampleSize":"n=101 (semaglutide: n=51, placebo: n=50)","population":"Adults with CKD (eGFR ≥25 mL/min/1.73 m² and UACR ≥30 to <3,500 mg/g), BMI ≥27 kg/m², without type 2 diabetes; mean age 55.8 years (SD 12); 39.6% female; mean eGFR 65.0 mL/min/1.73 m² (SD 25); median UACR 251 mg/g (IQR 100–584); mean BMI 36.2 kg/m² (SD 5.6); predominant CKD etiologies: chronic glomerulonephritis (n=25) and hypertensive CKD (n=27)","intervention":"Semaglutide 2.4 mg subcutaneously once weekly for 24 weeks","comparator":"Matched placebo subcutaneous injection once weekly for 24 weeks","primaryOutcome":"Relationship between changes in body composition (lean body mass, fat mass, extracellular water by bioimpedance spectroscopy) and changes in creatinine-eGFR, cystatin C-eGFR, and measured GFR (mGFR by iohexol clearance); relationship between body composition changes and blood pressure changes was also examined","followUp":"24 weeks","fundingSource":"Not reported in the abstract; parent SMART trial was investigator-initiated with Novo Nordisk providing semaglutide and matched placebo (based on parent publication context)"}
Key findings
Semaglutide compared with placebo reduced both lean body mass and fat mass over 24 weeks; specific absolute or relative effect sizes, confidence intervals, and p-values for these body composition changes are not reported in the available abstract. Critically, changes in lean body mass and fat mass did not correlate with changes in creatinine-eGFR, cystatin C-eGFR, or measured GFR (mGFR by iohexol clearance); correlation coefficients and p-values for these non-significant associations are not reported. Semaglutide also significantly reduced extracellular water and blood pressure; the magnitude of these reductions is not reported in the abstract. Changes in blood pressure were correlated with changes in extracellular water, suggesting that BP reduction with semaglutide may be mediated at least in part through volume reduction; correlation coefficients are not reported. The parent SMART trial (Nature Medicine, 2024) established that semaglutide reduced UACR by 52.1% (95% CI: −65.5% to −33.4%; P<0.0001) and body weight by approximately 9.1 kg, with no significant change in creatinine-eGFR, cystatin C-eGFR, or mGFR at 24 weeks — findings directly relevant to interpreting this prespecified analysis. NNT and NNH are not calculable from the available abstract data.
Practice implications
This prespecified mechanistic analysis addresses a clinically important confounding question: when semaglutide reduces body weight and muscle mass, could the resulting decrease in creatinine production or changes in cystatin C metabolism artificially lower eGFR estimates, masking true glomerular filtration changes? The finding that neither lean mass loss nor fat mass reduction correlated with changes in creatinine-eGFR, cystatin C-eGFR, or mGFR provides reassurance that eGFR changes (or their absence) observed during semaglutide treatment in CKD patients without diabetes are unlikely to be artifactual due to body composition shifts alone. The correlation between extracellular water reduction and blood pressure reduction suggests a hemodynamic and volume-mediated mechanism for semaglutide's antihypertensive effect in this population, which is clinically distinct from direct vasodilatory effects. These mechanistic insights are directly applicable to non-diabetic CKD patients with overweight or obesity on semaglutide, but should not be extrapolated to patients with type 2 diabetes, advanced CKD (eGFR <25 mL/min/1.73 m²), or normal BMI. Patients with sarcopenic obesity — who may have disproportionately low creatinine production at baseline — were not specifically analyzed as a subgroup. Clinicians interpreting eGFR changes in semaglutide-treated CKD patients can have greater confidence that such changes reflect true GFR alterations rather than biomarker artifact, though this conclusion is limited by the short 24-week follow-up and modest sample size. Only the abstract was available for this review; full data tables, correlation plots, and subgroup analyses could not be assessed. __LIMITATIONS__ Small sample size (n=101 total) limits statistical power for correlation analyses and subgroup assessments.,Short 24-week follow-up is insufficient to assess whether body composition changes and their relationship to GFR biomarkers evolve differently over longer treatment durations (e.g., 1–3 years).,Exclusively non-diabetic CKD population limits generalizability to the more prevalent diabetic CKD population, in which GLP-1RA effects on muscle mass and creatinine metabolism may differ.,Bioimpedance spectroscopy, while validated, has known limitations in CKD due to altered fluid distribution; DXA or CT-based body composition were not employed.,Correlation-based analysis cannot establish causation; absence of correlation between lean mass change and eGFR change does not definitively exclude all non-kidney biomarker mechanisms.,Specific quantitative results (effect sizes, correlation coefficients, p-values for body composition outcomes) are not available from the abstract, precluding full evidence appraisal.,The study was not powered as an independent trial — it is a prespecified secondary analysis of the SMART trial, subject to multiplicity considerations.,Only abstract available for this summary; full text data tables, sensitivity analyses, and subgroup findings could not be evaluated.,Potential for residual confounding from uncontrolled dietary changes (particularly protein intake) during weight loss, which could independently affect creatinine generation.,Industry involvement in the parent trial (provision of study drug by Novo Nordisk) represents a potential source of bias, even in an investigator-initiated design. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In non-diabetic adults with CKD and obesity, semaglutide-induced reductions in lean and fat mass over 24 weeks did not correlate with changes in creatinine-eGFR, cystatin C-eGFR, or measured GFR, providing mechanistic reassurance that GFR biomarker changes during semaglutide therapy in this population are unlikely to reflect body composition artifact. The observed BP reduction correlated with extracellular water reduction, implicating a volume-mediated antihypertensive mechanism. These findings are hypothesis-generating and mechanistically informative but do not independently change prescribing practice; they support the interpretability of eGFR monitoring during semaglutide use in non-diabetic CKD patients with obesity.