Semaglutide treatment in obese patients reduced body weight by 4% and HbA1c by 1.1% at 6 months, with modeling suggesting weight loss drives renoprotection more than direct renal actions.
Observational (n=636)
No
Does semaglutide improve body weight, HbA1c, blood pressure, and renal hemodynamics in obese patients with and without CKD?
A mathematical model of semaglutide effects suggests that weight loss may contribute more to renoprotection than direct renal actions, though discrepancies with clinical eGFR changes highlight the need for further mechanistic studies.
Patients with obesity and T2D often experience chronic kidney disease (CKD), hyperfiltration, and altered renal hemodynamics. Glucagon-like peptide-1 receptor agonists (GLP1) have been associated with clinical renoprotection but the mechanisms are unclear. The objective of this study was to develop and validate a mathematical model that integrates established GLP1–mediated effects on weight loss, glucose control, sodium transport, and renal hemodynamics, and we hypothesize this model can reproduce real-world clinical responses across varying levels of kidney function. De-identified clinical data were obtained from the UMMC Research Data Warehouse ( >1.5 million patients; >60 million encounters, 2013–2025). Obese patients (BMI ≥30 kg/m 2 ) treated with semaglutide with ≥1 estimated glomerular filtration rate (eGFR) measurement before and after GLP1 initiation with at least 2 follow-up encounters were included. Patients using other GLP1 were excluded. A total of 636 patients met criteria and were stratified by baseline renal function into CKD (eGFR < 60; n=138) and non-CKD (eGFR ≥60 ml/min/1.73 m 2 ; n=498). Mean weekly GLP1 dose was 0.6 mg, and 86% had diabetes. At 6 months, body weight (BW) and HbA1c declined as expected (−4% and −1.1%, respectively). Systolic blood pressure (SBP) decreased ~5 mmHg. eGFR increased slightly in CKD patients (+2 ml/min/1.73 m 2 ) but declined in the non-CKD group (−5 ml/min/1.73 m 2 ). Quantitative effects of semaglutide on appetite, insulin secretion, renal sodium handling, and afferent renal tone were incorporated into a mathematical model of physiology (HumMod). Simulations were run under diabetic conditions associated with elevated BMI (38 kg/m 2 ), SBP (140 mmHg), and cardiac output (7 L/min) with or without 75% renal mass removed (CKD and non-CKD, respectively). In the non-CKD model, weekly doses of 0.6 mg GLP1 were modeled for 6 months and was associated with a reduction in BW (-4%), SBP (-12 mmHg), HbA1c (-1%) and GFR (-6 ml/min/1.73m 2 ). GLP1 in our CKD model was also associated with a reduction in BW (-6%), SBP (-7 mmHg), HbA1c (-1%), albuminuria, and glomerular pressure. Interestingly, GFR was reduced (-3 ml/min/1.73m 2 ) in contrast to the clinical data. This mismatch may reflect GLP1 effects not yet represented in the model or limitations of creatinine-based eGFR measurements in patients undergoing substantial weight and muscle-mass loss. If GLP1’s effect on appetite and BW loss was removed from the mathematical model, the majority of the reductions in BP and GFR were mitigated, suggesting that the benefits from weight loss may contribute more to renoprotection than direct renal actions of GLP1. In summary, we developed a physiological model using HumMod that mimics many of the responses to GLP1 seen in routine clinical practice. However, the decline in GFR predicted by our model highlights the need for mechanistic studies that make direct measurements of renal hemodynamics in patients undergoing substantial GLP1–induced weight loss. This work was supported by grants from the National Heart, Lung, and Blood Institute (T32HL105324 and U54 HL169191), National Institute on Minority Health and Health Disparities (R00 MD014738), and the National Institute of General Medical Sciences (U54 GM115428 and P30 GM149404). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Mallette et al. (2026) conducted an observational in Obesity and kidney disease (n=636). Semaglutide was evaluated on Change in body weight, HbA1c, systolic blood pressure, and eGFR. Semaglutide treatment in obese patients reduced body weight by 4% and HbA1c by 1.1% at 6 months, with modeling suggesting weight loss drives renoprotection more than direct renal actions.