Why Do Patients with Type 2 Diabetes Lose Less Weight on GLP-1s? A Mathematical Modeling Analysis

Abstract

Objective: To investigate the extent to which attenuation of weight loss observed in patients with Type 2 Diabetes (T2D) treated with semaglutide can be quantitatively explained by changes in energy expenditure and urinary glucose excretion (UGE) that occur with improved glycemic control. Methods: A previously validated mathematical model of human energy balance dynamics was modified to simulate patients with T2D by including the effects of hyperglycemia on energy expenditure as well as UGE calculated based on estimated glomerular filtration rate (eGFR), renal threshold (RT) for glucose reabsorption, and estimated plasma glucose derived from measured glycated hemoglobin (HbA1c). Treatment with sodium glucose co-transporter 2 inhibitors (SGLT2i) was simulated by lowering RT. Results: Attenuated semaglutide induced weight losses in T2D patients without background SGLT2i therapy were partially explained by changes in UGE and energy expenditure. Patients with T2D on stable background SGLT2i therapy were predicted to have the greatest attenuation of weight loss. Conclusions: Changes in energy expenditure and UGE associated with glycemic improvements can substantially offset negative energy balance in patients with T2D treated with semaglutide, especially in patients on stable background SGLT2i therapy.