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

Source abstract

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. Study Importance Questions What is already known? : Patients with Type 2 Diabetes (T2D) lose significantly less weight on GLP-1 based pharmaceuticals than patients with obesity alone. The physiological basis for this gap remains poorly understood. What are the new findings? : Mathematical modeling demonstrates that reduced energy expenditure and urinary glucose excretion (UGE) associated with glycemic improvements during semaglutide treatment can play important roles in attenuating weight loss in people with T2D, especially in those on background therapy using sodium glucose co-transporter 2 (SGLT2) inhibitors. How might results change clinical practice or research? : These findings may help clinicians interpret attenuated weight loss in patients with T2D and set individualized expectations. The findings may also help pharmaceutical companies and regulators interpret data on weight loss differences between different patient populations and design trials to better understand weight loss variability in patients with T2D.