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

A recent study delves into why patients with Type 2 Diabetes (T2D) experience less weight loss when treated with semaglutide compared to those without. The research sought to quantify the impact of changes in energy expenditure and urinary glucose excretion (UGE) on weight loss, as these factors are influenced by improved glycemic control.

By modifying an existing mathematical model of human energy balance dynamics, the study incorporated the effects of hyperglycemia on energy expenditure and calculated UGE based on estimated glomerular filtration rate, renal threshold for glucose reabsorption, and estimated plasma glucose derived from measured glycated hemoglobin (HbA1c).

The researchers simulated the effects of semaglutide treatment and sodium glucose co-transporter 2 inhibitors (SGLT2i) therapy by adjusting the renal threshold. The analysis revealed that the reduced weight loss in T2D patients without background SGLT2i therapy could partly be attributed to alterations in UGE and energy expenditure.

Notably, patients already on stable background SGLT2i therapy were predicted to exhibit the most significant weight loss attenuation. The findings underscore the substantial role that changes in energy expenditure and UGE associated with glycemic improvements can play in offsetting the negative energy balance experienced by T2D patients treated with semaglutide, particularly those on stable background SGLT2i therapy.