Mind the Plateau: A Mathematical Modeling Analysis of Long-Term GLP-1 Receptor Agonist Treatment

Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed obesity treatment by inducing clinically significant weight loss. However, long-term use can lead to a plateau that may trigger discontinuation and weight regain.

Use mathematical modeling to test the hypothesis that the weight-loss plateau observed during long-term GLP-1 receptor agonist use reflects predictable changes in energy dynamics.

Secondary mathematical modeling applying Hall's human metabolism model to estimate changes in energy intake and expenditure over 176 weeks of treatment and 17 weeks after discontinuation.

Modeling was anchored to a single representative phenotype using average baseline demographics and weight dispersions from a clinical trial.

Percent change in body weight, body mass index (BMI), energy intake, energy expenditure.

Monte Carlo methods captured variability. Modeled trajectories of energy intake and expenditure illustrated energy balance dynamics.

Modeled weight loss peaked at 24.0% (95% confidence interval [CI], 22.6-25.4) by week 96, reducing weight from 108 kg (BMI, 40.0) to 82.9 kg (BMI, 33.0). A plateau persisted for ∼78 weeks despite continued treatment. Energy intake decreased 32.1% during the first 4 weeks, then rose to match energy expenditure by week 98 (2500 kcal, vs 2508 kcal, respectively). After discontinuation (week 176), energy intake exceeded baseline, contributing to a 5.3% weight loss reversal. Energy expenditure declined 9.2% from baseline by week 98 and stabilized.

Although GLP-1 receptor agonists achieve unprecedented weight loss, many individuals plateau but remain with overweight/obesity. This plateau reflects the narrowing of the energy intake and expenditure gap during long-term treatment. To attenuate this, systematic integration of nutrition and behavioral therapy could be tested as adjuncts, particularly approaches that support nutrient adequacy and prevent excess energy intake. Whether such strategies can sustain or extend GLP-1 receptor agonist-induced weight loss warrants future study.