Less frequent dosing of GLP-1 receptor agonists as a viable weight maintenance strategy

Abstract

Objective: Incretin mimetics are revolutionizing obesity treatment, but high prices and supply shortages limit patient access. Some clinicians have suggested less frequent dosing as an off-ramping strategy to maintain weight loss, but this approach lacks published evidence regarding its weight loss efficacy. We aim to provide such clinical evidence and to rationalize these results with mathematical modeling.

Methods: We present a real-world case series of two patients who took their incretin mimetic less frequently than recommended. We complement this case report with a pharmacokinetic-pharmacodynamic model of virtual patients that simulates long-term weight change with semaglutide and tirzepatide administered at various frequencies.

Results: Both real-world and virtual patients maintained significant weight loss under reduced dosing frequencies. Our results indicate that reducing frequency does not commensurately reduce efficacy. The majority of weight loss persists even when patients wait 2, 3, or perhaps even 4 weeks between doses.

Conclusions: Our findings support the hypothesis that less frequent administration of incretin mimetics can be a viable and cost-saving long-term weight maintenance strategy in conjunction with sustained lifestyle modification. Further research is warranted to validate the effectiveness of this off-label approach, define optimal dosing regimens to meet individual patient needs, and evaluate the cost-benefit implications.

FIGURE 1

BW loss remains high after reducing dose frequency. After weight loss plateaus with once‐weekly dosing, virtual patients increase their dosing interval (denoted $\mathrm{\tau }$) from 7 days to 10 days (green), 14 days (purple), or 28 days (brown) or retain a 7‐day dosing interval (blue). The red dashed curve depicts a patient who is always on the placebo (PBO₁), and the red dot dashed curve depicts a patient who switches from once‐weekly dosing to the placebo after weight loss plateaus (PBO₂). Black markers show weight loss data from Jastreboff et al. [7] (semaglutide in panel A) and Wilding et al. [6] (tirzepatide in other three panels) for the placebo (square markers) and the drug (circle markers). BW, body weight; PBO₁, patient always takes placebo; PBO₂, patient switches to placebo after 120 weeks on the drug. [Color figure can be viewed at wileyonlinelibrary.com]