TY - JOUR

T1 - Impact of dose-escalation schemes and drug discontinuation on weight loss outcomes with liraglutide 3.0 mg

T2 - A model-based approach

AU - Papathanasiou, Theodoros

AU - Strathe, Anders

AU - Agersø, Henrik

AU - Lund, Trine Meldgaard

AU - Overgaard, Rune Viig

N1 - This article is protected by copyright. All rights reserved.

PY - 2020

Y1 - 2020

N2 - AIMS: To investigate the impact of treatment changes on weight loss for the glucagon-like peptide-1 analogue, liraglutide, in subjects with overweight or obesity that may be needed in case of gastrointestinal tolerability issues during escalation.MATERIALS AND METHODS: Individual longitudinal body weight data from the main trial periods of three phase II/III trials in subjects with overweight or obesity (56-week treatment with once-daily liraglutide 1.2, 1.8, 2.4 or 3.0 mg or placebo, n=4952) were analysed using a non-linear mixed effect modelling approach. Individual pharmacokinetic profiles were derived based on published pharmacokinetic models. Baseline body weight, baseline HbA1c, age, gender, diabetes status (non-diabetic, pre-diabetic or with type 2 diabetes mellitus), race and trial region were investigated as covariates. As a form of external validation, the model was used to predict the weight regain following treatment cessation at week 56 (data not included in model development).RESULTS: A PK/PD model provided an adequate description of the weight loss trajectories for all studied doses. Gender and diabetes status were identified as the most influential covariates, and an underlying seasonal weight fluctuation was identified. Slower than the recommended, one-week dose-escalation algorithms led up to 2 weeks slower initial weight loss but similar long-term weight loss trajectories.CONCLUSIONS: The relationship between liraglutide systemic exposure and weight loss was successfully established in subjects with overweight or obesity. The model could predict the time-course of weight-regain following treatment cessation and suggests that gastrointestinal tolerability can be mitigated by slower escalation with only minor impact on the weight loss trajectory. This article is protected by copyright. All rights reserved.

AB - AIMS: To investigate the impact of treatment changes on weight loss for the glucagon-like peptide-1 analogue, liraglutide, in subjects with overweight or obesity that may be needed in case of gastrointestinal tolerability issues during escalation.MATERIALS AND METHODS: Individual longitudinal body weight data from the main trial periods of three phase II/III trials in subjects with overweight or obesity (56-week treatment with once-daily liraglutide 1.2, 1.8, 2.4 or 3.0 mg or placebo, n=4952) were analysed using a non-linear mixed effect modelling approach. Individual pharmacokinetic profiles were derived based on published pharmacokinetic models. Baseline body weight, baseline HbA1c, age, gender, diabetes status (non-diabetic, pre-diabetic or with type 2 diabetes mellitus), race and trial region were investigated as covariates. As a form of external validation, the model was used to predict the weight regain following treatment cessation at week 56 (data not included in model development).RESULTS: A PK/PD model provided an adequate description of the weight loss trajectories for all studied doses. Gender and diabetes status were identified as the most influential covariates, and an underlying seasonal weight fluctuation was identified. Slower than the recommended, one-week dose-escalation algorithms led up to 2 weeks slower initial weight loss but similar long-term weight loss trajectories.CONCLUSIONS: The relationship between liraglutide systemic exposure and weight loss was successfully established in subjects with overweight or obesity. The model could predict the time-course of weight-regain following treatment cessation and suggests that gastrointestinal tolerability can be mitigated by slower escalation with only minor impact on the weight loss trajectory. This article is protected by copyright. All rights reserved.

U2 - 10.1111/dom.13985

DO - 10.1111/dom.13985

M3 - Journal article

C2 - 32009288

VL - 22

SP - 969

EP - 977

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 6

ER -