Exposure-response analyses of liraglutide 3.0mg for weight management

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2016-05, Vol.18 (5), p.491
• Main Authors: Wilding, J P H, Overgaard, R V, Jacobsen, L V, Jensen, C B, le Roux, C W
• Format: Article
• Language: English
• Subjects: Antidiabetics; Body weight; Body weight loss; Diabetes; Diabetes mellitus; Dose-response effects; Drug dosages; Drug metabolism; Energy intake; Excretion; Gallbladder; Hemoglobin; Obesity; Overweight; Pancreatitis; Safety; Weight control
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12639

Aims Liraglutide 3.0mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion. Methods We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0mg); SCALE Diabetes (1.8; 3.0mg)] randomized, placebo-controlled trials (n=4372). Results There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at 21nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population. Conclusions These analyses support the use of liraglutide 3.0mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.