Neuropsychiatric safety with liraglutide 3.0 mg for weight management: Results from randomized controlled phase 2 and 3a trials

Abstract

Aims: Liraglutide, a GLP-1 receptor agonist, regulates appetite via receptors in the brain. Because of concerns regarding the potential of centrally-acting anti-obesity medications to affect mental health, pooled neuropsychiatric safety data from all phase 2 and 3a randomized, double-blind trials with liraglutide 3.0 mg were evaluated post hoc.

Methods: Data from the liraglutide weight-management programme were pooled. Across trials, individuals with a body mass index ≥30 or ≥27 kg/m2 with weight-related comorbidities were randomized to once-daily subcutaneous liraglutide 3.0 mg (n = 3384) or placebo (n = 1941), both with a 500 kcal/d deficit diet, plus exercise. Adverse events related to neuropsychiatric safety were collected in all trials. Additionally, in the phase 3a trials, validated mental-health questionnaires were prospectively and systematically administered.

Results: In the pooled analysis of 5325 randomized and exposed individuals, rates of depression (2.1 vs 2.1 events/100 person-years) and anxiety (1.9 vs 1.7 events/100 person-years) through adverse event reporting were similarly low in liraglutide and placebo groups. Nine (0.3%) individuals receiving liraglutide and 2 (0.1%) receiving placebo reported adverse events of suicidal ideation or behaviour. In phase 3a trials, mean baseline Patient Health Questionnaire-9 scores of 2.8 ± 3.0 vs 2.9 ± 3.1 for liraglutide vs placebo improved to 1.8 ± 2.7 vs 1.9 ± 2.7, respectively, at treatment end; 34/3291 individuals (1.0%) receiving liraglutide 3.0 mg vs 19/1843 (1.0%) receiving placebo reported suicidal ideation on the Columbia-Suicide Severity Rating Scale.

Conclusions: Results of this exploratory pooled analysis provide no cause for concern regarding the neuropsychiatric safety of treatment with liraglutide 3.0 mg in patients similar to those included in the examined trials. Although there was a small numerical imbalance in suicidal ideation with liraglutide through adverse event reporting, no between-treatment imbalances in suicidal ideation/behaviour or depression were noted through prospective questionnaire assessments.

Keywords: GLP-1 analogue; antiobesity drug; liraglutide; obesity therapy; randomized trial.

Conflict of interest statement

P. O. has received funding for research from Orexigen Therapeutics, Weight Watchers International and Novo Nordisk, honoraria from Novo Nordisk and Medscape/WebMD, and has been an advisory board member for Orexigen Therapeutics, Janssen and Pfizer. V. A. has received funding for research from AstraZeneca/BMS, Calibra, Eisai, Elcelyx, Janssen, Novo Nordisk, Sanofi and Theracos and has received consultancy fees from Adocia, ADA, AstraZeneca, Janssen, Medscape, Novo Nordisk, Sanofi and Tufts, all within the last 12 months. A. A. has been an advisory board member for BioCare, consultant for Basic Research, Gelesis, Novo Nordisk, Omega ACO, Pathway Genomics, Pfizer, Sanofi‐Aventis and S‐Biotek and is a recipient of travel expenses and/or modest honoraria (<$2,000) for lectures given at national and international meetings, often with support from one or more corporate sponsors. He is co‐inventor of a number of patents owned by the University of Copenhagen, in accordance with Danish law. He is a member of the board and a shareholder in the consultancy company Dentacom Aps, Denmark, and is a co‐founder and co‐owner of the University of Copenhagen spin‐out company, Mobile Fitness A/S, Denmark. He is also co‐founder, co‐owner and a member of the board of the University of Copenhagen spin‐out company Flaxslim ApS, Denmark. R. K. serves on the advisory boards for Novo Nordisk, Weight Watchers, Retrofit and Zafgen, and has received grant support, on behalf of Northwestern University, from Aspire Bariatrics, Eisai and Novo Nordisk. D. L. has received research funding from AstraZeneca, Boehringer‐Ingelheim and Novo Nordisk, and has received consultancy fees from Amgen, AstraZeneca, Boehringer‐Ingelheim, Novo Nordisk, Sanofi and Shire, and lecture fees from Amgen, AstraZeneca, Boehringer‐Ingelheim, Merck and Novo Nordisk. T. W. serves on advisory boards for Novo Nordisk, Nutrisystem and Weight Watchers and has received grant support, on behalf of the University of Pennsylvania, from Eisai Co. and Novo Nordisk. J. B. and A. C. are employed by and hold stock in Novo Nordisk. J. W. has received grant funding (via his institution), consultancy and lecture fees (institutional and personal) from Novo Nordisk, and consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Orexigen and Sanofi (both institutional and personal) in relation to treatments for obesity and/or diabetes.

© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.