title: Neuropsychiatric safety with liraglutide 3.0 mg for weight management: Results from randomized controlled phase 2 and 3a trials.
abstract: 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.
  
  
  
  Data from the liraglutide weight-management programme were pooled. Across trials, individuals with a body mass index ≥30 or ≥27 kg/m2with 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Weight Management Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Patrick M
authors.identifier: 0000-0002-0388-4046
authors.initials: PM
authors.lastname: O'Neil
authors.affiliation: Department of Internal Medicine, Endocrinology, Diabetes & Metabolism, MedStar Health Research Institute, Georgetown University School of Medicine, Hyattsville, Maryland.
authors.forename: Vanita R
authors.initials: VR
authors.lastname: Aroda
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Astrup
authors.affiliation: Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Robert
authors.initials: R
authors.lastname: Kushner
authors.affiliation: Departments of Medicine and Biochemistry & Molecular Biology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.
authors.forename: David C W
authors.initials: DCW
authors.lastname: Lau
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wadden
authors.affiliation: Novo Nordisk Inc., Plainsboro, New Jersey.
authors.forename: Jason
authors.initials: J
authors.lastname: Brett
authors.affiliation: Novo Nordisk A/S, Søborg, Denmark.
authors.forename: Ana-Paula
authors.initials: AP
authors.lastname: Cancino
authors.affiliation: Department of Obesity and Endocrinology, Obesity and Endocrinology Clinical Research Group, University of Liverpool, Liverpool, UK.
authors.forename: John P H
authors.initials: JPH
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000069450:Liraglutide / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced / Q000453:epidemiology; D008603:Mental Health; D008875:Middle Aged; D009483:Neuropsychological Tests; D020258:Neurotoxicity Syndromes / Q000453:epidemiology*; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology / Q000523:psychology; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D011795:Surveys and Questionnaires; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D000069450:Liraglutide
keywords: GLP-1 analogue; antiobesity drug; liraglutide; obesity therapy; randomized trial