TY - JOUR

T1 - Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder

T2 - A Randomized Clinical Trial

AU - Larsen, Julie R

AU - Vedtofte, Louise

AU - Jakobsen, Mathilde S L

AU - Jespersen, Hans R

AU - Jakobsen, Michelle I

AU - Svensson, Camilla K

AU - Koyuncu, Kamuran

AU - Schjerning, Ole

AU - Oturai, Peter S

AU - Kjaer, Andreas

AU - Nielsen, Jimmi

AU - Holst, Jens J

AU - Ekstrøm, Claus T

AU - Correll, Christoph U

AU - Vilsbøll, Tina

AU - Fink-Jensen, Anders

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Importance: Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.Objectives: To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders.Design, Setting, and Participants: This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016.Interventions: Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study.Main Outcomes and Measures: The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters.Results: Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract.Conclusions and Relevance: Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine.Trial Registration: clinicaltrials.gov Identifier: NCT01845259.

AB - Importance: Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.Objectives: To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders.Design, Setting, and Participants: This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016.Interventions: Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study.Main Outcomes and Measures: The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters.Results: Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract.Conclusions and Relevance: Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine.Trial Registration: clinicaltrials.gov Identifier: NCT01845259.

KW - Adult

KW - Antipsychotic Agents

KW - Benzodiazepines

KW - Clozapine

KW - Double-Blind Method

KW - Female

KW - Glucagon-Like Peptide-1 Receptor

KW - Humans

KW - Hypoglycemic Agents

KW - Liraglutide

KW - Male

KW - Middle Aged

KW - Obesity

KW - Outcome Assessment (Health Care)

KW - Overweight

KW - Prediabetic State

KW - Schizophrenia

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

U2 - 10.1001/jamapsychiatry.2017.1220

DO - 10.1001/jamapsychiatry.2017.1220

M3 - Journal article

C2 - 28601891

VL - 74

SP - 719

EP - 728

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 7

ER -