Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial

Julie R Larsen; Louise Vedtofte; Mathilde S L Jakobsen; Hans R Jespersen; Michelle I Jakobsen; Camilla K Svensson; Kamuran Koyuncu; Ole Schjerning; Peter S Oturai; Andreas Kjaer; Jimmi Nielsen; Jens J Holst; Claus T Ekstrøm; Christoph U Correll; Tina Vilsbøll; Anders Fink-Jensen

doi:10.1001/jamapsychiatry.2017.1220

Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial

Julie R Larsen, Louise Vedtofte, Mathilde S L Jakobsen, Hans R Jespersen, Michelle I Jakobsen, Camilla K Svensson, Kamuran Koyuncu, Ole Schjerning, Peter S Oturai, Andreas Kjaer, Jimmi Nielsen, Jens J Holst, Claus T Ekstrøm, Christoph U Correll, Tina Vilsbøll, Anders Fink-Jensen

63 Citations (Scopus)

Abstract

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 pointwas 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 Ofthe103patientsundergoingrandomization(60men[58.3%]and43women[41.7%]), 97were included in the efficacy analysis, with amean(SD) age of42.5 (10.5) years andmean(SD) bodymassindex(calculatedasweightinkilogramsdividedbyheightinmeterssquared)of33.8(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]). Atotal of96randomized participants (93.2%) completed the trial. Glucose tolerance improvedin the liraglutidegroupcomparedwith theplacebogroup(P< .001). Altogether, 30liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%)(P < .001;numberneededto treat, 2).Bodyweight decreased with liraglutide compared with placebo (-5.3 kg; 95%CI, -7.0to -3.7 kg). Reductions inwaist circumference (-4.1 cm; 95%CI, -6.0to -2.3 cm), systolic blood pressure (-4.9mmHg; 95%CI, -9.5 to -0.3mmHg), visceral fat (-250.19 g; 95%CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4mg/dL;95%CI, -23.2to-7.7mg/dL) occurred with liraglutidecomparedwith 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.

Original language	English
Journal	J A M A Psychiatry
Volume	74
Issue number	7
Pages (from-to)	719-728
Number of pages	10
ISSN	2168-622X
DOIs	https://doi.org/10.1001/jamapsychiatry.2017.1220
Publication status	Published - 1 Jul 2017

Keywords

Adult
Antipsychotic Agents
Benzodiazepines
Clozapine
Double-Blind Method
Female
Glucagon-Like Peptide-1 Receptor
Humans
Hypoglycemic Agents
Liraglutide
Male
Middle Aged
Obesity
Outcome Assessment (Health Care)
Overweight
Prediabetic State
Schizophrenia
Journal Article
Multicenter Study
Randomized Controlled Trial

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1001/jamapsychiatry.2017.1220

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Larsen, J. R., Vedtofte, L., Jakobsen, M. S. L., Jespersen, H. R., Jakobsen, M. I., Svensson, C. K., Koyuncu, K., Schjerning, O., Oturai, P. S., Kjaer, A., Nielsen, J., Holst, J. J., Ekstrøm, C. T., Correll, C. U., Vilsbøll, T., & Fink-Jensen, A. (2017). Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial. J A M A Psychiatry, 74(7), 719-728. https://doi.org/10.1001/jamapsychiatry.2017.1220

Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial. / Larsen, Julie R; Vedtofte, Louise; Jakobsen, Mathilde S L et al.
In: J A M A Psychiatry, Vol. 74, No. 7, 01.07.2017, p. 719-728.

Research output: Contribution to journal › Journal article › Research › peer-review

Larsen, JR, Vedtofte, L, Jakobsen, MSL, Jespersen, HR, Jakobsen, MI, Svensson, CK, Koyuncu, K, Schjerning, O, Oturai, PS, Kjaer, A, Nielsen, J, Holst, JJ , Ekstrøm, CT, Correll, CU, Vilsbøll, T & Fink-Jensen, A 2017, 'Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial', J A M A Psychiatry, vol. 74, no. 7, pp. 719-728. https://doi.org/10.1001/jamapsychiatry.2017.1220

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title = "Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial",

abstract = "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 pointwas 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 Ofthe103patientsundergoingrandomization(60men[58.3%]and43women[41.7%]), 97were included in the efficacy analysis, with amean(SD) age of42.5 (10.5) years andmean(SD) bodymassindex(calculatedasweightinkilogramsdividedbyheightinmeterssquared)of33.8(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]). Atotal of96randomized participants (93.2%) completed the trial. Glucose tolerance improvedin the liraglutidegroupcomparedwith theplacebogroup(P< .001). Altogether, 30liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%)(P < .001;numberneededto treat, 2).Bodyweight decreased with liraglutide compared with placebo (-5.3 kg; 95%CI, -7.0to -3.7 kg). Reductions inwaist circumference (-4.1 cm; 95%CI, -6.0to -2.3 cm), systolic blood pressure (-4.9mmHg; 95%CI, -9.5 to -0.3mmHg), visceral fat (-250.19 g; 95%CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4mg/dL;95%CI, -23.2to-7.7mg/dL) occurred with liraglutidecomparedwith 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.",

keywords = "Adult, Antipsychotic Agents, Benzodiazepines, Clozapine, Double-Blind Method, Female, Glucagon-Like Peptide-1 Receptor, Humans, Hypoglycemic Agents, Liraglutide, Male, Middle Aged, Obesity, Outcome Assessment (Health Care), Overweight, Prediabetic State, Schizophrenia, Journal Article, Multicenter Study, Randomized Controlled Trial",

author = "Larsen, {Julie R} and Louise Vedtofte and Jakobsen, {Mathilde S L} and Jespersen, {Hans R} and Jakobsen, {Michelle I} and Svensson, {Camilla K} and Kamuran Koyuncu and Ole Schjerning and Oturai, {Peter S} and Andreas Kjaer and Jimmi Nielsen and Holst, {Jens J} and Ekstr{\o}m, {Claus T} and Correll, {Christoph U} and Tina Vilsb{\o}ll and Anders Fink-Jensen",

year = "2017",

month = jul,

day = "1",

doi = "10.1001/jamapsychiatry.2017.1220",

language = "English",

volume = "74",

pages = "719--728",

journal = "J A M A Psychiatry",

issn = "2168-622X",

publisher = "The JAMA Network",

number = "7",

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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 pointwas 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 Ofthe103patientsundergoingrandomization(60men[58.3%]and43women[41.7%]), 97were included in the efficacy analysis, with amean(SD) age of42.5 (10.5) years andmean(SD) bodymassindex(calculatedasweightinkilogramsdividedbyheightinmeterssquared)of33.8(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]). Atotal of96randomized participants (93.2%) completed the trial. Glucose tolerance improvedin the liraglutidegroupcomparedwith theplacebogroup(P< .001). Altogether, 30liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%)(P < .001;numberneededto treat, 2).Bodyweight decreased with liraglutide compared with placebo (-5.3 kg; 95%CI, -7.0to -3.7 kg). Reductions inwaist circumference (-4.1 cm; 95%CI, -6.0to -2.3 cm), systolic blood pressure (-4.9mmHg; 95%CI, -9.5 to -0.3mmHg), visceral fat (-250.19 g; 95%CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4mg/dL;95%CI, -23.2to-7.7mg/dL) occurred with liraglutidecomparedwith 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.

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 pointwas 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 Ofthe103patientsundergoingrandomization(60men[58.3%]and43women[41.7%]), 97were included in the efficacy analysis, with amean(SD) age of42.5 (10.5) years andmean(SD) bodymassindex(calculatedasweightinkilogramsdividedbyheightinmeterssquared)of33.8(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]). Atotal of96randomized participants (93.2%) completed the trial. Glucose tolerance improvedin the liraglutidegroupcomparedwith theplacebogroup(P< .001). Altogether, 30liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%)(P < .001;numberneededto treat, 2).Bodyweight decreased with liraglutide compared with placebo (-5.3 kg; 95%CI, -7.0to -3.7 kg). Reductions inwaist circumference (-4.1 cm; 95%CI, -6.0to -2.3 cm), systolic blood pressure (-4.9mmHg; 95%CI, -9.5 to -0.3mmHg), visceral fat (-250.19 g; 95%CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4mg/dL;95%CI, -23.2to-7.7mg/dL) occurred with liraglutidecomparedwith 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.

KW - Adult

KW - Antipsychotic Agents

KW - Benzodiazepines

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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

SN - 2168-622X

VL - 74

SP - 719

EP - 728

JO - J A M A Psychiatry

JF - J A M A Psychiatry

IS - 7

ER -

Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial

Abstract

Keywords

UN SDGs

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