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 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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Schjerning reports receiving speaker honoraria from Lundbeck Pharma. Dr Nielsen reports receiving speaker honoraria from Hemocue, Lundbeck, and Bristol-Myers Squibb and research grants from H. Lundbeck and Pfizer. Dr Holst reports consulting for Merck Sharp & Dohme, Novo Nordisk A/C, and Roche. Dr Correll reports consulting and/or advising or receiving honoraria from AbbVie, Acadia, Actavis, Actelion, Alexza, Alkermes, Bristol-Myers Squibb, Cephalon, Eli Lilly and Company, Forum, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Merck Sharp & Dohme, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, Takeda, Teva, and Vanda; providing expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka; serving on a data safety monitoring board for Eli Lilly and Company, Janssen, Lundbeck, Pfizer, Takeda, and Otsuka; and receiving grant support from Bristol-Myers Squibb, Otsuka, Lundbeck, and Takeda. Dr Vilsbøll reports receiving lecture fees from Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk A/C, Sanofi, and Zealand Pharma and serving on the advisory boards of AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk A/C, and Sanofi. Dr Fink-Jensen reports sponsoring the study and receiving an unrestricted grant from Novo Nordisk A/S. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Study Participants

All randomized participants who received at least 1 dose of the trial compound (liraglutide or placebo) and who had at least 1 assessment after baseline were included in the efficacy analyses. Five participants from the liraglutide group and 1 from the placebo group were excluded from the analyses. Another participant in the liraglutide group was excluded after the first assessment and was therefore included in the efficacy analyses without completing the 16 weeks of treatment. All participants who were randomized and had received at least 1 dose of liraglutide or placebo were included in the safety analyses. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); HbA1c,hemoglobin A1c. To convert hemoglobin A1c to mmol/mol, subtract 2.15% and multiply by 10.929.

Figure 2.. Oral Glucose Tolerance Test Results

Plasma glucose excursion, C-peptide level, and glucagon secretion were evaluated at fixed time points before and after ingestion of oral glucose (0 indicates intake). Values represent the mean calculated by a repeated mixed-model analysis. When comparing the liraglutide group with the placebo group, the model includes the covariates age; sex; illness duration; treatment with olanzapine, clozapine, or both; baseline body mass index; and baseline Clinical Global Impressions Scale severity score. The analyses include all participants who were randomized, received at least 1 dose of the trial compound (liraglutide or placebo), and had at least 1 assessment after baseline. To convert C-peptide to nanomoles per liter, multiply by 0.331; glucagon to nanograms per liter, multiply by 1.0; and glucose levels to millimoles per liter, multiply by 0.0555.