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

This randomized clinical trial investigates the effect of liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders in patients with prediabetes who are overweight or obese.

Key Points

Question

Can the glucagon-like peptide-1 receptor agonist liraglutide reduce body weight and improve cardiometabolic disturbances in antipsychotic-treated patients?

Findings

In this randomized clinical trial of 103 patients with schizophrenia spectrum disorders treated with clozapine or olanzapine, glucose tolerance improved significantly and 30 liraglutide-treated patients with prediabetes (63.8%) developed normal glucose tolerance compared with 8 placebo-treated patients (16.0%). Liraglutide induced a placebo-subtracted body weight loss of 5.3 kg.

Meaning

Glucagon-like peptide-1 receptor agonists offer a novel and effective approach to mitigation of some of the cardiometabolic adverse effects associated with the commonly used and efficacious antipsychotic drugs clozapine and olanzapine.

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