Liraglutide Improves Cardiometabolic Disturbances in Schizophrenia Tx With Clozapine

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The mortality rate among individuals with schizophrenia is double or triple that of the general population.
The mortality rate among individuals with schizophrenia is double or triple that of the general population.

In a randomized double-blind trial reported in JAMA Psychiatry, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide improved glucose tolerance and metabolic parameters in patients with schizophrenia spectrum disorders.1

The mortality rate among individuals with schizophrenia is double or triple that of the general population, and approximately 60% of the increased mortality is a result of cardiovascular disease and other somatic diseases.2,3 Both outcomes are substantially influenced by the elevated rates of obesity, type 2 diabetes, and other metabolic impairments observed in this patient population. Medications that are used to treat schizophrenia can induce these conditions, especially clozapine and olanzapine, which are also 2 of the most effective antipsychotic drugs.4


Such effects are mediated by the increased appetite and delayed satiety signaling associated with these medications. Results of earlier research on approaches to limit the weight gain linked to antipsychotics have been unsatisfactory. GLP-1 "is an incretin hormone secreted from the L cells in the intestinal mucosa in response to nutrients… [that] stimulates insulin secretion and inhibits glucagon secretion, thereby lowering plasma glucose levels," wrote the authors of the present investigation.5 The GLP-1 receptor agonist liraglutide received approval from the US Food and Drug Administration for the treatment of type 2 diabetes at a dose of 1.8 mg once daily, and for the treatment of obesity at a dose of 3 mg once daily.

The current study examined the effects of a daily 1.8-mg dose of liraglutide as an adjunctive treatment to clozapine or olanzapine in 103 adult patients (58.3% men) with schizophrenia spectrum disorder, prediabetes, and a body mass index of 27 kg/m2 or greater. Those with schizoaffective disorder and type 2 diabetes were excluded. Participants were randomly assigned to placebo or a daily 1.8-mg dose of subcutaneous liraglutide for 16 weeks. Each group was similar in characteristics such as sex, mean age, and mean body mass index. Change in glucose tolerance, as indicated by results of a 75-g oral glucose tolerance test, was the primary endpoint, and changes in body weight and various metabolic values served as secondary endpoints.

Of the 96 patients who completed the trial, the results show the following observations in the liraglutide group vs the placebo group:

  • 63.8% vs 16.0% developed normal glucose tolerance (P <.001; number needed to treat, 2)
  • Greater reductions in body weight (−5.3 kg; 95% CI, −7.0 to −3.7 kg)
  • Greater 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)

As for adverse events, although participants in the liraglutide group reported higher rates of nausea compared with placebo (62% vs 32%; P =.008), such complaints decreased over the course of the study period. 

"Liraglutide improved glucose tolerance and metabolic variables and induced a body weight loss superior to that of placebo without adversely affecting the mental status of the participants," the authors concluded. Further research should expand on these findings by exploring the "safety and effectiveness of different GLP-1 receptor agonists in antipsychotic-treated patients."


  1. Larsen JR, Vedtofte L, Jakobsen MSL. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder a randomized clinical trial. JAMA Psychiatry. 2017;74(7):719-728.
  2. Laursen TM, Munk-Olsen T, Vestergaard M. . Curr Opin Psychiatry. 2012;25(2):83-88.
  3. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005;150(6):1115-1121.
  4. Allison DB, Mentore JL, Heo M, et al. . Am J Psychiatry. 1999;156(11):1686-1696.
  5. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439. 
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