Glucagon‐like peptide‐1 receptor agonists for antipsychotic‐associated cardio‐metabolic risk factors: A systematic review and individual participant data meta‐analysis

Siskind, Dan; Hahn, Margaret; Correll, Christoph U.; Fink‐Jensen, Anders; Russell, Anthony W.; Bak, Nikolaj; Broberg, Brian V.; Larsen, Julie; Ishøy, Pelle L.; Vilsbøll, Tina; Knop, Filip K.; Kisely, Steve; Ebdrup, Bjørn H.

doi:10.1111/dom.13522

Cited by 144Schizophrenia research and treatmentPharmacology and Obesity TreatmentDiabetes Treatment and Management

Glucagon‐like peptide‐1 receptor agonists for antipsychotic‐associated cardio‐metabolic risk factors: A systematic review and individual participant data meta‐analysis

Siskind, Dan, Hahn, Margaret, Correll, Christoph U., Fink‐Jensen, Anders, Russell, Anthony W., Bak, Nikolaj, Broberg, Brian V., Larsen, Julie +5 more·2019·Diabetes, Obesity and Metabolism

DOI 10.1111/dom.13522

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Abstract

Aims: To evaluate if glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) reduce antipsychotic‐associated body weight gain in patients with schizophrenia, when compared to controls. Materials and methods: We systematically searched PubMed/EMBASE/PsycINFO/Cochrane using the search terms ‘(antipsychotic and GLP‐1RA)’. Individual participant data from studies randomizing patients to GLP‐1RA or control were meta‐analysed. The primary outcome was difference in body weight between GLP‐1RA and control; secondary outcomes included cardio‐metabolic variables and adverse drug reactions (ADRs). Multiple linear regression was conducted including sex, age, psychosis severity, metabolic variable, ADRs, and GLP‐1RA agent. Results: Three studies (exenatide once‐weekly = 2; liraglutide once‐daily = 1) provided participant‐level data (n = 164, age = 40.0 ± 11.1 years, body weight = 105.8 ± 20.8 kg). After 16.2 ± 4.0 weeks of treatment, body weight loss was 3.71 kg (95% CI = 2.44‐4.99 kg) greater for GLP‐1RA versus control (p < 0.001), number‐needed‐to‐treat ≥5% body weight loss = 3.8 (95% CI = 2.6‐7.2). Waist circumference, body mass index, HbA1c, fasting glucose and visceral adiposity were each significantly lower with GLP‐1RA. Sex, age, psychosis severity, nausea, any ADR, and GLP‐1RA agent did not significantly impact outcomes. Body weight loss with GLP‐1RAs was greater for clozapine/olanzapine‐treated patients (n = 141) than other antipsychotics (n = 27) (4.70 kg, 95% CI = 3.13‐6.27 vs. 1.5 kg, 95% CI = −1.47‐4.47) (p < 0.001). Nausea was more common with GLP‐1RAs than control (53.6% vs. 27.5%, p = 0.002, number‐needed‐to‐harm = 3.8). Conclusion: GLP‐1RAs are effective and tolerable for antipsychotic‐associated body weight gain, particularly clozapine/olanzapine‐treated patients. With few included patients, further studies are required before making routine use recommendations for GLP‐1RAs.

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Yuen, J. W. Y., Kim, D. D., Procyshyn, R. M., Panenka, W. J., Honer, W. G., & Barr, A. M. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.609240 · Cited by 92 · see citing works
An analysis on the role of glucagon-like peptide-1 receptor agonists in cognitive and mental health disorders
Giorgi, R. D., Ghenciulescu, A., Dziwisz, O., Taquet, M., Adler, A., Koychev, I. G., Upthegrove, R., Solmi, M., McCutcheon, R. A., Pillinger, T., et al. (2025) · Nature Mental Health · doi:10.1038/s44220-025-00390-x · Cited by 90 · see citing works
The use of liraglutide 3.0 mg daily in the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first episode psychosis: results of a pilot randomized, double-blind, placebo-controlled trial
Whicher, C. A., Price, H. C., Phiri, P., Rathod, S., Barnard‐Kelly, K., Ngianga, K., Thorne, K., Asher, C., Peveler, R. C., McCarthy, J., et al. (2021) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14334 · Cited by 77 · see citing works
Does Switching Antipsychotics Ameliorate Weight Gain in Patients With Severe Mental Illness? A Systematic Review and Meta-analysis
Siskind, D. J., Gallagher, E., Winckel, K., Hollingworth, S., Kisely, S. R., Firth, J., Correll, C. U., & Marteene, W. (2020) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaa191 · Cited by 75 · see citing works
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Pharmacological Management of Glucose Dysregulation in Patients Treated with Second-Generation Antipsychotics
Cernea, S., Dima, L., Correll, C. U., & Manu, P. (2020) · Drugs · doi:10.1007/s40265-020-01393-x · Cited by 74 · see citing works
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Metformin in the management of antipsychotic-induced weight gain in adults with psychosis: development of the first evidence-based guideline using GRADE methodology
Fitzgerald, I., O’Connell, J., Keating, D., Hynes-Ryan, C., McWilliams, S., & Crowley, E. K. (2021) · Evidence-Based Mental Health · doi:10.1136/ebmental-2021-300291 · Cited by 68 · see citing works
One-year follow-up on liraglutide treatment for prediabetes and overweight/obesity in clozapine- or olanzapine-treated patients
Svensson, C. K., Larsen, J. R., Vedtofte, L., Jakobsen, M. S. L., Jespersen, H. R., Jakobsen, M. I., Koyuncu, K., Schjerning, O., Nielsen, J., Ekstrøm, C. T., et al. (2019) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12982 · Cited by 66 · see citing works
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New discoveries for an old drug: a review of recent olanzapine research
Meftah, A. M., Deckler, E., Citrome, L., & Kantrowitz, J. T. (2019) · Postgraduate Medicine · doi:10.1080/00325481.2019.1701823 · Cited by 64 · see citing works
Strategies to counter antipsychotic-associated weight gain in patients with schizophrenia
Marteene, W., Winckel, K., Hollingworth, S., Kisely, S. R., Gallagher, E., Hahn, M., Ebdrup, B. H., Firth, J., & Siskind, D. J. (2019) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2019.1674809 · Cited by 62 · see citing works
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Antipsychotic-Induced Weight Gain in Severe Mental Illness: Risk Factors and Special Considerations
Stogios, N., Humber, B. E., Agarwal, S. M., & Hahn, M. (2023) · Current Psychiatry Reports · doi:10.1007/s11920-023-01458-0 · Cited by 60 · see citing works
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Therapeutic management of atypical antipsychotic‑related metabolic dysfunctions using GLP‑1 receptor agonists: A systematic review
Vasiliu, O. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.12054 · Cited by 60 · see citing works
The clozapine to norclozapine ratio: a narrative review of the clinical utility to minimize metabolic risk and enhance clozapine efficacy
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Drugs affecting body weight, body fat distribution, and metabolic function—mechanisms and possible therapeutic or preventive measures: an update.
Verhaegen, A. A., & Van Gaal, L. F. (2021) · Current Obesity Reports · doi:10.1007/s13679-020-00419-5 · Cited by 53 · see citing works
Antipsychotic-Induced Metabolic Syndrome: A Review
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Efficacy and safety of semaglutide versus placebo for people with schizophrenia on clozapine with obesity (COaST): a phase 2, multi-centre, participant and investigator- blinded, randomised controlled trial in Australia.
Siskind, D., Baker, A., Arnautovska, U., Warren, N., Russell, A., DeMonte, V., Halstead, S., Iyer, R., Korman, N., McKeon, G., et al. (2025) · The Lancet Psychiatry · doi:10.1016/s2215-0366(25)00129-4 · Cited by 62 · see citing works
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Glucagon‐like peptide agonists for weight management in antipsychotic‐induced weight gain: A systematic review and meta‐analysis
Bak, M., Campforts, B. C. M., Domen, P. A. E., van Amelsvoort, T., & Drukker, M. (2024) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.13734 · Cited by 52 · see citing works
Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders
Chen, Q., Cao, T., Li, N., Zeng, C., Zhang, S., Wu, X., Zhang, B., & Cai, H. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.667874 · Cited by 50 · see citing works
A systematic review of licensed weight-loss medications in treating antipsychotic-induced weight gain and obesity in schizophrenia and psychosis.
Lee, K., Abraham, S., & Cleaver, R. (2022) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2022.07.006 · Cited by 53 · see citing works
Clozapine Optimization: A Delphi Consensus Guideline From the Treatment Response and Resistance in Psychosis Working Group
Wagner, E. M., Siskind, D. J., Falkai, P., Howes, O. D., Correll, C. U., Lee, J., Honer, W. G., Kane, J. M., Fernández-Egea, E., Barnes, T. R. E., et al. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad030 · Cited by 45 · see citing works
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Effect of the GLP-1 receptor agonist semaglutide on metabolic disturbances in clozapine-treated or olanzapine-treated patients with a schizophrenia spectrum disorder: study protocol of a placebo-controlled, randomised clinical trial (SemaPsychiatry)
Sass, M. R., Danielsen, A. A., Köhler‐Forsberg, O., Storgaard, H., Knop, F. K., Nielsen, M. Ø., Sjödin, A. M., Mors, O. N., Correll, C. U., Ekstrøm, C. T., et al. (2023) · BMJ Open · doi:10.1136/bmjopen-2022-068652 · Cited by 41 · see citing works
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When therapeutic drugs lead to diabetes
Fève, B., & Scheen, A. J. (2022) · Diabetologia · doi:10.1007/s00125-022-05666-w · Cited by 38 · see citing works
Efficacy and tolerability of pharmacological interventions on metabolic disturbance induced by atypical antipsychotics in adults: A systematic review and network meta-analysis
Wang, Y., Wang, D., Cheng, J., Fang, X., Chen, Y., Yu, L., Ren, J., Tian, Y., & Zhang, C. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211035391 · Cited by 36 · see citing works
Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel
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Holistic prevention and management of physical health side-effects of psychotropic medication: second report of the Lancet Psychiatry Physical Health Commission
Halstead, S., Yap, C. X., Warren, N., Agarwal, S. M., Brand, B. A., Chan, S. K. W., Cipriani, A., Correll, C. U., Crossley, N. A., D’Ambrosio, E., et al. (2025) · The Lancet Psychiatry · doi:10.1016/s2215-0366(25)00162-2 · Cited by 34 · see citing works
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Glucagon-like peptide-1 receptor-agonists treatment for cardio-metabolic parameters in schizophrenia patients: a systematic review and meta-analysis
Khaity, A. M., Al-dardery, N. M., Albakri, K. A., Abdelwahab, O. A., Hefnawy, M. T., Yousef, Y. S. A. H., Taha, R. E. W., Swed, S., Hafez, W., Hurlemann, R., et al. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1153648 · Cited by 35 · see citing works
Impaired hormonal regulation of appetite in schizophrenia: A narrative review dissecting intrinsic mechanisms and the effects of antipsychotics
Lis, M., Stańczykiewicz, B., Liśkiewicz, P., & Misiak, B. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104744 · Cited by 33 · see citing works
Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia
Qubad, M., & Bittner, R. A. (2023) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253231158152 · Cited by 33 · see citing works
Risk factors, prevention and treatment of weight gain associated with the use of antidepressants and antipsychotics: a state-of-the-art clinical review
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GLP‐1 agonists and the gut microbiome: A bidirectional relationship
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The Potential Role of GLP-1 Agonists in Psychiatric Disorders: A Paradigm Shift in Mental Health Treatment
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Brain insulin action: Implications for the treatment of schizophrenia
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Effect of liraglutide 3.0mg treatment on weight reduction in obese antipsychotic-treated patients
Lee, S. E., Lee, N. Y., Kim, S. H., Kim, K.-A., & Kim, Y. S. (2021) · Psychiatry Research · doi:10.1016/j.psychres.2021.113830 · Cited by 27 · see citing works
Semaglutide and Early-Stage Metabolic Abnormalities in Individuals With Schizophrenia Spectrum Disorders
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Peripheral mechanisms of acute olanzapine induced metabolic dysfunction: A review of in vivo models and treatment approaches
Shamshoum, H., Medak, K. D., & Wright, D. C. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113049 · Cited by 26 · see citing works
Effect of Glucagon-like Peptide-1 Receptor Agonists on Cardio-Metabolic Risk Factors among Obese/Overweight Individuals Treated with Antipsychotic Drug Classes: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials
Patoulias, D., Michailidis, T., Dimosiari, A., Fragakis, N., Tse, G., & Rizzo, M. (2023) · Biomedicines · doi:10.3390/biomedicines11030669 · Cited by 27 · see citing works
GLP-1 receptor agonists and weight loss in schizophrenia – past, present, and future
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Australian and New Zealand Journal of Psychiatry Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines for the management of schizophrenia
Suetani, S., Dark, F. L., Every‐Palmer, S., Galletly, C. A., O'Donoghue, B. N., Halstead, S., Keating, D., Korman, N., Lappin, J., Lawn, S., et al. (2026) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/00048674251406058 · Cited by 23 · see citing works
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The effect of GLP-1RAs on mental health and psychotropics-induced metabolic disorders: A systematic review
Breit, S., & Hubl, D. (2025) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2025.107415 · Cited by 20 · see citing works
Metabolic disorders induced by psychotropic drugs
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GLP1 receptor agonism protects against acute olanzapine-induced hyperglycemia
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Drug–drug interactions involving combinations of antipsychotic agents with antidiabetic, lipid-lowering, and weight loss drugs
Buzea, A., Manu, P., Dima, L., & Correll, C. U. (2022) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2022.2147425 · Cited by 19 · see citing works
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Antipsychotic Drugs and Dysregulated Glucose Homeostasis
Smith, E. C. C., Agarwal, S. M., Panganiban, K. J., Maksyutynska, K., Monteiro, J., Lee, J., Prasad, F., Ji, A., Shah, D., Cavalier, S., et al. (2025) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2025.2240 · Cited by 18 · see citing works
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Metformin co-commencement at time of antipsychotic initiation for attenuation of weight gain: a systematic review and meta-analysis
Yu, O., Lu, M., Lai, T. K. Y., Hahn, M., Agarwal, S. M., O'Donoghue, B. N., Ebdrup, B. H., & Siskind, D. J. (2024) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253241255476 · Cited by 18 · see citing works
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Overcoming clozapine’s adverse events: a narrative review of systematic reviews and meta-analyses
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Metabolic profile of methylazoxymethanol model of schizophrenia in rats and effects of three antipsychotics in long-acting formulation
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Stress, psychiatric disease, and obesity: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022
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Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia
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Management of Cardiovascular Health in People with Severe Mental Disorders
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Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats
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GLP-1 agonists: superior for mind and body in antipsychotic-treated patients?
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Psychotropic effects of GLP-1R agonists
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Glucagon-Like Peptide-1 Receptor Agonists in Psychiatry: A Pharmacoepidemiological Scoping Review
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What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia
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Proinflammatory biomarkers are associated with prediabetes in patients with schizophrenia
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A systematic review of preclinical studies exploring the role of insulin signalling in executive function and memory
Ottomana, A. M., Presta, M., O’Leary, A., Sullivan, M., Pisa, E., Giovanni Laviola, A., Glennon, J. C., Zoratto, F., Slattery, D. A., & Macrı̀, S. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105435 · Cited by 11 · see citing works
Home-based Intervention with Semaglutide Treatment of Neuroleptic-Related Prediabetes (HISTORI): protocol describing a prospective, randomised, placebo controlled and double-blinded multicentre trial
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Real‐world comprehensive care of people living with schizophrenia: recommendations across different settings and clinical stages
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Effects of semaglutide on body weight in clozapine-treated people with schizophrenia and obesity: study protocol for a placebo-controlled, randomised multicentre trial (COaST)
Siskind, D. J., Baker, A., Russell, A. W., Warren, N., Robinson, G., Parker, S., Medland, S. E., Kisely, S. R., Hager, T., & Arnautovska, U. (2023) · BJPsych Open · doi:10.1192/bjo.2023.532 · Cited by 9 · see citing works
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Impact of Glucagon-like Peptide-1 Receptor Agonists on Mental Illness: Evidence from a Mendelian Randomization Study
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A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine
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Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats
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A Novel Synthetic Interfering Peptide Tat-3L4F Attenuates Olanzapine-Induced Weight Gain Through Disrupting Crosstalk Between Serotonin Receptor 2C and Protein Phosphatase and Tensin Homolog in Rats
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Metabolic adverse effects of antipsychotics: the state of the problem and management options
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Interaction of Semaglutide and Ziprasidone in a Patient With Schizophrenia: A Case Report
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Perspectives of clozapine-naïve outpatients with treatment-resistant schizophrenia on clozapine commencement: a mixed-methods convergent study
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Glucagon-like peptide-1 serum levels are associated with weight gain in patients treated with clozapine
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Excess mortality from cancer in people with mental illness—Out of sight and out of mind
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GLP-1R Agonists for Weight Loss in Psychiatric Disorders: A Systematic Review and Meta-analysis
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Weight gain under antipsychotic and mood stabilizing treatment: a narrative review about mechanisms and future options
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Current and Novel Approaches to Mitigate Cardiometabolic Adverse Effects of Second-Generation Antipsychotics
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Leptin Serum Levels are Associated With GLP-1 Receptor Agonist-Mediated Effects on Glucose Metabolism in Clozapine- or Olanzapine-Treated, Prediabetic, Schizophrenia Patients
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Long‐term delirium and survival outcomes in patients treated with GLP ‐1 receptor agonists versus metformin in type 2 diabetes: A population‐based cohort study
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Weight change from incretin-based weight loss medications across categories of second-generation antipsychotics
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Promising translatable pharmacological interventions for body weight management in individuals with severe mental illness – a narrative review
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Liraglutide 3.0 mg once daily for the treatment of overweight and obesity in patients hospitalised at a forensic psychiatric department: A 26‐week open‐label feasibility study
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Newly FDA-approved psychotropic agents-a recap
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Authors: Siskind, D., Hahn, M., Correll, C. U., Fink‐Jensen, A., Russell, A. W., Bak, N., Broberg, B. V., Larsen, J., Ishøy, P. L., Vilsbøll, T., Knop, F. K., Kisely, S., & Ebdrup, B. H.
Affiliations: The University of Queensland (AU)
Centre for Addiction and Mental Health (CA)
Northwell Health (US)
University of Copenhagen (DK)
Novo Nordisk (Denmark) (DK)
Corresponding author: Siskind, Dan
ORCID: Siskind, Dan
Hahn, Margaret
Correll, Christoph U.
Fink‐Jensen, Anders
Russell, Anthony W.
Bak, Nikolaj
Broberg, Brian V.
Larsen, Julie
Ishøy, Pelle L.
Vilsbøll, Tina
Knop, Filip K.
Kisely, Steve
Ebdrup, Bjørn H.
Venue: Diabetes, Obesity and Metabolism
Publisher: Wiley
Published: 2018-10-07
Volume: 21
Issue: 2
Pages: 293-302
ISSN: 1462-8902 (ISSN-L)
1463-1326
DOI: 10.1111/dom.13522
OpenAlex: W2890415448
Cited by: 144
References: 58
Citations by year: 2026: 22 · 2025: 30 · 2024: 17 · 2023: 21 · 2022: 10 · 2021: 23 · 2020: 11 · 2019: 9 · 2018: 1
FWCI: 1.68
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Diabetes Obesity and Metabolism (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Griffith Research Online (submittedVersion)
Funders: Canadian Institutes of Health Research
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: GLP-1 receptor agonists, antipsychotic-induced weight gain, schizophrenia, weight loss, exenatide, liraglutide, cardiometabolic risk, clozapine, olanzapine, adverse drug reactions, nausea, visceral fat, HbA1c, waist circumference, body mass index, fasting blood glucose, antipsychotic adverse effects
MeSH terms: Liraglutide, Exenatide, Glucagon-Like Peptide-1 Receptor Agonists, Adolescent, Adult, Aged, Body Weight, Cardiovascular Diseases, Drug Administration Schedule, Female, Humans, Hypoglycemic Agents, Male, Metabolic Diseases, Middle Aged, Obesity, Risk Factors, Schizophrenia, Antipsychotic Agents, Weight Gain, Young Adult

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Glucagon‐like peptide‐1 receptor agonists for antipsychotic‐associated cardio‐metabolic risk factors: A systematic review and individual participant data meta‐analysis

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