Efficacy and Safety of Semaglutide Versus Placebo on Cardiometabolic Profile in Patients With Schizophrenia With Metabolic Syndrome

NCT07770282 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: EMF/Psych/2026-27/35
• Study Type: interventional
• Target: 600
• Locations: 0 countries
• Sites: N/A

Brief Summary

Patients with schizophrenia on second-generation antipsychotics have a high burden of metabolic syndrome and elevated cardiovascular risk, with few effective treatment options. This multicentre, double-blind, placebo-controlled randomised trial evaluates whether adjunctive oral semaglutide 3 mg once daily, added to treatment as usual, reduces 10-year cardiovascular risk (QRISK3) and improves insulin resistance, lipids, weight and metabolic biomarkers over 24 weeks compared with placebo, while confirming psychiatric safety and tolerability.

Conditions

Metabolic Syndrome; Cardiovascular Risk; Insulin Resistance; Schizophrenia Disorder; Antipsychotic-induced Weight Gain

Keywords

Semaglutide; Metabolic syndrome; QRISK3; Cardiometabolic risk; Schizophrenia

Outcome Measures

Primary Outcomes (1)

• Change in QRISK3 (QResearch Cardiovascular Risk Prediction Algorithm Version 3),10-year cardiovascular risk score

  QRISK3 is a cardiovascular risk prediction tool that calculates the 10-year absolute risk of developing cardiovascular disease (heart attack or stroke). The scale produces a percentage score ranging from 0% to 100%, where 0% represents minimum cardiovascular risk and 100% represents maximum theoretical risk. Risk stratification is typically classified as: \<5% = low risk, 5-10% = intermediate risk, 10-20% = high risk, and \>20% = very high risk. A score of \>20% (or approaching 100%) represents the worst clinical situation, indicating substantially elevated 10-year cardiovascular disease risk requiring intensive preventive interventions, including lifestyle modification and pharmacological treatment (statins, antihypertensives). QRISK3 incorporates clinical variables (age, blood pressure, cholesterol), demographic factors, and comorbidities to stratify risk and guide evidence-based prevention strategies in primary care settings.

  Baseline to Week 24

Secondary Outcomes (9)

• Change in LDL/HDL ratio

  Baseline, Week 12, Week 24

• Change in insulin resistance (HOMA-IR)

  Baseline to Week 24

• Change in high-sensitivity CRP (hs-CRP)

  Baseline to Week 24

• Change Waist circumference

  Baseline, Week 12, Week 24

• Change in Leptin/Adiponectin ratio

  Baseline, Week 24

Study Arms (2)

Semaglutide

EXPERIMENTAL

Drug: Semaglutide - oral tablet 3 mg once daily in the morning (titrated up from a low starting dose over 5 days), added to ongoing second-generation antipsychotic (TAU), for 24 weeks.

Drug: Semaglutide + TAU

Placebo

PLACEBO COMPARATOR

Drug: Placebo - matching oral tablet once daily in the morning, added to ongoing second-generation antipsychotic (TAU), for 24 weeks.

Drug: Placebo + TAU

Interventions

Semaglutide + TAU DRUG

Semaglutide - oral tablet 3 mg once daily in the morning (titrated up from a low starting dose over 5 days), added to ongoing second-generation antipsychotic (TAU), for 24 weeks.

Semaglutide

Placebo + TAU DRUG

Placebo - matching oral tablet once daily in the morning, added to ongoing second-generation antipsychotic (TAU), for 24 weeks

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Clinically diagnosed schizophrenia (ICD-11) on a second-generation antipsychotic (SGA) for more than 6 months.
• Metabolic syndrome per NCEP ATP III definition.
• Aged above 25 years, any gender.
• Patient / Legally Authorised Representative (LAR) provides voluntary written informed consent.

You may not qualify if:

• ● On clozapine, aripiprazole, or a combination of SGAs.
• Any contraindication to semaglutide.
• Comorbid severe psychiatric, medical or neurological disorder.
• History of organicity or significant head injury.
• Pregnant or breastfeeding.

Sponsors & Collaborators

• Indian Council of Medical Research: collaborator
• All India Institute of Medical Sciences, Bhubaneswar: lead

Related Publications (6)

• Bak M, Fransen A, Janssen J, van Os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One. 2014 Apr 24;9(4):e94112. doi: 10.1371/journal.pone.0094112. eCollection 2014.

  PMID: 24763306 BACKGROUND

• Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999 Nov;156(11):1686-96. doi: 10.1176/ajp.156.11.1686.

  PMID: 10553730 BACKGROUND

• Walss-Bass C, Weintraub ST, Hatch J, Mintz J, Chaudhuri AR. Clozapine causes oxidation of proteins involved in energy metabolism: a possible mechanism for antipsychotic-induced metabolic alterations. Int J Neuropsychopharmacol. 2008 Dec;11(8):1097-104. doi: 10.1017/S1461145708008882. Epub 2008 May 9.

  PMID: 18466668 BACKGROUND

• Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, Kissling W, Davis JM, Leucht S. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010 Nov;123(2-3):225-33. doi: 10.1016/j.schres.2010.07.012. Epub 2010 Aug 7.

  PMID: 20692814 BACKGROUND

• Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr Bull. 2013 Mar;39(2):306-18. doi: 10.1093/schbul/sbr148. Epub 2011 Dec 29.

  PMID: 22207632 BACKGROUND

• Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007 Oct;64(10):1123-31. doi: 10.1001/archpsyc.64.10.1123.

  PMID: 17909124 BACKGROUND

MeSH Terms

Conditions

Schizophrenia; Metabolic Syndrome; Insulin Resistance

Interventions

semaglutide

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Central Study Contacts

Debadatta Mohapatra, MD

CONTACT

+91 9437658251; psych_debadatta@aiimsbhubaneswar.edu.in

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Active drug and placebo supplied as identical-appearing tablets, manufactured centrally at the primary site. Randomisation/allocation by a blinded Pharmacology Co-PI with no access to participant data; outcome assessors and statistician remain blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 10, 2026
• First Posted: August 18, 2026
• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): July 30, 2030
• Study Completion (Estimated): December 30, 2030
• Last Updated: August 18, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share