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.
Schizophrenia affects approximately 0.3-1.4% of the Indian population and is associated with a life expectancy reduced by up to 20 years, largely due to cardiovascular disease. Roughly one in three patients has metabolic syndrome, a risk substantially increased by second-generation antipsychotics (SGAs). Existing pharmacological options (metformin, topiramate, aripiprazole) offer only modest to minimal benefit, and major GLP-1 receptor agonist trials have excluded people with severe mental illness. This is a multicentre, two-arm, parallel-group, double-blind, placebo-controlled randomised controlled trial. 600 clinically stable adults with schizophrenia (ICD-11) and metabolic syndrome (NCEP ATP III), on an SGA for over six months, will be randomised 1:1 to adjunctive oral semaglutide 3 mg once daily or matching placebo, both added to treatment as usual (TAU). Dosing is titrated from a low starting dose to 3 mg/day. Central computer-generated block randomisation stratified by centre is used, with allocation concealment by sequentially numbered opaque sealed envelopes (SNOSE). Assessments occur at baseline, 12 weeks and 24 weeks, with weekly telephonic safety follow-up. The primary endpoint is change in QRISK3 at 24 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
600
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.
Placebo - matching oral tablet once daily in the morning, added to ongoing second-generation antipsychotic (TAU), for 24 weeks
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.
Time frame: Baseline to Week 24
Change in LDL/HDL ratio
Change from baseline in lipid ratio from fasting lipid profile
Time frame: Baseline, Week 12, Week 24
Change in insulin resistance (HOMA-IR)
Change in HOMA-IR from fasting glucose and serum insulin
Time frame: Baseline to Week 24
Change in high-sensitivity CRP (hs-CRP)
Change in hs-CRP measured by ELISA
Time frame: Baseline to Week 24
Change Waist circumference
Anthropometric change from baseline
Time frame: Baseline, Week 12, Week 24
Change in Leptin/Adiponectin ratio
Change in metabolic biomarker measured by ELISA
Time frame: Baseline, Week 24
Change in PANSS score
Change in Positive and Negative Syndrome Scale (psychiatric safety), The assessment instrument employs a standardized scoring mechanism with a theoretical range spanning from a minimum of 30 to a maximum of 210 points. This metric demonstrates an inverse relationship between numerical score and outcome favorability; therefore, higher scores are indicative of more severe or unfavorable conditions, whereas lower scores denote relatively improved or more favorable circumstances. Consequently, respondents achieving scores proximate to the minimum threshold (30) represent optimal outcomes, while those obtaining scores approaching the maximum threshold (210) signify substantially compromised or critical situations requiring immediate clinical or interventional consideration.
Time frame: Baseline, Week 12, Week 24
Change in CGI-SCH score
The CGI-SCH is a clinician-rated assessment scale measuring overall severity of schizophrenia symptoms. The scale ranges from 1 to 7, where 1 represents "normal, not at all ill" (minimum score) and 7 represents "among the most extremely ill" (maximum score). Scores are interpreted as: 1-2 = normal to borderline, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, and 7 = most extremely ill. A score of 7 indicates the worst clinical situation, reflecting severe and pervasive psychotic symptoms with significant functional impairment. The CGI-SCH is widely used in clinical trials and practice to track global severity and treatment response in schizophrenia over time.
Time frame: Baseline, Week 12, Week 24
Change in WHO QOL-BREF
The WHO QOL-BREF is a 26-item self-report instrument measuring overall quality of life across four domains: Physical Health, Psychological Health, Social Relationships, and Environment. Each item is rated on a 1-5 scale, yielding a minimum total score of 26 (poorest quality of life) and a maximum total score of 130 (best quality of life). Unlike severity scales, higher scores indicate better quality of life, while lower scores indicate poorer quality of life. A score of 26 represents the worst clinical situation, reflecting severely compromised physical health, psychological distress, social isolation, and inadequate environmental resources. Domain scores range from 4-20 each and can be analyzed separately to identify specific areas of impairment. The WHO QOL-BREF is widely used in clinical practice and research to evaluate functional quality of life, treatment outcomes, and overall well-being in various populations.
Time frame: Baseline, Week 12, Week 24
Treatment-emergent adverse events (TEAE)
Frequency and severity of TEAEs; safety and tolerability
Time frame: Continuous, weekly to Week 24
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