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

Efficacy and Safety of Semaglutide Versus Placebo on Cardiometabolic Profile in Patients With Schizophrenia With Metabolic Syndrome: A Multicentre, Double-Blind, Randomised Controlled Trial (ESCaMS Trial)

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.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• ● 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.