What happened
A secondary analysis of the HISTORI randomized trial examined insulin sensitivity and pancreatic beta-cell measures. Participants were adults being treated for schizophrenia with second-generation antipsychotic medicine who also had prediabetes and a BMI in the overweight or obesity range. The double-blind trial assigned 154 people to weekly semaglutide or placebo for 30 weeks.
Semaglutide was increased to 1.0 mg weekly. Of the 154 randomized participants, 141 completed follow-up, and 131 had complete insulin data for this analysis. The average age was 38.3 years, and 56% were women.
The placebo-adjusted change in fasting glucose favored semaglutide by 0.87 mmol/L. The active-treatment group also had improvement in a model-based insulin-sensitivity measure and a reduction in an insulin-resistance measure. Participants assigned semaglutide lost an average of 9.2 kilograms. Mediation analysis suggested that weight loss explained part of the change in insulin sensitivity and resistance.
Not every metabolic measure improved clearly. Changes in fasting insulin, C-peptide, and beta-cell function did not meet the study's threshold for statistical significance. These findings keep the result focused on the measured glucose and insulin-response outcomes rather than a claim that pancreatic function broadly improved.
The parent HISTORI report used HbA1c as its primary outcome. It also assessed body weight, physical and mental quality of life, and schizophrenia symptoms. The trial found no significant worsening in the measured schizophrenia symptom score, although gastrointestinal symptoms were more frequent with semaglutide.
What it means
People taking second-generation antipsychotics are often underrepresented in weight and diabetes trials, even though metabolic complications can affect long-term health. HISTORI provides randomized evidence in a specifically defined group receiving ongoing psychiatric treatment.
The secondary analysis adds detail beyond body weight and HbA1c. It suggests that semaglutide improved how the body responded to insulin over 30 weeks, with some of that change linked statistically to weight loss. Psychiatric treatment continued during the study rather than being replaced by metabolic care.
What it does not mean
The trial does not show that semaglutide is appropriate for every person who gains weight while taking an antipsychotic. Participants had schizophrenia, prediabetes, a BMI of at least 27, and care within two Danish regions. Results may differ with other diagnoses, antipsychotic regimens, diabetes status, care systems, or medical histories.
A 30-week study cannot establish long-term cardiovascular outcomes, diabetes prevention, durability after semaglutide ends, or uncommon harms. The insulin analysis also had fewer complete cases than the randomized population, and mediation analysis can suggest a pathway without proving it.
The findings do not support stopping, changing, or reducing an antipsychotic without psychiatric guidance. Decisions about semaglutide require coordination across mental-health and medical care, including monitoring for gastrointestinal effects, glucose changes, and any change in psychiatric status.
Educational information only. This brief is not medical advice. Do not start, stop, or change treatment based on it.
How this brief was reported
Obesity Treatment News is a BariatricPal publication. We review linked source material, explain what changed, and state what the evidence does not establish.
Editorial standards, corrections, and commerce disclosure · About BariatricPal · About the brief author · Contact BariatricPal