Semaglutide for Antipsychotic Weight Gain

Semaglutide (Ozempic) reduces metabolic problems from antipsychotics

STUDY: Ganeshalingam AA et al, Diabetes Care 2026;49(5):1–8

STUDY TYPE: Randomized, placebo-controlled trial

FUNDING: Region Sjælland, Steno Diabetes Center Zealand, Novo Nordisk Foundation, Novo Nordisk A/S (drug supply only)

Background

Around 1 in 8 Americans take a GLP-1 agonist for obesity or diabetes, but can they reduce metabolic burdens on antipsychotics.

The Study

This double-blind 30-week RCT from Denmark randomized 154 adults with schizophrenia, prediabetes, and obesity (mean BMI 40) who were on stable antipsychotic treatment to semaglutide 1.0 mg weekly or placebo. Primary outcomes were insulin sensitivity, insulin resistance, and β-cell function measured by HOMA2 estimates. Completion rate was 91.5%.

Semaglutide produced 9.2 kg of weight loss versus essentially none with placebo. Insulin sensitivity improved significantly (mean difference +8.60; P = 0.001), and insulin resistance fell (−0.69; P = 0.006). Fasting glucose dropped by 0.87 mmol/L. Mediation analysis showed that weight loss drove virtually all of these gains. β-Cell function barely budged and didn’t reach significance, suggesting the improvements in insulin resistance were driven by the weight loss. The drug was well tolerated.

Practice Implications

1. This trial joins a handful of others, along with practice guidelines that endorse GLP-1RAs for antipsychotic weight gain.
2. Treating obesity may not be in your therapeutic lane, but managing side effects is, and this use is not off-label when the GLP-1RA is approved in obesity. Learn how to use them in our Carlat article.
3. Still, metformin is first line. This one works better early, before the weight gain kicks in, while GLP-1RAs are appropriate for actual obesity or for some patients with BMIs below 30.