Semaglutide, a second-generation GLP-1 receptor agonist, was associated with significantly reduced body weight and other metabolic factors in adults with schizophrenia, prediabetes, and overweight/obesity compared with placebo, new research showed.
In a randomized controlled trial of patients with the three conditions who were already taking second-generation antipsychotic (SGA) medication, those who also received 30 weeks of semaglutide at a dose of up to 1 mg/wk had a weight reduction of 9 kg (20 lb) compared with those receiving a placebo, as well as a greater reduction in blood glucose and triglycerides.
The active treatment group also had significant improvement on a physical quality of life (QOL) measure. There were no between-group differences on mental QOL or Positive and Negative Syndrome Scale (PANSS)-6 scores — showing that there was no treatment-related worsening of mental health, the researchers noted.
“We believe semaglutide represents a promising option to counteract weight gain in patients prescribed antipsychotics known for strong metabolic side effects, such as clozapine and olanzapine,” lead author Ashok A. Ganeshalingam, MD, Department of Endocrinology, Odense University Hospital, Odense, Denmark, told Medscape Medical News.
“Importantly, by addressing weight gain proactively, clinicians may also improve long-term adherence to antipsychotic therapy,” Ganeshalingam added.
The findings were published online on September 3 in JAMA Psychiatry.
Second-Generation GLP-1 Receptor Agonist
The placebo-controlled, double-blind randomized controlled trial was conducted from 2022 to 2024 and included 154 adult patients (57% women; mean age, 38 years) from Denmark. All had schizophrenia, prediabetes (A1c, 5.7%-6.4% of total hemoglobin), and overweight or obesity (BMI, at least 27).
Patients with type 2 diabetes were excluded because “they were already eligible to receive semaglutide through routine clinical care,” the researchers noted.
For 30 weeks, half of the participants self-injected once-weekly subcutaneous semaglutide, and the other half took a matching placebo in addition to their normal SGA. Semaglutide doses were titrated up to 1 mg/wk over 8 weeks.
The primary outcome was the change in blood glucose as measured by A1c. Secondary outcomes included changes in body weight; changes in schizophrenia symptoms, as measured by the PANSS-6; and changes in physical and mental QOL, as measured by version 2 of the 36-item Short Form Survey (SF-36v2).
Ganeshalingam noted that the investigators chose A1c as the primary endpoint because they were uncertain whether semaglutide would be potent enough to induce clinically significant weight loss in this population.
“Antipsychotics act on the satiety center, and earlier studies with first-generation GLP-1 receptor agonists showed only modest effects,” he said.
‘Striking’ Findings
At 30 weeks, results showed that patients receiving semaglutide 1 mg/wk had a significantly greater reduction in A1c (difference, -0.46%) and body weight (difference, -9.2 kg) than those receiving placebo (P < .001 for both comparisons).
Ganeshalingam noted that this magnitude of weight loss was comparable to what was reported previously in the STEP 10 trial with a 2.4 mg/wk dose of the drug.
“This finding was striking, as it suggests that antipsychotic-induced weight gain is not permanent and can be reversed,” he said.
Additionally, compared with 81% of the active treatment group, 19% of the placebo group achieved an A1c of less than 5.7% of total hemoglobin (P < .001).
They also had a significantly greater increase in high-density cholesterol (difference, 10.8 mg/dL; P = .007), reduction in triglycerides (difference, -29.2 mg/dL; P = .03), and improvement in QOL on the SF-36v2 Physical Component Summary (difference, 3.8 points; P = .001) compared with the placebo.
There were no significant score differences between treatment groups on the PANSS-6 or the SF-36v2 Mental Component Summary, which was not surprising, as participants had stable antipsychotic treatment prior to the study, Ganeshalingam noted.
“That said, we were reassured to see that semaglutide did not worsen schizophrenia symptoms, even though the intervention was relatively intensive. It was important to confirm that the introduction of an injectable treatment did not destabilize mental health,” he said.
He added it is possible that if a patient knows that semaglutide may counteract side effects such as weight gain, adherence might improve and indirectly lead to better psychiatric outcomes.
“At present, there is no clear biological mechanism to suggest that weight loss directly improves schizophrenia symptoms. However, in our study, weight loss was associated with improvements in self-reported physical quality of life, which may, over time, also impact negative symptoms,” Ganeshalingam said.
Proof of Concept
Adverse events (AEs) were reported in 73% of participants of both treatment groups. Although the semaglutide group reported higher rates of nausea (29% vs 12%, respectively; P = .03), constipation (25% vs 4%; P < .001), and abdominal pain (16% vs 4%; P = .02) than the placebo group, the incidence of these events declined over time.
There were 68 hospitalizations among 15 members of the semaglutide group and 47 hospitalizations among 24 members of the placebo group. There was no significant between-group difference for serious AEs.
Additionally, 91.5% of all participants finished the study, with just three members of the semaglutide group and 10 of the placebo group discontinuing at some point.
“Our study provides proof-of-concept that semaglutide is safe, tolerable, and effective in patients with schizophrenia, without adverse effects on mental health. This is a breakthrough in a field where treatment options have been scarce,” Ganeshalingam said.
“Importantly, it also opens the door to discussing whether semaglutide should be introduced early — possibly alongside antipsychotic initiation — to prevent weight gain and metabolic complications,” he added.
Practice Changing Research?
Commenting for Medscape Medical News, Christoph U. Correll, MD, clinical professor of psychiatry and molecular medicine at Hofstra/Northwell, Hempstead, New York, said, “This was a much-needed study” because of the cardiometabolic problems that often accompany those with severe mental illness, especially schizophrenia.
Correll, who was not involved with the research, noted that although the idea of adding an already-approved weight-management drug such as semaglutide may seem like an easy option, it’s not so simple because of the need for evidence of efficacy in this vulnerable population, along with whether they would adhere to a once-weekly self-injection regimen.
In the current study, results with semaglutide “seem to be on par with what we’ve seen in the general population, and patients on antipsychotics and with schizophrenia are not disadvantaged. They can also benefit hugely,” he said.
Correll noted that the decrease in A1c by almost half and the loss of 9 kg in weight by the active-treatment group “was remarkable.” He was also impressed that 81% achieved normalized hemoglobin A1c and that 96% completed the study.
He added that although more studies are still needed, the data from this and previous research are leaning toward a practice-changing regimen.
“We may have to change our guidelines from offering metformin to everyone who has weight gain or insulin resistance and prediabetes to offering a GLP-1 receptor agonist,” Correll said.
The study was funded by the Novo Nordisk Foundation, the Steeno Diabetes Center Sjælland, the Steno Diabetes Center Odense, Slagelse Research Grants, and the Region Zealand Health Research Foundation. Ganeshalingam reported receiving travel funds from Novo Nordisk to attend a conference, grants from Aase and Ejnar Danielsens Fond, and a 1-year PhD salary from the Steno Diabetes Center Odense. Financial conflicts of interest for the other study authors are listed in full in the original article. Correll reported consulting for all companies that make antipsychotics, including Novo Nordisk. He is also a member of Medscape Psychiatry’s editorial advisory board.