Semaglutide Cuts Weight by 9 kg and Reverses Prediabetes in Schizophrenia Patients

Patients with schizophrenia die on average 15–20 years earlier than the general population, largely due to cardiovascular disease and type 2 diabetes. Second-generation antipsychotics (SGAs), the mainstay of treatment, dramatically worsen metabolic health by promoting weight gain, insulin resistance, and dyslipidemia. Despite this well-known hazard, effective pharmacological interventions for this population have remained elusive—until now.

The HISTORI trial (NCT05193578) was a multicenter, double-blinded, placebo-controlled RCT conducted across community mental health services in two Danish regions between January 2022 and May 2024. Researchers enrolled 154 SGA-treated adults aged 18–60 with schizophrenia, prediabetes (HbA1c 5.7%–6.4%), and overweight or obesity (BMI ≥27). Participants were randomized 1:1 to receive subcutaneous semaglutide—titrated to 1.0 mg/week over 8 weeks—or matched placebo for 30 weeks. The primary endpoint was change in HbA1c; secondary endpoints included body weight, schizophrenia symptom severity (PANSS-6), and physical and mental quality of life (SF-36v2).

The results were striking. Semaglutide reduced HbA1c by 0.46 percentage points (95% CI, −0.56 to −0.36) compared to placebo, with 81% of semaglutide-treated patients achieving normoglycemia (HbA1c <5.7%) versus only 19% in the placebo group (P<.001). Body weight dropped by a mean of 9.21 kg (95% CI, −11.68 to −6.75). Cardiometabolic benefits extended to lipids: HDL cholesterol rose by 10.81 mg/dL (P=.007) and triglycerides fell by 29.20 mg/dL (P=.03). Physical quality of life improved by 3.75 points on the SF-36v2 (P=.001).

Critically, semaglutide did not worsen psychiatric outcomes. PANSS-6 scores and mental quality of life were statistically unchanged between arms, directly addressing a major safety concern in this population. Trial completion was high—96% in the semaglutide group and 87% in the placebo group—suggesting good tolerability. Gastrointestinal adverse events were more frequent with semaglutide, consistent with its known profile, but rates of serious adverse events did not differ significantly between groups, though a slightly higher hospitalization rate was noted in the semaglutide arm.

These findings have immediate clinical relevance. They provide the first robust RCT evidence that GLP-1 receptor agonists can reverse prediabetes and substantially reduce weight in SGA-treated patients with schizophrenia—a population historically excluded from metabolic intervention trials. The 30-week duration and relatively modest top dose (1.0 mg vs the 2.4 mg used for obesity) suggest even greater benefits may be achievable. Psychiatrists and endocrinologists should consider semaglutide as part of integrated cardiometabolic care for this high-risk group.