Short summary

We hypothesize that administration of semaglutide 1.34 mg/ml during a weekly visit by a study-nurse for 6 months is able to reduce HbA1c, weight and psychotic symptoms and improve quality of life, patient-related outcome, medicineadherence and the cardiometabolic risk factor profile in SGA-treated patients with schizophrenia spectrum disorder, prediabetes and overweight compared to placebo.

Rationale

Patients with schizophrenia have a 2 to 3 fold higher mortality rate than the general population. A recent Danish study found that the life expectancy of men and women with schizophrenia was reduced by 20.1 and 15.9 years respectively. Approximately 1/3 of the excess mortality has been attributed to type 2 diabetes mellitus (T2DM), which develops in 10-15%, and to CVD.

In general, life-style interventions have failed to counteract development of metabolic syndrome (MetS) and prediabetes in schizophrenia. Consequently, interest has focused on glucagon-like peptide 1 analogues (GLP-1), which increase satiety and delay gastric emptying, thereby reducing food intake and weight. Moreover, GLP-1 analogs potentiate glucose-stimulated insulin secretion and hence insulin sensitivity, whereby they counteract development of MetS and pre-diabetes. Finally, certain GLP-1 analogues have beneficial effects on cardiovascular outcomes in high-risk patients with T2DM.

The potential of GLP-1 analogues to improve the metabolic profile of patients with schizophrenia was recently successfully tested. In a RCT, including 97 patients (placebo/active comparator: 50/47) with schizophrenia, prediabetes and a BMI ≥27 kg/m2, 16 weeks of liraglutide (1.8 mg Victoza® daily) reduced body weight, waist circumference and abdominal fat mass, LDL cholesterol, glucose levels and insulin resistance, without any worsening in the psychiatric disorder. The beneficial effect of GLP-1 analogues in second generation antipsychotics (SGA)-treated patients was confirmed in a 2018 meta-analysis which, however, only included two additional and smaller trials of exanatide (Bydureon®), and only one of these studies was placebo-controlled. The review concluded that GLP-1 analogue treatment is effective and tolerable for SGA related weight gain, but with the few included patients, more studies are required.

We will investigate whether the GLP-1Ra Semaglutide 1.34 mg/ml that is approved for the treatment of type 2-diabetes has preventive effect in the development of diabetes and MetS. Treatment involves injection of Semaglutide 1.34 mg/ml once a week or corresponding volume of placebo once a week. The effect will be measured by Changes in HbA1c, Metabolic measures, Quality of life measures, Psychotic symptoms and SGA adherence measures, PRO-data. The duration of the trial is 30 weeks.

Description of the cohort

Patients 18-40 years of age with schizophrenia spectrum disorder (specifically ICD10 codes DF20,21, 25) and prediabetes and overweight will be recruited from outpatient clinics in Region of Southern Denmark and Region Zealand.

Data and biological material

Questionnaires and interviews regarding psychotic symptoms, medication adherence, quality of life in regard to weight, general well-being, physical activity, food-craving.

Blood-samples concerning hormone status and cardiovascular risk markers.

Screening for cardiovascular autonomic neuropathy by a hand held apparatus.

PET/CT imaging on subgroup concerning atherosclerosis.

Collaborating researchers and departments

OPUS clinics and community psychiatry centers of Region of Southern. Mental Health Hospital and University Clinic in the Region of Southern Denmark.

• Niels Bilenberg, Clinical Professor, M.D.

Region Zealand Community Psychiatry

• Sidse Arnfred, Clinical Professor, M.D.
• Nicolai Gundtoft Uhrenholt, Physician, Ph.D. Student.

Department of Endocrinology M / Steno Diabetes Centre Odense (SDCO). Odense University Hospital.

• Ashok Ganeshalingam, Physician, Ph.D. Student.

Department of Steno Diabetes Centre Zealand.

• Peter Gæde, MD, DMSci, Chief Physician, Associate Professor.