Glucagon-like peptide-1 receptor agonists for weight management in mental illness: a network meta-analysis

Background/Objectives: This network meta-analysis involved nine randomized controlled trials, comprising 595 participants (average age = 37.8 years, 55.3% female, 83.9% schizophrenia spectrum disorders), evaluating the comparative risk–benefit profiles of glucagon-like peptide-1 receptor agonists in individuals with obesity comorbid with mental illness. Subjects/Methods: Outcomes included body weight (primary); body mass index (BMI); waist circumference; blood-based measures, including fasting plasma glucose, hemoglobin A1c (HbA1c), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides; systolic and diastolic blood pressure; death; all-cause discontinuation; adverse event-related discontinuation; serious adverse events (SAEs), injection site-related adverse events, headache, dizziness, nausea, vomiting, constipation, and diarrhea; psychiatric hospitalization; and changes in overall schizophrenia symptoms. Results: Treatment arms comprised subcutaneous exenatide (S-EXE)(twice-daily [BID]/once-weekly [QW]), subcutaneous liraglutide (S-LIR)(once-daily [QD]), and subcutaneous semaglutide (S-SEM)(QW), alongside a control group (placebo, k = 8; non-placebo, k = 1). S-LIR(QD) and S-SEM(QW) were significantly associated with reduced body weight compared with control, with standardized mean differences (95% confidence intervals) of −0.945 (− 1.784 to −0.106) and −2.101 (− 2.978 to −1.224), respectively. S-LIR(QD) was associated with waist circumference and HbA1c level reductions, lower SAE incidences, and higher nausea, vomiting, and constipation incidences compared with the control. S-SEM(QW) was associated with reduced BMI, waist circumference, fasting plasma glucose, and HbA1c levels, and higher nausea, vomiting, and constipation compared with the control. Each drug did not differ from control regarding other outcomes. Conclusions: S-SEM(QW) may be the preferred treatment option, given its largest estimated effects versus control on body weight; however, its comparative ranking is uncertain due to sparse networks, substantial heterogeneity, and predominant indirect evidence.