Glucagonlike Peptide-1 (GLP-1) Receptor Agonists for Cardiometabolic Risk in Severe Mental Illness: A Narrative Review

People with severe mental illness face a substantially increased cardiometabolic risk and premature mortality, largely driven by antipsychotic-associated metabolic disturbances, including significant weight gain, insulin resistance, dyslipidemia, impaired glucose homeostasis, and increased rates of metabolic syndrome. Despite existing recommendations for monitoring and early intervention, managing this risk remains a significant clinical challenge. Glucagonlike peptide-1 receptor agonists have emerged as a potential adjunctive therapeutic strategy in this context. This narrative review evaluated the efficacy and safety of these agents in adults with severe mental illness receiving chronic antipsychotic treatment. A structured search was conducted in PubMed/MEDLINE and the Cochrane Library, complemented by relevant clinical guidelines and consensus documents. Randomized controlled trials, systematic reviews, and meta-analyses published between 2015 and 2025 in English or Portuguese were included, and the strength of evidence was assessed using the Strength of Recommendation Taxonomy. Nine studies were included, comprising six randomized controlled trials and three evidence synthesis studies. Liraglutide and semaglutide consistently demonstrated clinically meaningful reductions in body weight and improvements in glycemic control, without evidence of worsening psychiatric symptoms. In contrast, exenatide did not show additional weight loss compared with placebo, although some hemodynamic benefits were observed. The most common adverse events were mild to moderate gastrointestinal symptoms. Overall, the available evidence suggests a favorable balance between cardiometabolic benefits and psychiatric safety, particularly in patients treated with high metabolic risk antipsychotics such as clozapine and olanzapine. GLP-1 receptor agonists appear to be a promising adjunctive option for cardiometabolic risk reduction in this population. These findings support their consideration as a clinically relevant strategy, especially in patients at higher cardiometabolic risk. However, current evidence is limited by small sample sizes and short follow-up periods, and further long-term studies are needed to support broader clinical implementation.