Effects of GLP-1 receptor agonists on cardiometabolic outcomes in heart transplant recipients: A systematic review and meta-analysis of observational studies

Background: Cardiometabolic complications drive late morbidity and mortality after heart transplantation. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established therapies for diabetes and obesity, heart transplant recipients have been excluded from pivotal trials due to concerns regarding gastrointestinal intolerance, altered drug absorption, and possible interactions with immunosuppressants. We therefore performed a systematic review and meta-analysis of observational studies to evaluate metabolic, renal, and safety outcomes associated with GLP-1 RA therapy in adult heart transplant recipients. Methods: Using a prespecified protocol registered with PROSPERO (CRD420251243172), we conducted a systematic review and meta-analysis of observational studies published in PubMed, Embase, Cochrane CENTRAL, and Scopus through January 31, 2025, evaluating GLP-1 RA therapy in adult heart transplant recipients. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the ROBINS-I tool. For mixed solid-organ transplant studies, heart-transplant subgroup data were used when explicitly reported by the study authors. When heart-specific quantitative outcome data were not separately available, mixed solid-organ cohort data were described as indirect evidence and interpreted cautiously. Discrepancies were resolved through discussion, with adjudication by a third reviewer when necessary. Random-effects meta-analyses with restricted maximum likelihood estimation were performed for outcomes reported by at least 2 sufficiently similar studies. Results: Four observational studies (N=245) met inclusion criteria. Meta-analysis demonstrated significant reductions in body mass index (pooled mean difference -2.24 kg/m²; 95% CI -3.49 to -0.98; p=0.0005; I²=56.8%) and hemoglobin A1c (-0.62% points; 95% CI -0.94 to -0.31; p=0.0001; I²=0%). Secondary outcomes showed reductions in body weight (-7.82 kg; p=0.032) and LDL cholesterol (-11.88 mg/dL; p=0.034). Renal function remained stable. Reported safety data were limited, as available observational studies did not identify a consistent short-term signal of harm associated with immunosuppression management or graft outcomes. Conclusions: GLP-1 RA therapy was associated with improved weight- and glycemia-related outcomes in adult heart transplant recipients. Available observational studies did not identify a consistent signal of harm associated with immunosuppression management or graft outcomes, but the safety data were sparse and insufficient to rule out clinically important effects. Prospective trials are needed to confirm long-term cardiovascular and graft outcomes.