Nutrition, Metabolism, and Cardiovascular Diseases · Nov 2026
Clinical and Genetic Evidence for the Effects of Glucagon-like peptide-1 Receptor Agonists on Cardiovascular Phenotypes in Metabolic Disorders: An Integrated Meta-Analysis and Drug Target Mendelian Randomization Study
By Tian Y, Bai S, Guo Q et al.
Background and Aims This study integrated a systematic review and meta-analysis of randomized controlled trials (RCTs) with drug-target Mendelian randomization (MR) to evaluate the effects of glucagon-like peptide-1receptor agonists (GLP-1RAs) on cardiovascular phenotypes in metabolic disorders. Methods and Results We searched major databases for RCTs evaluating vascular and cardiac phenotypes following GLP-1RA therapy in adults with type 2 diabetes and/or obesity. Primary outcomes were cf-PWV and LVM, and secondary outcomes included cardiac chamber volumes, functional indices, and NT-proBNP. Drug-target MR was performed using GLP1R cis-eQTLs as genetic instruments to infer causal effects on corresponding cardiovascular traits. Peak diastolic strain rate (PDSR) served as the genetic proxy for intrinsic myocardial relaxation. Twenty-two RCTs (n = 2,219) were analyzed. Both meta-analysis and MR demonstrated significant improvements in cf-PWV and LVM. Diastolic filling pressures (E/e’ and E/A) improved in clinical trials, corroborated by MR evidence of enhanced intrinsic relaxation (PDSR). While clinical analysis showed significant reductions in chamber volumes (LAV, LVESV) and NT-proBNP, MR analysis yielded null results. LVEF and LVGCS remained unchanged across both methodologies. LVGLS showed a marginal improvement in the meta-analysis that was not robust to sensitivity analyses or supported by MR. Two-step MR analysis further revealed that BMI mediated only a small fraction of the total effect on primary outcomes. Conclusions GLP-1RAs improve arterial stiffness, myocardial mass, and diastolic function in metabolic disorders. The concordance between clinical and genetic evidence supports these as core therapeutic benefits, providing strong validation for GLP-1RAs in mitigating adverse cardiovascular remodeling.