Is the steady-state concentration, duration of action, or molecular weight of GLP-1RA associated with cardiovascular and renal outcomes in type 2 diabetes?

Importance: Disparities were found in the cardiovascular and renal outcomes among different glucagon-like peptide 1 receptor agonist (GLP-1RA) subtypes. However, whether the characteristics of GLP-1RA itself are associated with these disparities remains unclear. Objective: To assess the association between the steady-state concentration, duration of action, or molecular weight of GLP-1RA and the risks of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). Data Sources: PubMed, MEDLINE, EMBASE, Cochrane and Clinicaltrial.gov from inception to April 2022. Study Selection: Randomized controlled trials (RCTs) investigating GLP-1RAs in patients with T2D were included. Data Extraction And Synthesis: Literature screening and data extraction were performed independently by 2 researchers. The outcomes were computed as odds ratio (OR) and its 95% confidence interval (CI). Subgroup analyses were conducted according to steady-state concentration, duration of action and molecular weight of GLP-1RAs. Main Outcomes and Measures: Primary outcomes were major adverse cardiovascular events (MACE), composite renal outcome and all-cause mortality. Results: In all, 61 RCTs were included. When compared with non-GLP-1RA agents, GLP-1RAs with high steady-state concentration were associated with greater risk reduction in MACE (p for subgroup difference = 0.01) and the composite renal outcome (p for subgroup difference = 0.008) in patients with T2D. Greater risk reductions in MACE between GLP-1RA users versus non-GLP-RA users were observed in long acting stratum when compared with short acting stratum (p for subgroup difference = 0.04) in patients with T2D. The molecular weight of GLP-1RAs was not associated with the risk of cardiovascular and renal outcomes. Conclusions and Relevance: GLP-1RAs with high steady-state concentrations might be associated with greater risk reductions in cardiovascular and renal outcomes in patients with T2D. Long acting GLP-1RAs might outperform short acting ones in reducing the risk of cardiovascular outcomes. These findings provided new insights for guiding the clinical applications of GLP-1RAs in patients with T2D.