Cardiovascular and Kidney Outcomes and Mortality With Long-Acting Injectable and Oral Glucagon-Like Peptide 1 Receptor Agonists in Individuals With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Trials.

Summary

Across 10 randomized outcomes trials (n=71,351), long-acting GLP-1RAs reduced MACE by 14%, HHF by 14%, composite kidney events by 17%, and all-cause mortality by 12%, with consistent benefits for injectable and oral formulations. No excess risks of severe hypoglycemia, retinopathy, or pancreatic events were observed.

Key Findings

• Reduced MACE by 14% (HR 0.86; 95% CI 0.81–0.90) across 10 trials (n=71,351).
• Reduced hospitalization for heart failure by 14% (HR 0.86; 95% CI 0.79–0.93) and composite kidney outcome by 17% (HR 0.83; 95% CI 0.75–0.92).
• Benefits were consistent across subcutaneous and oral GLP-1RA formulations with no heterogeneity by route.
• No increased risks of severe hypoglycemia, retinopathy, or pancreatic events were detected.

Clinical Implications

Use long-acting GLP-1RAs for cardiorenal risk reduction in T2D irrespective of administration route; consider combining with SGLT2 inhibitors. Reassure patients about no increased risks of severe hypoglycemia, retinopathy, or pancreatic events.

Limitations

• Trial-level meta-analysis limits detailed subgroup analyses and may introduce ecological bias.
• Variations in trial design, populations, and outcome definitions across included studies.

Future Directions

Individual participant data meta-analyses to refine subgroup effects; pragmatic trials to evaluate combination strategies with SGLT2i and real-world effectiveness across diverse populations.