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-1RA reduced MACE (HR 0.86), heart failure hospitalizations (HR 0.86), composite kidney outcomes (HR 0.83), and all-cause mortality (HR 0.88) with consistent effects for oral and injectable formulations and no major safety signals.

Key Findings

• Long-acting GLP-1RA reduced MACE by 14% (HR 0.86; 95% CI 0.81–0.90).
• Hospitalization for heart failure decreased by 14% (HR 0.86; 95% CI 0.79–0.93).
• Composite kidney outcomes decreased by 17% (HR 0.83; 95% CI 0.75–0.92).
• All-cause mortality decreased by 12% (HR 0.88; 95% CI 0.82–0.93), with no heterogeneity by oral vs subcutaneous route.

Clinical Implications

Supports prescribing long-acting GLP-1RA (including oral semaglutide) to reduce ASCVD events, HF hospitalizations, kidney disease progression, and mortality; route of administration can be individualized without loss of efficacy.

Limitations

• Trial-level meta-analysis limits granularity for subgroup and interaction analyses and may introduce ecological bias.
• Heterogeneity in trial populations, background therapies, and follow-up durations.

Future Directions

Head-to-head and combination therapy trials (e.g., GLP-1RA plus SGLT2i) powered for cardiorenal endpoints; patient-level meta-analyses to refine treatment personalization.