Cardiovascular, Kidney Outcomes and Mortality with Long-Acting Injectable and Oral Glucagon-Like Peptide-1 Receptor Agonists in Persons With Type 2 Diabetes – a Systematic Review and Meta-Analyses of Randomized Trials

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posted on 2025-03-29, 00:10 authored by Matthew M.Y. Lee, Naveed Sattar, Rodica Pop-Busui, John Deanfield, Scott S. Emerson, Silvio E. Inzucchi, Johannes F.E. Mann, Nikolaus Marx, Sharon L. Mulvagh, Neil R. Poulter, Sunil V. Badve, Richard E. Pratley, Vlado Perkovic, John B. Buse, Darren K. McGuire

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE) in type 2 diabetes (T2D), although it remains unclear if benefits extend to both subcutaneous and oral formulations.

PURPOSE

These meta-analyses, including new data from the SOUL (oral semaglutide) and FLOW trials, examined cardiovascular and kidney benefits and risks of long-acting (defined as having pharmacokinetics sufficient to provide 24-hour activity) GLP-1RAs in T2D.

DATA SOURCES

Systematic review of PubMed (to Feb 07, 2025). PROSPERO: CRD42024607253.

STUDY SELECTION

Randomized placebo-controlled CVOTs of GLP-1RAs with ≥500 individuals with T2D.

DATA EXTRACTION

A random effects model estimated hazard ratios (HR) for MACE; its components; all-cause mortality; hospitalization for heart failure (HHF); a composite kidney outcome (kidney failure (kidney replacement therapy or persistent eGFR <15 mL/min/1.73m2), sustained ≥50% eGFR decline or nearest equivalent, or kidney-related death); worsening kidney function; and safety outcomes.

DATA SYNTHESIS

Across 10 trials (n=71,351), long-acting GLP-1RAs reduced MACE by 14% (HR 0.86 [95% CI 0.81-0.90]; I2=27.6%), all-cause mortality by 12% (HR 0.88 [0.82-0.93]; I2=17.5%), HHF by 14% (HR 0.86 [0.79-0.93]; I2=2.1%), and the composite kidney outcome by 17% (HR 0.83 [0.75-0.92]; I2=20.4%). All MACE components showed a consistent 14% reduction. There was no significant heterogeneity by GLP-1RA administration route (subcutaneous vs. oral). There were no increased risks of severe hypoglycemia, retinopathy, or pancreatic events.

LIMITATIONS

Trial-level meta-analyses preclude detailed subgroup analyses and may introduce ecological bias.

CONCLUSIONS

As a group, long-acting GLP-1RAs, including both injectable and oral formulations, reduce MACE, all-cause mortality, HHF, and kidney events in T2D.

Funding

The funders (Novo Nordisk) had no role in the design and conduct of the study; collection, management, analyses, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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Keywords

Glucagon-like Peptide-1 Receptor Agonist (GLP-1 RA)Type 2 Diabetes Meta-Analysis Cardiovascular Prospective Randomized Trial

Licence

CC BY-NC-SA 4.0