Long-Acting GLP-1RAs Lower Cardiovascular, Kidney Risks and Mortality in Type 2 Diabetes, Meta-Analysis Finds

Analyzing data from 71,351 patients, Matthew M.Y. Lee, School of Cardiovascular & Metabolic Health, University of Glasgow, Glasgow, U.K., and colleagues found that these medications reduced major adverse cardiovascular events (MACE) and hospitalization for heart failure by 14%, lowered kidney-related complications by 17%, and decreased all-cause mortality by 12%. Importantly, these improvements were achieved without an increased risk of severe hypoglycemia, retinopathy, or pancreatic disorders, reinforcing the potential of GLP-1RAs as a valuable therapeutic option for individuals with T2D at risk of cardiovascular and renal complications.

Glucagon-like peptide-1 receptor agonists are known to reduce MACE in type 2 diabetes, but the extent of benefits across both subcutaneous and oral formulations remains uncertain. A meta-analysis incorporating data from the Semaglutide Cardiovascular Outcomes Trial (SOUL) and the Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial was conducted to evaluate cardiovascular and kidney-related outcomes. Long-acting GLP-1RAs, defined by their ability to provide 24-hour pharmacological activity, were assessed through a systematic review of PubMed up to 7 February 2025. Randomized placebo-controlled trials with at least 500 participants were included.

A random-effects model estimated hazard ratios for MACE, its components, all-cause mortality, hospitalization for heart failure, and kidney outcomes, including kidney failure, significant eGFR decline, and kidney-related death. Additionally, worsening kidney function and safety outcomes were analyzed to determine the risks and benefits of long-acting GLP-1RAs in T2D management.

Key Findings:

• Analysis of 10 trials involving 71,351 participants showed that long-acting GLP-1RAs reduced the incidence of major adverse cardiovascular events (MACE) by 14% (HR 0.86).
• Hospitalization for heart failure (HHF) decreased by 14% (HR 0.86).
• The composite kidney outcome, including kidney failure, significant eGFR decline, or kidney-related death, was reduced by 17% (HR 0.83).
• All-cause mortality declined by 12% (HR 0.88).
• There was a consistent 14% reduction across all MACE components.
• There were no significant differences between subcutaneous and oral GLP-1RA administration routes.
• There was no increased risk of severe hypoglycemia, retinopathy, or pancreatic events.

While long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), including both injectable and oral formulations, have shown significant reductions in major adverse cardiovascular events, hospitalization for heart failure, kidney complications, and all-cause mortality in individuals with type 2 diabetes, researchers highlight certain limitations. They noted that "trial-level meta-analyses restrict detailed subgroup analyses and may introduce ecological bias, potentially affecting the precision of findings across diverse patient populations."

Despite these limitations, they concluded that "the overall evidence supports the cardiovascular and renal benefits of long-acting GLP-1RAs, reinforcing their role as an effective therapeutic option in T2D management."

Reference:

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, SOUL Trial Investigators; 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. Diabetes Care 2025; dc250241. https://doi.org/10.2337/dc25-0241