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Cardiovascular and Kidney Outcomes and Mortality With Long-Acting Injectable and Oral Glucagon-Like Peptide 1

Matthew M Y Lee1, Naveed Sattar1, Rodica Pop-Busui2

  • 1School of Cardiovascular & Metabolic Health, University of Glasgow, Glasgow, U.K.

Diabetes Care
|March 29, 2025
PubMed
Abstract

Insights

Long-acting glucagon-like peptide 1 receptor agonists (GLP-1RA), including oral and injectable forms, significantly reduce cardiovascular events, heart failure hospitalizations, and kidney disease progression in type 2 diabetes patients. These benefits were observed without increasing risks of severe hypoglycemia or retinopathy.

Area of Science:

  • Cardiology
  • Nephrology
  • Endocrinology

Background:

  • Glucagon-like peptide 1 receptor agonists (GLP-1RA) are known to reduce major adverse cardiovascular events (MACE) in type 2 diabetes (T2D).
  • Uncertainty exists regarding whether these cardiovascular benefits apply to both subcutaneous and oral GLP-1RA formulations.

Purpose of the Study:

  • To evaluate the cardiovascular (CV) and kidney benefits and risks of long-acting GLP-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes (T2D).
  • Inclusion of new data from the Semaglutide cardiOvascular oUtcomes triaL (SOUL) and the Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial.

Main Methods:

  • Systematic review of randomized placebo-controlled trials (RCTs) of GLP-1RA with ≥500 participants with T2D, published up to February 7, 2025.
  • Meta-analysis using a random-effects model to estimate hazard ratios (HRs) for MACE, its components, all-cause mortality, hospitalization for heart failure (HHF), composite kidney outcomes, and safety events.
  • Trials included long-acting GLP-1RA with pharmacokinetics providing 24-hour activity.

Main Results:

  • Across 10 trials (n=71,351), long-acting GLP-1RA reduced MACE by 14% (HR 0.86), HHF by 14% (HR 0.86), composite kidney outcomes by 17% (HR 0.83), and all-cause mortality by 12% (HR 0.88).
  • Consistent 14% reduction observed for all MACE components.
  • No significant heterogeneity was found based on GLP-1RA administration route (subcutaneous vs. oral); no increased risks of severe hypoglycemia, retinopathy, or pancreatic events were noted.

Conclusions:

  • Long-acting GLP-1RA, encompassing both injectable and oral formulations, demonstrate significant benefits in reducing MACE, HHF, kidney events, and all-cause mortality in patients with T2D.
  • These findings support the broad use of long-acting GLP-1RA for comprehensive risk reduction in T2D.
  • Trial-level meta-analyses have limitations, including potential ecological bias and preclusion of detailed subgroup analyses.

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