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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

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Lee, Matthew M.Y., Sattar, Naveed, Pop-Busui, Rodica, Deanfield, John, Emerson, Scott S., Inzucchi, Silvio E., Mann, Johannes F.E., Marx, Nikolaus +8 more·2025·Diabetes Care
DOI 10.2337/dc25-0241
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Abstract

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP-1RA) reduce the incidence of major adverse cardiovascular events (MACE) in type 2 diabetes (T2D), although whether benefits extend to both subcutaneous and oral formulations remains unclear. PURPOSE: In these meta-analyses, including new data from the Semaglutide cardiOvascular oUtcomes triaL (SOUL) (oral semaglutide) and Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial, we examined cardiovascular (CV) and kidney benefits and risks of long-acting (defined as having pharmacokinetics sufficient to provide 24-h activity) GLP-1RA in T2D. DATA SOURCES: A systematic review of PubMed was conducted (to 7 February 2025). STUDY SELECTION: Randomized placebo-controlled CV and kidney outcomes trials of GLP-1RA with ≥500 individuals with T2D were included. DATA EXTRACTION: A random-effects model was used to estimate hazard ratios (HRs) for MACE, its components, all-cause mortality, hospitalization for heart failure (HHF), a composite kidney outcome (kidney failure [kidney replacement therapy or persistent estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2], 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-1RA reduced incidence rate of MACE by 14% (HR 0.86 [95% CI 0.81, 0.90]; I2 = 27.6%), HHF by 14% (0.86 [0.79, 0.93]; I2 = 2.1%), and the composite kidney outcome by 17% (0.83 [0.75, 0.92]; I2 = 20.4%) and all-cause mortality by 12% (0.88 [0.82, 0.93]; I2 = 17.5%). A consistent 14% reduction was seen for all MACE components. 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-1RA, including both injectable and oral formulations, reduce incidence of MACE, HHF, and kidney events and all-cause mortality in T2D.

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  • A meta-analysis of cardiovascular outcomes trials indicates that spontaneous medullary thyroid carcinomas have been diagnosed in 6 patients receiving GLP-1RA versus 2 with placebo.

    “A meta-analysis of cardiovascular outcomes trials indicates that spontaneous medullary thyroid carcinomas have been diagnosed in patients receiving GLP-1RA (6 with active vs. 2 with placebo treatment) (79).”

    From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [79]

    The Results section reports medullary thyroid cancer in both treatment groups, but gives 4 cases with GLP-1RA and 2 with placebo across 11 trials—not the claimed 6 versus 2. It does not describe these cases as spontaneous. No page number is available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Large cardiovascular outcome trials in high-risk patients with type 2 diabetes have consistently demonstrated reductions in major adverse cardiovascular events (MACE) with GLP-1 RAs.

    “Large cardiovascular outcome trials in high-risk patients with type 2 diabetes have consistently demonstrated reductions in major adverse cardiovascular events (MACE) with GLP-1 RAs.”

    From Weight maintenance after discontinuation of GLP-1 therapies (2026) · cites this paper as [28]

  • In a meta-analysis of 10 RCTs including over 71,000 participants, GLP-1 RAs reduced the incidence of MACE by 14%.

    “GLP-1 RAs reduced the incidence of MACE by 14%”

    From Weight maintenance after discontinuation of GLP-1 therapies (2026) · cites this paper as [28]

  • A meta-analysis of GLP-1 RA registration trials demonstrated a 14% relative reduction in the risk of hospitalization for heart failure (HR 0.86, 95% CI 0.79-0.93).

    “A recently published meta-analysis of GLP-1 RA registration trials, including those for the commonly used medications dulaglutide, liraglutide, and semaglutide (both subcutaneous and oral), demonstrated a 14% relative reduction in the risk of hospitalization for heart failure (HR 0.86, 95% CI 0.79–0.93) (255).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [255]

  • Results of trials with GLP-1 RAs liraglutide, semaglutide, albiglutide, efpeglenatide, and dulaglutide have all shown evidence of a reduction in major atherosclerotic cardiovascular outcomes (MI, stroke, or cardiovascular death).

    “Results of trials with the GLP-1 RAs liraglutide (once daily) and semaglutide, albiglutide, efpeglenatide, and dulaglutide (once weekly) have all shown evidence of a reduction in major atherosclerotic cardiovascular outcomes (MI, stroke, or cardiovascular death) (251–256).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [255]

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Authors
Lee, M. M. Y., Sattar, N., Pop-Busui, R., Deanfield, J., Emerson, S. S., Inzucchi, S. E., Mann, J. F. E., Marx, N., Mulvagh, S. L., Poulter, N. R., Badve, S. V., Pratley, R. E., Perkovic, V., Buse, J. B., McGuire, D. K., & SOUL Trial Investigators
Affiliations
  • University of Glasgow (GB)
  • 2Department of Medicine, Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, OR
  • University College London (GB)
  • University of Washington (US)
  • Yale University (US)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Universitätsklinikum Aachen (DE)
  • Dalhousie University (CA)
  • Imperial College London (GB)
  • UNSW Sydney (AU)
  • AdventHealth Orlando (US)
  • University of North Carolina at Chapel Hill (US)
  • Parkland Health & Hospital System (US)
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2025-03-29
Volume
48
Issue
5
Pages
846-859
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc25-0241
OpenAlex
W4408960968
Cited by
63
References
0
Citations by year
2026: 41 · 2025: 21 · 2024: 1
FWCI
8.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes Care (publishedVersion)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
Funders
  • Abbott Laboratories
  • Amgen
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Sanofi
  • Biogen
  • Nevro
  • University of Glasgow
  • Novo Nordisk
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
GLP-1 receptor agonists, type 2 diabetes, long-acting injectables, oral semaglutide, cardiovascular outcomes, major adverse cardiovascular events, heart failure hospitalization, renal outcomes, renal failure, estimated glomerular filtration rate decline, all-cause mortality, renal safety, SOUL trial, FLOW trial, cardiovascular risk reduction, renal risk
MeSH terms
Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, Administration, Oral, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Humans, Hypoglycemic Agents, Randomized Controlled Trials as Topic, Glucagon-Like Peptide 1

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