Comparative effects of glucagon-like peptide-1-based regimens on peripheral arterial and limb events in type 2 diabetes: a network meta-analysis of randomized trials
9 affiliations
- 1Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
- 2Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- 3Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- 4Social Determinants of Health Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- 5Department of Cardiology, University Hospitals Birmingham, Birmingham, UK
- 6Queen Elizabeth Hospital, Birmingham, UK
- 7Department of Medicine, University of Arizona Sarver Heart Center, Phoenix, USA
- 8Department of Medicine, University of Arizona Sarver Heart Center, Tucson, AZ USA
- 9Emory University, Atlanta, Georgia USA
Abstract
Background: Peripheral artery disease (PAD) is a disabling condition in patients with type 2 diabetes mellitus (T2DM), yet lower-extremity outcomes are rarely prespecified in trials of GLP-1-based therapies. We compared individual GLP-1-based regimens for PAD-related vascular and limb events.
Methods: We searched PubMed, Embase, Scopus, Web of Science, the Cochrane Central Register of Controlled Trials (CENTRAL), ProQuest, medRxiv, ClinicalTrials.gov, and the WHO ICTRP from inception through June 3, 2025, and updated the search on July 16, 2026. Randomized controlled trials (RCTs) in adults with T2DM were eligible. Events from trial reports and registries were harmonized using MedDRA v26.0. Bayesian random-effects network meta-analyses were the primary analyses, frequentist models assessed robustness, and confidence was evaluated with CINeMA. Treatment effects were reported as risk ratios (RRs) with 95% credible intervals (CrIs).
Results: Forty-five RCTs involving 110,333 participants were included. For PAOD (33 RCTs; 90,742 participants; 572 events), subcutaneous semaglutide was associated with a lower risk than placebo (RR: 0.37; 95% CrI: 0.14–0.86), with low confidence; the finding was supported by frequentist and sensitivity analyses. In direct placebo-controlled trials, PAOD occurred in 18/4,088 participants receiving subcutaneous semaglutide (4.4 per 1,000) and 33/3,650 receiving placebo (9.0 per 1,000). For PVD (18 RCTs; 69,809 participants; 111 events), albiglutide (RR: 0.11; 95% CrI: 0.01–0.50) and efpeglenatide (RR: 0.09; 95% CrI: 0.01–0.57) were associated with lower risks than placebo, with high confidence for both comparisons. Insulin also showed a favorable Bayesian estimate versus placebo (RR: 0.06; 95% CrI: <0.01–0.49; moderate confidence). No credible Bayesian differences were identified for amputation, necrosis, or peripheral embolism and thrombosis; confidence was predominantly low or very low.
Conclusions: The findings suggest agent- and outcome-specific signals rather than a class-wide limb benefit. Because events were rare and usually derived from adverse-event reporting, the results do not establish clinical superiority or support treatment selection based on limb protection alone. Dedicated PAD-focused trials with standardized adjudicated outcomes are needed.
Trial registration: PROSPERO CRD420251244166.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13098-026-02271-4.
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BibTeX
@article{amanibeni2026comparative,
title = {{Comparative effects of glucagon-like peptide-1-based regimens on peripheral arterial and limb events in type 2 diabetes: a network meta-analysis of randomized trials}},
author = {Reza Amani-Beni and Bahar Darouei and Shiva Maleki and Hossein Sadri and Arsham Seifnezhad and Reza Eshraghi and Ashkan Bahrami and Pouya Ebrahimi and Farhan Shahid and Subramanya Upadhyaya and Mohammad Reza Movahed and Guillermo Umpierrez},
journal = {Diabetology \& Metabolic Syndrome},
year = {2026},
month = aug,
doi = {10.1186/s13098-026-02271-4},
url = {https://doi.org/10.1186/s13098-026-02271-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Comparative effects of glucagon-like peptide-1-based regimens on peripheral arterial and limb events in type 2 diabetes: a network meta-analysis of randomized trials
AU - Reza Amani-Beni
AU - Bahar Darouei
AU - Shiva Maleki
AU - Hossein Sadri
AU - Arsham Seifnezhad
AU - Reza Eshraghi
AU - Ashkan Bahrami
AU - Pouya Ebrahimi
AU - Farhan Shahid
AU - Subramanya Upadhyaya
AU - Mohammad Reza Movahed
AU - Guillermo Umpierrez
PY - 2026
DA - 2026/08/08
JO - Diabetology & Metabolic Syndrome
DO - 10.1186/s13098-026-02271-4
UR - https://doi.org/10.1186/s13098-026-02271-4
AB - Background: Peripheral artery disease (PAD) is a disabling condition in patients with type 2 diabetes mellitus (T2DM), yet lower-extremity outcomes are rarely prespecified in trials of GLP-1-based therapies. We compared individual GLP-1-based regimens for PAD-related vascular and limb events. Methods: We searched PubMed, Embase, Scopus, Web of Science, the Cochrane Central Register of Controlled Trials (CENTRAL), ProQuest, medRxiv, ClinicalTrials.gov, and the WHO ICTRP from inception through June 3, 2025, and updated the search on July 16, 2026. Randomized controlled trials (RCTs) in adults with T2DM were eligible. Events from trial reports and registries were harmonized using MedDRA v26.0. Bayesian random-effects network meta-analyses were the primary analyses, frequentist models assessed robustness, and confidence was evaluated with CINeMA. Treatment effects were reported as risk ratios (RRs) with 95% credible intervals (CrIs). Results: Forty-five RCTs involving 110,333 participants were included. For PAOD (33 RCTs; 90,742 participants; 572 events), subcutaneous semaglutide was associated with a lower risk than placebo (RR: 0.37; 95% CrI: 0.14–0.86), with low confidence; the finding was supported by frequentist and sensitivity analyses. In direct placebo-controlled trials, PAOD occurred in 18/4,088 participants receiving subcutaneous semaglutide (4.4 per 1,000) and 33/3,650 receiving placebo (9.0 per 1,000). For PVD (18 RCTs; 69,809 participants; 111 events), albiglutide (RR: 0.11; 95% CrI: 0.01–0.50) and efpeglenatide (RR: 0.09; 95% CrI: 0.01–0.57) were associated with lower risks than placebo, with high confidence for both comparisons. Insulin also showed a favorable Bayesian estimate versus placebo (RR: 0.06; 95% CrI: <0.01–0.49; moderate confidence). No credible Bayesian differences were identified for amputation, necrosis, or peripheral embolism and thrombosis; confidence was predominantly low or very low. Conclusions: The findings suggest agent- and outcome-specific signals rather than a class-wide limb benefit. Because events were rare and usually derived from adverse-event reporting, the results do not establish clinical superiority or support treatment selection based on limb protection alone. Dedicated PAD-focused trials with standardized adjudicated outcomes are needed. Trial registration: PROSPERO CRD420251244166. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13098-026-02271-4.
SN - 1758-5996
ER -