Subcutaneous semaglutide and peripheral arterial occlusive disease in type 2 diabetes: network meta-analysis of randomized trials
R Amani-Beni, B Darouei, S Maleki, H Sadri, A Seifnezhad, R Eshraghi, A Bahrami, P Ebrahimi, S Upadhyaya, F Shahid, M Movahed, G UmpierrezAbstract
Background
Peripheral arterial occlusive disease (PAOD) outcomes are rarely prespecified in randomised type 2 diabetes trials, limiting comparative inference across glucagon-like peptide-1 receptor agonists (GLP-1RAs).
Purpose
To compare GLP-1RA regimens for PAOD risk in adults with type 2 diabetes.
Methods
We conducted a PRISMA-NMA systematic review and network meta-analysis. PubMed, Embase, Scopus, Web of Science, Cochrane CENTRAL, ProQuest, medRxiv, trial registries (ClinicalTrials.gov; WHO ICTRP), and Google Scholar were searched from inception to June 2025. PAOD was defined using MedDRA v26.0. Bayesian random-effects consistency NMA estimated risk ratios (RRs) with 95% credible intervals (CrIs) and ranked treatments using SUCRA. A sensitivity analysis restricted to FDA-approved, marketed agents was performed. Risk of bias was assessed using the Cochrane risk of bias-2 (ROB-2) tool. Confidence was appraised using CINeMA. Robustness was examined with frequentist random-effects NMA; inconsistency was assessed by net-splitting (direct vs indirect) and between-design Cochran’s Q.
Results
From 5,703 records, 31 randomised trials were included (11 interventions; 68,681 participants; 324 events). Semaglutide subcutaneous (SC) lowered PAOD risk versus placebo (RR: 0.38, 95% CrI: 0.14 to 0.91); no other regimen differed credibly from placebo. In active comparisons, insulin (RR: 0.22, 95% CrI: 0.04 to 0.88), semaglutide oral (PO) (RR: 0.09, 95% CrI: 0.01 to 0.87), and semaglutide SC (RR: 0.13, 95% CrI: 0.01 to 0.75) lowered risk versus a GLP-1RA+insulin combination regimen. SUCRA ranked semaglutide PO and SC as the most favourable, while GLP-1RA+insulin ranked among the least favourable and below placebo. In the FDA-approved marketed-agent sensitivity analysis (24 trials; 51,081 participants; 205 events), semaglutide SC remained protective versus placebo (RR 0.39, 95% CrI 0.14 to 0.93). CINeMA rated high confidence for semaglutide SC versus placebo and semaglutide PO versus GLP-1RA+insulin, and moderate confidence for five additional key contrasts; most other comparisons were low/very low, mainly due to imprecision. Frequentist NMA was consistent: semaglutide SC versus placebo with RR of 0.52 (95% CI: 0.29 to 0.91), with no material incoherence; rank probabilities favoured semaglutide PO/SC, and GLP-1RA+insulin was most likely worst. Heterogeneity was minimal (tau2: 0.00; I2: 0.0%, 95% CI: 0.0 to 44.6); global Q of 10.30 (p=0.989) and within-design Q of 6.31 (p=0.934). Funnel plot inspection showed no marked asymmetry.
Conclusions
Semaglutide SC was associated with lower PAOD risk versus placebo with high confidence and robustness in a clinically relevant sensitivity analysis. Most other comparisons remain uncertain, highlighting the need for consistent PAOD endpoint capture in future trials.Figure 1 Network MapFor image description, please refer to the figure legend and surrounding text.Figure 2 League table & SUCRAFor image description, please refer to the figure legend and surrounding text.