Dario Giugliano

The impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on peripheral artery disease (PAD) remains uncertain. We assessed the association between GLP-1RA use and major limb events in individuals with type 2 diabetes (T2D) and PAD. We performed a literature search from inception to 31 March 2026 for randomized controlled trials and cohort studies comparing GLP-1RA use versus placebo, active comparators or non-use on lower limb outcomes in individuals with T2D and PAD. The primary outcome was a composite of major limb events, as defined by the investigators of the original studies included in the meta-analysis. Secondary outcomes included lower extremity amputation (LEA), revascularization, gangrene, major adverse cardiovascular events (MACE) and all-cause mortality. Subgroup analyses, leave-one-out sensitivity analyses, and meta-regression analysis were also performed. Twelve studies (2 RCTs and 10 matched cohort studies) with thirteen arms involving 418,282 participants were included. Treatment with GLP-1RAs was associated with a significantly lower risk of major limb events by 27% (thirteen arms, RR 0.73, 95% CI 0.65-0.82). Reduced risks were also observed for LEA (RR 0.76, 95% CI 0.66-0.87), revascularization (RR 0.81, 95% CI 0.77-0.86), gangrene (RR 0.80, 95% CI 0.77-0.85), MACE (RR 0.76, 95% CI 0.63-0.90) and all-cause mortality (RR 0.67, 95% CI 0.61-0.73). Subgroup and sensitivity analyses did not substantially change point estimates. Among adults with T2D and PAD, treatment with GLP-1RAs was associated with a lower risk of major limb events. There is a need of dedicated studies with standardized limb-specific endpoints to confirm the protective role of GLP-1RAs on limb events in people with T2D and PAD.

Aims: The aim of this systematic review and meta‐analysis was to evaluate the effect of GLP‐1RAs on functional walking distance and the risk of major adverse limb events (MALE) or lower extremity amputation (LEA) in people with type 2 diabetes and peripheral artery disease (PAD). Materials and Methods: We searched many electronic databases up to 10 October 2025 for randomised controlled trials (RCTs) and cohort studies. We included studies enrolling adults with type 2 diabetes and PAD, comparing GLP‐1RAs against placebo or other glucose‐lowering drugs. The primary outcomes were walking distance, MALE, or LEA. Data were pooled using a random‐effects model, with hazard ratios (HR) or risk ratios (RR). Risk of bias was assessed using RoB2 for RCTs and ROBINS‐I for cohort studies; evidence certainty was evaluated using the GRADE approach. Results: We included seven studies (3 RCTs, 4 cohorts) enrolling 107 092 participants. The meta‐analysis of two RCTs with 847 participants demonstrated a significant improvement in walking distance with liraglutide or semaglutide (HR = 1.10, 95% CI 1.05–1.15, p < 0.001), with no heterogeneity (I ² = 0.0%) and moderate certainty of evidence. In the additional meta‐analysis of two RCTs with 3592 participants, the incidence of MALE or LEA did not differ significantly between patients receiving exenatide or semaglutide and those receiving placebo. The meta‐analysis of four cohort studies with 104 292 participants showed that GLP‐1RAs reduced the risk of LEA (RR = 0.53, 95% CI 0.39–0.73, p < 0.001), with high heterogeneity (I ² = 85.96%), totally related to one study, and very low certainty of evidence. Subgroup analyses showed a significant difference ( p < 0.001) between GLP‐1RA therapies, with the strongest associations with LEA reduction for tirzepatide and semaglutide (55% and 54% risk reduction, respectively); there was no difference in the LEA outcome excluding from the analysis patients with type 2 diabetes and diabetic foot ulcers at baseline. Conclusions: This meta‐analysis suggests that GLP‐1RAs are associated with a significant improvement in functional walking distance and a reduction in the risk of LEA in people with type 2 and PAD. Further dedicated RCTs are needed to confirm these limb‐specific benefits of GLP‐1RAs.

Aims: To compare major limb events in individuals with type 2 diabetes who initiated either injective or oral semaglutide versus other glucose‐lowering therapies (GLT) in a real‐world setting. Materials and Methods: This was a single‐centre retrospective observational study on new users of diabetes medications. Participants had to have type 2 diabetes and a diagnosis of peripheral artery disease (PAD) or foot ulcers. Participant characteristics were assessed before and after propensity score matching. The primary outcome was major limb events (a composite of peripheral percutaneous transluminal angioplasty [PTA] or critical limb ischaemia [CLI]); secondary outcomes included singularly PTA, CLI, gangrene and lower extremity amputation (LEA). Results: We analysed two matched groups of 167 participants each, who were predominantly males (57%), aged 61 years, with a 12‐year duration of diabetes, a baseline HbA1c of 8.0% and body mass index (BMI) of 31 kg/m ² . During a median follow‐up of 30.1 months, a primary‐outcome event occurred in 72 of the participants (43.0%; incidence, 8.1 events per 100 person‐years) in the semaglutide group, as compared with 93 of the participants (56.0%; incidence, 10.4 events per 100 person‐years) in the GLT group (hazard ratio [HR] = 0.77; 95% confidence interval [CI], 0.61–0.97; p = 0.029). Among the secondary outcomes, LEA (both major and minor) was 50% lower (HR = 0.50; 95% CI, 0.30–0.83, p = 0.008) in the semaglutide group as compared with the other group. Conclusions: Among people with type 2 diabetes and PAD or foot ulcers, the use of semaglutide was associated with a significantly lower risk of major limb events than other GLTs.

Aims: In a six‐month randomized clinical trial, improved peripheral perfusion has been shown with liraglutide, associated with favourable vascular effects in people with type 2 diabetes and peripheral artery disease (PAD). We aimed to evaluate the durability of these benefits and to elucidate some mechanisms underlying liraglutide's effect over an 18‐month follow‐up. Methods: STARDUST was a randomized clinical trial which compared liraglutide up to 1.8 mg/day with tailored therapeutic prescriptions to manage cardiovascular risk factors in 55 participants with type 2 diabetes and PAD. We report data of people who have reached the 18‐month follow‐up for the primary outcome (transcutaneous oxygen pressure, TcPO ₂ ) and also for additional secondary outcomes (markers of inflammation, angiogenesis and kidney function), as well as glycemic and metabolic parameters. TcPO ₂ was assessed with transcutaneous oximetry. Circulating levels of angiogenic progenitor cells and serum inflammation markers were evaluated by flow cytometry and enzyme‐linked immunosorbent assay, respectively. Results: Compared with the control group, significant differences favouring the liraglutide group were observed at 18 months for TcPO ₂ [estimated treated difference (95% CI), 10.9 mmHg (7.6 to 14.1 mmHg), p < 0.001]. At 18 months of follow‐up, participants in the liraglutide group, as compared with those in the control group, had a significant reduction in urine albumin to creatinine ratio (estimated difference, −103.9 mg/g Cr, 95%CI, −170.8 to −37.1, p = 0.003), C‐reactive protein (−0.5 mg/dL, 95%CI, −0.8 to −0.2, p = 0.002), as well as interleukin‐6 (−32.6 pg/mL, 95%CI, −54.6 to −10.5, p = 0.004). Compared with the control group, participants in the liraglutide group showed significantly higher concentrations of circulating progenitor cells and endothelial progenitor cells at both 6 and 18 months, for CD34 ⁺ , CD133 ⁺ , KDR ⁺ , CD34 ⁺ /KDR ⁺ and CD34 ⁺ /CD133 ⁺ /KDR ⁺ . Liraglutide was also associated with a higher increase in vascular endothelial growth factor A at 18 months (70.1 pg/mL, 95%CI, 44.7 to 95.4, p < 0.001). Conclusions: In people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion, with amelioration of markers of angiogenesis and inflammation over an 18‐month follow‐up.