Peripheral arterial disease (PAD) is a severe complication in patients with type II diabetes, primarily affecting peripheral vessels, especially below-the-knee (BTK) arteries. This condition leads to significant symptomatic and functional deterioration.
ACC/AHA guidelines recommend the use of SGLT2 inhibitors and GLP-1 receptor agonists (GLP-1 RAs) for the treatment of type II diabetes. However, there are no specifications regarding patients with PAD. Currently, the only class I medication indicated for claudication is cilostazol, whose use is limited due to variable tolerance and certain contraindications.
GLP-1 RAs have demonstrated benefits in reducing HbA1c, weight, swelling, blood pressure, and renal complications, with positive effects at both macrovascular and microvascular levels.
Given this, researchers hypothesized that the use of semaglutide (1 mg administered weekly) could lead to functional and symptomatic improvement in patients with type II diabetes and PAD.
The study randomized patients 1:1 to semaglutide 1 mg or placebo. The primary endpoint was the change in maximum walking distance (MWD), assessed on a treadmill at week 52. Secondary outcomes included MWD at week 57, vascular quality of life as measured by the Vascular Quality of Life Questionnaire-6 (VascuQoL-6), and pain-free walking distance.
Patients included had HbA1c levels below 10%, were in early stages of PAD (Fontaine stage IIa), could walk >200 meters, and had an ankle-brachial index (ABI) of ≤0.9, or a toe-brachial index (TBI) of ≤0.7. Exclusion criteria encompassed patients with scheduled orthopedic surgery due to walking limitations, peripheral revascularization within the last 180 days, recent acute myocardial infarction (AMI) or stroke, hospitalization for angina or transient ischemic attack (TIA) in the last 180 days, and renal function below 30 mL/min/1.73 m².
A total of 792 patients from 112 centers across 20 countries were included. The average age was 68 years, and 27% of subjects were women. Most reported moderate to severe walking limitations. Regarding baseline medication, over 80% of participants were on statins, and 40% were taking SGLT2 inhibitors.
An analysis of the primary endpoint revealed significant improvement in the change index of MWD in the semaglutide-treated group (1.13 [1.06 to 1.21], p=0.0004), with clinically relevant impact (odds ratio [OR] 1.79 [95% confidence interval [CI] 1.32–2.43], p=0.0002). This translated into a mean difference of 26.4 meters in the distance walked.
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Most analyzed subgroups favored semaglutide, particularly those with a body mass index (BMI) <28.6 or ≥28.6, as well as varying HbA1c levels. An additional exploratory analysis evaluated a composite outcome including bailout events, major adverse limb events (MALE), and mortality, showing a 54-% reduction in these events (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.24-0.84).
Conclusion
Semaglutide has been shown to reduce major adverse cardiovascular events (MACE) and improve cardiometabolic outcomes in patients with type II diabetes. This study expands its potential benefit, demonstrating improvements in walking capacity and quality of life in patients with PAD and type II diabetes.
Presented by Marc P. Bonaca in Late-Breaking Clinical Trials, ACC 25, March 29, Chicago, EE.UU.
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