Semaglutide Demonstrates Functional and Vascular Benefits in Patients with PAD and Type 2 Diabetes: STRIDE Trial Findings

Peripheral artery disease (PAD) is a common complication in patients with type 2 diabetes, significantly increasing the risk of cardiovascular events, reduced mobility, and diminished quality of life. While glucose-lowering therapies have evolved in recent years, few have demonstrated meaningful improvements in vascular function among this high-risk population. The STRIDE trial (Semaglutide Treatment to Improve Function in Diabetic Patients with PAD) was designed to explore whether semaglutide, a GLP-1 receptor agonist known for its metabolic and cardiovascular benefits, could also enhance vascular health and physical performance in patients living with both PAD and type 2 diabetes. The trial’s findings offer promising new insights into the multifaceted role of semaglutide in managing complex cardiometabolic conditions.

Background on Semaglutide

Semaglutide is a prescription medication initially developed to treat type 2 diabetes, but it has gained widespread attention for its effectiveness in aiding weight loss. It works by mimicking a natural hormone called GLP-1 (glucagon-like peptide-1), which helps regulate blood sugar levels, slows digestion, and reduces appetite. Available under brand names like Ozempic (for diabetes) and Wegovy (for weight management), semaglutide is typically administered as a once-weekly injection. Clinical trials have shown that it can help patients lose up to 15% or more of their body weight when combined with lifestyle changes. However, its growing popularity has led to concerns over misuse, especially through unregulated online sales, prompting regulatory bodies in the UK and elsewhere to crack down on unauthorised advertising and improper prescribing practices. Despite its promise, semaglutide can cause side effects such as nausea, vomiting, and, in rare cases, more serious complications like pancreatitis.

STRIDE Trial

The STRIDE trial (Semaglutide Treatment in Peripheral Arterial Disease), a large international Phase 3 randomised controlled study, evaluated the efficacy of once-weekly subcutaneous semaglutide (1 mg) in patients with type 2 diabetes and symptomatic peripheral arterial disease (PAD). A total of 796 participants with documented PAD and impaired walking performance (mean maximal treadmill distance: 185 meters at 12% incline) were followed for 52 weeks.

Primary Efficacy Outcomes

Patients receiving semaglutide demonstrated a statistically significant and clinically meaningful improvement in maximal treadmill walking distance (MWD), with a median increase of 26 meters compared to placebo (mean improvement: ~40 meters).
This exceeded the 20-meter threshold generally accepted as clinically relevant for symptomatic PAD interventions.

Secondary and Exploratory Endpoints

Significant improvements were observed in pain-free walking distance, patient-reported walking impairment questionnaire (WIQ) scores, and overall quality of life indices.
Semaglutide recipients showed a mean reduction in body weight (~4 kg) and modest improvements in glycemic control (HbA1c).
The ankle-brachial index (ABI), a surrogate for macrovascular perfusion, improved significantly, suggesting enhanced limb perfusion.

Cardiovascular and Procedural Events

Although not powered for major adverse cardiovascular events (MACE), there was an observed ~50% relative risk reduction in the composite of limb revascularisation procedures or all-cause mortality (4% vs 8% in placebo).
This finding, while exploratory, supports prior evidence of GLP-1 receptor agonists’ potential vasculoprotective effects.

Mechanistic Implications

The data suggest semaglutide’s benefits in PAD may extend beyond metabolic control and weight reduction, potentially through modulation of endothelial function, systemic inflammation, and improvement in microvascular perfusion.
Benefit was consistent across multiple subgroups, including age, sex, BMI, baseline ABI, and A1c strata.

Safety and Tolerability

Adverse events were consistent with known GLP-1 receptor agonist profiles. Gastrointestinal symptoms, particularly nausea, were more common in the semaglutide group but led to few discontinuations.
No signal of increased risk for pancreatitis, gallbladder disease, or other serious adverse events was observed.

Clinical Significance

The STRIDE trial represents a significant advancement in PAD management, establishing semaglutide as the first pharmacologic agent to demonstrate substantial improvements in both functional and vascular endpoints in patients with PAD and type 2 diabetes. These results highlight the therapeutic potential of GLP-1 RAs in expanding cardiovascular care beyond glycemic control and suggest their role in addressing critical mobility impairments in high-risk populations.

Conclusion

The STRIDE trial adds to the growing body of evidence supporting semaglutide’s potential beyond glycemic control. In patients with both PAD and type 2 diabetes, semaglutide not only improved functional capacity but also showed favourable effects on vascular health. These findings suggest that GLP-1 receptor agonists like semaglutide may play a more comprehensive role in managing diabetic patients with coexisting vascular disease. Further studies are warranted to confirm these results and explore long-term outcomes, but STRIDE offers a significant step forward in addressing the dual burden of metabolic and vascular dysfunction in this vulnerable patient population.