What is the role of GLP-1 (Glucagon-like peptide-1) receptor agonists, such as liraglutide (Victoza) or semaglutide (Ozempic), in managing peripheral vascular disease?

GLP-1 Receptor Agonists in Peripheral Vascular Disease: STRIDE Trial Summary

GLP-1 receptor agonists, particularly liraglutide and semaglutide, show promising cardiovascular benefits for patients with peripheral arterial disease (PAD), with consistent risk reductions in major adverse cardiovascular events and potentially higher absolute risk reductions in this high-risk population. 1

STRIDE Trial and GLP-1 Receptor Agonists in PAD

The STRIDE trial specifically examined the cardiovascular efficacy of GLP-1 receptor agonists in patients with peripheral arterial disease:

• The analysis included data from the LEADER and SUSTAIN-6 trials, which studied liraglutide and semaglutide respectively in patients with type 2 diabetes and high cardiovascular risk 1
• 12.7% of patients in LEADER and 14.0% in SUSTAIN-6 had PAD at baseline
• Patients with PAD were at approximately 35% increased risk of major adverse cardiovascular events (MACE) compared to those without PAD

Key Findings:

• Liraglutide: Reduced MACE in PAD patients with HR 0.77 (95% CI 0.58-1.01)
• Semaglutide: Reduced MACE in PAD patients with HR 0.61 (95% CI 0.33-1.13)
• Higher absolute risk reductions were observed in patients with PAD:
  • Liraglutide: 4.13%-point reduction (vs. 1.42%-point in non-PAD patients)
  • Semaglutide: 4.63%-point reduction (vs. 1.90%-point in non-PAD patients)

Clinical Recommendations for GLP-1 RAs in Vascular Disease

The 2024 European Society of Cardiology guidelines recommend GLP-1 receptor agonists for patients with peripheral arterial and aortic diseases (PAAD) and diabetes 2:

• For patients with PAAD and type 2 diabetes, tight glycemic control is recommended, preferably with agents that have proven cardiovascular benefits, including GLP-1 receptor agonists
• GLP-1 RAs with demonstrated cardiovascular benefits (liraglutide, semaglutide, dulaglutide) are preferred agents

The American Diabetes Association and KDIGO consensus report also supports the use of GLP-1 RAs in patients with diabetes and vascular disease 2:

• Long-acting GLP-1 RAs are recommended for patients with type 2 diabetes and CKD who don't achieve glycemic targets with metformin and/or SGLT2 inhibitors
• GLP-1 RAs with proven cardiovascular benefit are preferred

Mechanisms of Benefit in Vascular Disease

GLP-1 receptor agonists provide multiple beneficial effects on the vascular system:

• Anti-inflammatory and anti-atherosclerotic effects 3, 4
• Improved endothelial function and nitric oxide generation 4
• Increased microvascular recruitment and blood flow 4
• Weight reduction, blood pressure lowering, and improved lipid profiles 2, 3
• Vasodilation and natriuresis 3

Recent Evidence Beyond Diabetes

The SELECT trial (2023) demonstrated that semaglutide 2.4 mg weekly reduced cardiovascular events in patients with preexisting cardiovascular disease and obesity without diabetes 5:

• Primary cardiovascular endpoint (CV death, nonfatal MI, or nonfatal stroke) occurred in 6.5% of semaglutide group vs. 8.0% in placebo group (HR 0.80; 95% CI 0.72-0.90; P<0.001)
• This suggests potential benefits for vascular disease even in non-diabetic patients

Clinical Application and Considerations

When considering GLP-1 RAs for patients with peripheral vascular disease:

• FDA-approved indication: Liraglutide (Victoza) is specifically approved "to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease" 6

• Contraindications and cautions 2:

  • Personal or family history of medullary thyroid cancer
  • Multiple endocrine neoplasia syndrome type 2
  • History of pancreatitis (use with caution)
  • Severe renal impairment (use with caution for liraglutide and semaglutide)

• Common adverse effects 2:

  • Gastrointestinal symptoms (nausea, vomiting, diarrhea)
  • Start at low doses and titrate slowly to improve tolerability

Bottom Line

GLP-1 receptor agonists, particularly liraglutide and semaglutide, provide cardiovascular benefits for patients with peripheral arterial disease, with potentially greater absolute risk reductions in this high-risk population. The evidence supports their use as part of a comprehensive approach to managing patients with peripheral vascular disease, especially those with concomitant diabetes.