Why not use SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors and GLP-1 (Glucagon-Like Peptide-1) receptor agonists for Peripheral Artery Disease (PAD)?

SGLT2 Inhibitors and GLP-1 Receptor Agonists Are Recommended for Peripheral Artery Disease

SGLT2 inhibitors and GLP-1 receptor agonists with proven cardiovascular benefit are strongly recommended in patients with type 2 diabetes and peripheral artery disease (PAD) to reduce cardiovascular events, independent of baseline or target HbA1c and concomitant glucose-lowering medication. 1

Evidence Supporting Use in PAD

The 2024 European Society of Cardiology (ESC) guidelines for the management of peripheral arterial and aortic diseases explicitly recommend both medication classes for patients with PAD and diabetes:

• SGLT2 inhibitors with proven CV benefit are recommended in patients with T2DM and PAD (Class I, Level A recommendation) 1
• GLP-1 receptor agonists with proven CV benefit are recommended in patients with T2DM and PAD (Class I, Level A recommendation) 1

These recommendations are based on strong evidence showing these medications reduce cardiovascular events in patients with PAD, which is critical since PAD patients face high cardiovascular morbidity and mortality.

Specific Benefits in PAD Population

SGLT2 Inhibitors

• Reduce cardiovascular death, heart failure hospitalizations, and progression of kidney disease 2
• Empagliflozin specifically showed reduction in CV death (HR 0.57) and all-cause mortality (HR 0.62) in PAD patients 1
• Concerns about amputation risk appear limited to canagliflozin in the CANVAS trial, but this was not confirmed in the CREDENCE trial 1
• Other SGLT2 inhibitors (empagliflozin, dapagliflozin) appear safe in PAD patients 3

GLP-1 Receptor Agonists

• Reduce major adverse cardiovascular events (MACE) in patients with established atherosclerotic disease 1
• Provide a 12-14% reduction in MACE risk 4
• May reduce stroke risk more effectively than SGLT2 inhibitors 4
• Beneficial for weight management in overweight/obese patients 2

Prioritization in Treatment Algorithm

The ESC guidelines recommend prioritizing glucose-lowering agents with proven CV benefits in PAD patients 1:

1. First priority: SGLT2 inhibitors and GLP-1 receptor agonists with proven CV benefit
2. Second priority: Agents with proven CV safety
3. Last priority: Agents without proven CV benefit or safety

This prioritization is crucial as PAD patients have significantly elevated cardiovascular risk.

Safety Considerations

SGLT2 Inhibitors

• Monitor for genital mycotic infections, urinary tract infections, and volume depletion 2
• Exercise caution with canagliflozin in patients at high risk for amputation 1
• Consider discontinuing at least 3 days before planned surgery 2

GLP-1 Receptor Agonists

• Generally well-tolerated with gastrointestinal side effects being most common
• May be preferred over SGLT2 inhibitors in patients with high amputation risk 1

Clinical Decision-Making

When treating PAD patients with diabetes:

1. Assess cardiovascular risk profile (all PAD patients are high-risk)
2. Implement SGLT2 inhibitors and/or GLP-1 receptor agonists regardless of baseline HbA1c
3. Select specific agent based on:
   • Comorbidities (heart failure → favor SGLT2i; stroke risk → favor GLP-1 RA)
   • Amputation risk (high risk → exercise caution with canagliflozin)
   • Renal function (adjust dosing accordingly)

Conclusion

The misconception that SGLT2 inhibitors and GLP-1 receptor agonists should not be used in PAD is incorrect. Current guidelines strongly recommend both medication classes for PAD patients with diabetes to reduce cardiovascular events and mortality. The benefits of these medications in reducing cardiovascular events, heart failure hospitalizations, and progression of kidney disease outweigh potential risks when used appropriately.