Is it safe to start empagliflozin (Jardiance) in a patient with peripheral arterial disease and type 2 diabetes, and what dosing, monitoring, and contraindications should be considered?

Empagliflozin (Jardiance) is Safe and Beneficial in Patients with Peripheral Arterial Disease and Type 2 Diabetes

Empagliflozin should be started in patients with PAD and type 2 diabetes, as it reduces cardiovascular death, major adverse cardiovascular events (MACE), and demonstrates superior limb survival compared to placebo. 1

Evidence Supporting Use in PAD

The 2024 ACC/AHA PAD guidelines provide robust support for SGLT2 inhibitors, specifically empagliflozin, in this population 1:

• In EMPA-REG OUTCOME, 21% of patients (n=1,462) had known PAD at baseline
• Empagliflozin reduced cardiovascular death, nonfatal MI, and nonfatal stroke (10.5% vs 12.1%; P=0.04) 1
• Critically, subgroup analysis showed superior limb survival in PAD patients treated with empagliflozin versus placebo 1

This directly contrasts with canagliflozin, which initially raised amputation concerns in the CANVAS trial (though the FDA removed the black box warning in August 2020 after conflicting subsequent data) 1.

Dosing and Initiation

Per FDA labeling 2:

• Start with 10 mg once daily in the morning, with or without food
• May increase to 25 mg once daily for additional glycemic control if tolerated
• Assess renal function before initiating: Not recommended if eGFR <30 mL/min/1.73 m² for glycemic control (though can be used for heart failure indication)
• Correct volume depletion before starting, particularly important in PAD patients who may have compromised perfusion

Critical Monitoring Parameters

Before Starting:

• Volume status assessment - PAD patients are at higher risk for volume depletion complications 2
• Renal function (eGFR and creatinine) - monitor as clinically indicated 2
• Foot examination - document baseline ulcers, neuropathy, or tissue loss

During Therapy:

• Signs of volume depletion: orthostatic hypotension, dizziness, syncope (especially in elderly or those on loop diuretics) 2
• Genital mycotic infections (5% or greater incidence) 2
• Urinary tract infections (5% or greater incidence) - evaluate and treat promptly; watch for progression to urosepsis/pyelonephritis 2
• Foot surveillance: regular examination for new ulcers or tissue breakdown, though empagliflozin has not shown increased amputation risk 1

Contraindications

Per FDA labeling 2:

• Hypersensitivity to empagliflozin (serious reactions including angioedema have occurred)
• Patients on dialysis

Critical Warnings Specific to PAD Population

Ketoacidosis Risk 2:

• Assess for metabolic acidosis signs regardless of blood glucose
• Higher risk situations requiring temporary discontinuation:
  • Major surgery (common in PAD patients undergoing revascularization)
  • Prolonged fasting
  • Severe illness or infection
  • Reduced oral intake

Hypoglycemia 2:

• Reduce insulin or insulin secretagogue doses when initiating to prevent hypoglycemia
• PAD patients with neuropathy may not recognize hypoglycemic symptoms

Fournier's Gangrene 2:

• Rare but life-threatening necrotizing fasciitis of the perineum
• Assess immediately if patient presents with genital/perineal pain, tenderness, erythema, swelling, fever, or malaise
• Particularly relevant in PAD patients with compromised tissue perfusion

Why Empagliflozin Over Other SGLT2 Inhibitors in PAD

Empagliflozin is the preferred SGLT2 inhibitor in PAD because:

1. No amputation signal: Unlike canagliflozin's initial concerns, empagliflozin showed superior limb survival in PAD patients 1
2. Proven cardiovascular mortality benefit: 38% reduction in cardiovascular death in EMPA-REG OUTCOME 3
3. No increased stroke risk: Sensitivity analysis showed HR 1.08 (95% CI 0.81-1.45; P=0.60) for stroke 4
4. Renoprotective effects: 39% reduction in incident or worsening nephropathy, important as PAD patients often have concurrent kidney disease 5

Additional Cardiovascular Benefits Beyond Glycemic Control

Empagliflozin provides multiple mechanisms of benefit in PAD 6, 7:

• Improves vascular insulin sensitivity and endothelial function
• Enhances skeletal and cardiac muscle microvascular perfusion
• Reduces oxidative stress in vascular endothelium
• Lowers peripheral and central arterial pressures
• Promotes angiogenesis and arteriogenesis in ischemic tissue

Common Pitfalls to Avoid

1. Withholding due to amputation fears: This concern applies to canagliflozin, not empagliflozin, which showed limb survival benefit 1
2. Inadequate volume assessment: PAD patients may have baseline hypoperfusion; ensure euvolemia before starting 2
3. Continuing during acute illness: Temporarily discontinue during severe infections, surgery, or prolonged fasting to prevent ketoacidosis 2
4. Ignoring renal function: While beneficial for renal outcomes, don't start if eGFR <30 for glycemic indication 2
5. Missing genital infections: Educate patients about mycotic infection symptoms and treat promptly 2