Is it safe to prescribe Farxiga (dapagliflozin) to a patient with Peripheral Arterial Disease (PAD)?

Is Farxiga Safe in Patients with PAD?

Yes, Farxiga (dapagliflozin) is safe to prescribe to patients with peripheral arterial disease (PAD) and is actually recommended for cardiovascular risk reduction in patients with type 2 diabetes and PAD. 1

Evidence Supporting Safety and Efficacy

Cardiovascular Benefits in PAD Patients

SGLT-2 inhibitors with proven cardiovascular benefit, including dapagliflozin, are recommended (Class I) for patients with type 2 diabetes and PAD to reduce cardiovascular events, independent of baseline HbA1c or concomitant glucose-lowering medications. 1

• In the DECLARE-TIMI 58 trial, dapagliflozin demonstrated significant reduction in cardiovascular death or hospitalization for heart failure (4.9% vs 5.8%; P=0.005) in patients with type 2 diabetes 1
• The cardiovascular and kidney benefits of dapagliflozin were consistent regardless of whether patients had PAD at baseline (P-interaction=0.79 for CV death/HHF) 2
• Patients with PAD experienced similar relative risk reductions for cardiovascular death/heart failure hospitalization (HR 0.86) and progression of kidney disease (HR 0.78) compared to those without PAD 2

Amputation Risk: The Critical Safety Question

Dapagliflozin does NOT increase amputation risk, distinguishing it from canagliflozin's initial safety concerns. 1, 2

The amputation concern arose specifically with canagliflozin in the CANVAS trial (6.3 vs 3.4 amputations per 1,000 patient-years; P<0.001), which led to an FDA black box warning in May 2017 1. However:

• The FDA removed the black box warning for canagliflozin in August 2020 due to conflicting subsequent data 1
• These findings were NOT reproduced in the CREDENCE trial with canagliflozin 1
• Dapagliflozin showed no significant difference in amputation rates (HR 1.09; 95% CI 0.84-1.40) in DECLARE-TIMI 58 2
• A meta-analysis of 51,713 patients found SGLT-2 inhibitors overall were not associated with increased amputation risk (pooled RR 1.24; 95% CI 0.96-1.60), even among patients with established PAD 3
• Post-hoc analyses from EMPA-REG OUTCOME showed empagliflozin was associated with superior limb survival versus placebo in PAD patients 1

Limb-Related Safety Profile

In DECLARE-TIMI 58, there were no significant differences between dapagliflozin and placebo for:

• Limb ischemic adverse events (HR 1.07; 95% CI 0.90-1.26) 2
• Peripheral revascularization procedures 2
• Total amputation events (236 patients with at least one amputation) 2

The interaction testing showed no differential effect based on PAD status (P-interaction=0.30 for limb ischemic events and 0.093 for amputation). 2

Clinical Implementation

When to Prescribe Dapagliflozin in PAD

Prescribe dapagliflozin for patients with type 2 diabetes and PAD to:

• Reduce major adverse cardiovascular events (MACE) 1
• Reduce cardiovascular death and heart failure hospitalization 1, 2
• Slow progression of kidney disease 2
• Achieve glycemic control with target HbA1c <7% (53 mmol/mol) 1

Vigilance Recommendations (Not Contraindications)

While dapagliflozin is safe, maintain vigilance in patients with high-risk features for limb complications: 1

• History of prior amputation
• Active diabetic foot ulcers
• Severe peripheral neuropathy
• Critical limb-threatening ischemia

This vigilance applies to all diabetes medications in high-risk PAD patients, not specifically to dapagliflozin. 1

Integration with Guideline-Directed Medical Therapy

Dapagliflozin should be part of comprehensive PAD management that includes: 4, 5

• Single antiplatelet therapy (clopidogrel 75 mg daily preferred) 4
• High-intensity statin therapy (target LDL-C <55 mg/dL) 4, 5
• Blood pressure control with ACE inhibitors or ARBs 4
• Smoking cessation 4
• Supervised exercise therapy 4

Key Distinction from Canagliflozin

The amputation signal was specific to canagliflozin in CANVAS and has not been observed with dapagliflozin or empagliflozin. 1 The 2024 ACC/AHA PAD guidelines explicitly state that "these data provide robust support for use of these agents to reduce MACE among patients with PAD and type 2 diabetes," referring to SGLT-2 inhibitors as a class 1. The evidence for dapagliflozin specifically shows no increased limb-related risk 2, 3.

Bottom line: Prescribe Farxiga confidently in PAD patients with type 2 diabetes for cardiovascular protection, with standard foot care monitoring that all diabetic PAD patients require regardless of glucose-lowering agent used. 1