Jardiance and Lower Limb Amputation Risk
Jardiance (empagliflozin) has NOT been shown to increase the risk of lower limb amputation in post-hoc analyses from the EMPA-REG OUTCOME study, distinguishing it from canagliflozin which carries an FDA Black Box Warning for this risk. 1
Evidence-Based Risk Assessment
Empagliflozin-Specific Data
The American College of Cardiology guidelines explicitly state that amputation risk has not been observed with empagliflozin in post-hoc analyses from the EMPA-REG OUTCOME study. 1 This contrasts sharply with canagliflozin, which demonstrated a significantly increased amputation rate (6.3 vs. 3.4 per 1,000 patient-years; p <0.001) and prompted an FDA Black Box Warning. 1
Class Effect Controversy
The question of whether amputation risk represents a class effect for all SGLT2 inhibitors remains unclear: 1
- Canagliflozin: Clear increased risk with FDA Black Box Warning 1, 2
- Empagliflozin: No increased risk observed in major trials 1
- Dapagliflozin: No increased risk observed to date 1
- Ertugliflozin: Numerical excess noted (0.5% vs 0.1% with placebo) 1
However, one pharmacovigilance study using the WHO global database found a disproportionality signal for empagliflozin (PRR 4.96), though this analysis was limited by small case numbers and inherent biases of spontaneous reporting systems. 3
Clinical Recommendations for Jardiance Use
When to Use Jardiance Without Amputation Concerns
Jardiance can be used in standard diabetes populations without specific amputation risk factors, as major cardiovascular outcome trials showed no increased amputation risk. 1
High-Risk Patients Requiring Vigilance
Even with empagliflozin, vigilance is suggested in patients with: 1
- History of prior amputation
- Significant peripheral arterial disease
- Severe peripheral neuropathy
- Active lower extremity soft tissue ulcers or infections
- Active diabetic foot ulcers
The 2020 ACC guidelines specifically recommend using canagliflozin with caution in these high-risk patients, but do not extend this same caution explicitly to empagliflozin. 1
Practical Management Approach
Patient Education and Monitoring
Educate all patients starting Jardiance about proper foot care and early recognition of tissue loss or infection, with referral to a multidisciplinary team when indicated. 1
Monitor for lower limb ulcerations and soft tissue infections during therapy. 1
Comparative Safety Profile
If amputation risk is a primary concern in a high-risk patient, empagliflozin or dapagliflozin should be preferred over canagliflozin, as studies have not found significant increases in amputations with these agents. 4, 5
Recent meta-analyses suggest that the apparent increased amputation risk with SGLT2 inhibitors in some observational studies may actually reflect a protective effect of GLP-1 receptor agonists used as comparators, rather than true harm from SGLT2 inhibitors. 6
Key Caveats
The amputation signal with canagliflozin was primarily driven by a single study (CANVAS), and the mechanism remains unclear. 4
Scandinavian registry data showed increased amputation risk when comparing all SGLT2 inhibitors to GLP-1 receptor agonists (HR 2.32), but this included predominantly dapagliflozin and empagliflozin with minimal canagliflozin use. 7
Despite these conflicting signals, the preponderance of high-quality evidence from cardiovascular outcome trials supports that empagliflozin does not carry the same amputation risk as canagliflozin. 1