Is there a link between Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors and an increased risk of amputations in patients with type 2 diabetes who have ongoing foot infections?

SGLT2 Inhibitors and Amputation Risk in Patients with Ongoing Foot Infections

Patients with active foot infections or ongoing foot ulcers should only receive SGLT2 inhibitors after careful shared decision-making with comprehensive education on foot care and amputation prevention, as these patients are at higher risk for amputation complications. 1

Evidence for Amputation Risk

Canagliflozin-Specific Risk

• Canagliflozin carries an FDA Black Box Warning for increased amputation risk, with 6.3 vs. 3.4 amputations per 1,000 patient-years compared to placebo (p < 0.001) in the CANVAS trial. 1, 2
• The FDA label specifically warns that canagliflozin is associated with increased risk of lower limb amputations, most frequently involving the toe and midfoot. 2
• Patients should be instructed to monitor for new pain, tenderness, sores, ulcers, or infections involving the leg or foot and seek immediate medical attention if these develop. 2

Risk with Other SGLT2 Inhibitors

• Empagliflozin and dapagliflozin have not consistently shown increased amputation risk in large randomized trials, though post-hoc analyses and pharmacovigilance data suggest vigilance is warranted. 1, 3
• A meta-analysis of randomized controlled trials showed no statistically significant association between SGLT2 inhibitors as a class and amputation risk (RR 1.28,95% CI 0.93-1.76), though substantial heterogeneity existed. 4
• Observational studies have shown conflicting results, with some suggesting increased risk (adjusted HR 2.12,95% CI 1.19-3.77 compared to older oral agents) while others found no significant association. 5, 6

High-Risk Patient Identification

Use caution when prescribing SGLT2 inhibitors to patients with:

• Active diabetic foot ulcers or soft tissue infections 1
• History of prior amputation 1
• Severe peripheral neuropathy 1
• Severe peripheral vascular disease 1
• Established peripheral arterial disease 1

Clinical Decision Algorithm

For Patients WITH Active Foot Infections or Ulcers:

1. Avoid SGLT2 inhibitors until the infection/ulcer is completely resolved 1
2. If cardiovascular or renal benefits are critically needed, consider GLP-1 receptor agonists as an alternative, which have similar cardiovascular benefits without amputation risk 1
3. If SGLT2 inhibitor use is deemed essential despite active foot problems, engage in detailed shared decision-making documenting risks and benefits 1

For Patients at High Risk (History of Amputation, Severe PAD, Neuropathy):

1. Prefer empagliflozin or dapagliflozin over canagliflozin if SGLT2 inhibitor therapy is indicated, as these agents have not shown consistent amputation signals in major trials 1, 7
2. Provide comprehensive foot care education emphasizing daily foot inspection, proper footwear, and immediate reporting of any wounds 1, 2
3. Establish regular podiatry follow-up before initiating therapy 1
4. Consider alternative agents (GLP-1 receptor agonists) if amputation risk outweighs cardiovascular/renal benefits 1

For Standard Risk Patients:

• SGLT2 inhibitors can be used safely with routine foot care education 1
• Educate patients to report any foot wounds immediately 1

Monitoring Requirements

All patients on SGLT2 inhibitors require:

• Education on foot care importance, especially those with diabetic neuropathy 1
• Instructions to report any foot pain, tenderness, sores, ulcers, or infections immediately 1, 2
• Routine preventative foot care counseling 2

Common Pitfall to Avoid

The most critical error is initiating or continuing SGLT2 inhibitors in patients with active, ongoing foot infections without addressing the infection first and without explicit discussion of amputation risk. The guideline language is clear: these patients require "careful shared decision-making" rather than routine prescribing. 1 This is not a contraindication, but it demands heightened caution and patient education that goes beyond standard counseling.