Sodium-glucose cotransporter 2 (SGLT2) inhibitors have become a cornerstone of treatment for type 2 diabetes because of their cardiovascular and kidney benefits. In 2017, however, an unexpected signal appeared: a higher rate of lower-limb amputation in people taking canagliflozin. Because people with diabetes already carry a substantial risk of foot ulceration and amputation, understanding what the evidence does and does not show is clinically important for patients, caregivers, and clinicians.
The Original Signal: The CANVAS Program
The CANVAS Program combined two randomized trials of canagliflozin versus placebo in 10,142 participants with type 2 diabetes and elevated cardiovascular risk. As reported by Neal and colleagues in the New England Journal of Medicine (2017), canagliflozin reduced a composite of major cardiovascular events, but amputations occurred more often: 6.3 versus 3.4 per 1,000 patient-years (hazard ratio 1.97; 95% CI 1.41–2.75). Most amputations were at the level of the toe or metatarsal. Because the finding was not a pre-specified primary outcome, it prompted further analysis of trial and real-world data rather than a firm conclusion about cause.
What Later Trials and Pooled Analyses Show
The CREDENCE trial (Perkovic et al., New England Journal of Medicine, 2019) tested canagliflozin in 4,401 people with type 2 diabetes and chronic kidney disease. Amputation rates were 12.3 per 1,000 patient-years with canagliflozin and 11.2 with placebo (hazard ratio 1.11; 95% CI 0.79–1.56), a difference that was not statistically significant. Absolute amputation rates were notably higher in both arms than in CANVAS, reflecting the higher baseline risk of a population with kidney disease.
A systematic review and meta-analysis by Heyward and colleagues (PLOS ONE, 2020) examined 12 randomized trials and 18 observational studies. In the primary random-effects analysis of seven trials with events, the pooled relative risk was 1.28 (95% CI 0.93–1.76), which was not statistically significant. A fixed-effects analysis suggested increased risk (RR 1.27; 95% CI 1.09–1.48), and the signal was concentrated in canagliflozin (RR 1.59; 95% CI 1.26–2.01), while dapagliflozin, empagliflozin, and ertugliflozin showed no significant increase. The authors concluded there was no consistent evidence of increased amputation risk with SGLT2 inhibitors as a class, but that the canagliflozin finding warranted continued study. The observational studies were too heterogeneous to pool, which limits conclusions from real-world data.
Regulatory Interpretation
In 2017 the U.S. Food and Drug Administration (FDA) added a boxed warning about leg and foot amputation to canagliflozin labelling. In August 2020, after reviewing data from three clinical trials, the FDA removed the boxed warning, stating that amputation risk, while still increased, appeared lower than previously described, particularly with appropriate monitoring. The risk remains described in the Warnings and Precautions section of the prescribing information, and the FDA advised attention to preventative foot care and to new pain, tenderness, sores, ulcers, or infections in the legs and feet.
Practical Clinical Considerations
The available evidence does not establish a mechanism, and proposed explanations such as volume depletion or effects on limb perfusion remain hypotheses. What the data consistently show is that baseline limb risk matters. Populations with established peripheral artery disease, prior amputation, neuropathy, or foot ulcers have high background amputation rates regardless of treatment, so the same medication may carry different absolute risks in different people. The relevant clinical response is therefore not avoidance of an entire drug class, which offers proven cardiovascular and kidney benefits, but individualized assessment: documenting foot risk status, examining the feet regularly, reinforcing daily foot inspection and protective footwear, and promptly evaluating any new wound, pain, or signs of infection or ischemia.
Key Takeaways
An increased amputation signal was observed with canagliflozin in CANVAS but was not confirmed as statistically significant in CREDENCE or in the primary pooled analysis of trials across the SGLT2 inhibitor class. Evidence for dapagliflozin, empagliflozin, and ertugliflozin shows no significant increase, although the data are limited by few events and heterogeneity. Regulators have retained the amputation warning in labelling while removing the boxed warning. For people with diabetes, foot risk stratification and ongoing foot surveillance remain the foundation of amputation prevention, whichever glucose-lowering agent is used.
References
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017.
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE). N Engl J Med. 2019.
- Heyward J, Mansour O, Olson L, Singh S, Alexander GC. Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: a systematic review and meta-analysis. PLOS ONE. 2020;15(6):e0234065.
- U.S. Food and Drug Administration. FDA removes boxed warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Drug Safety Communication. 2020.
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