Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now a cornerstone of type 2 diabetes care because of their cardiovascular and kidney benefits. Early in their use, however, a signal of increased lower-limb amputation emerged, raising an important question for people who already have neuropathy, peripheral arterial disease (PAD) or previous foot ulceration. This article reviews what the trial and meta-analytic evidence shows.
The Original Signal: The CANVAS Program
The CANVAS Program, reported by Neal and colleagues in the New England Journal of Medicine in 2017, randomized 10,142 participants with type 2 diabetes and elevated cardiovascular risk to canagliflozin or placebo. Canagliflozin reduced major cardiovascular events, but amputations occurred more often: 6.3 versus 3.4 per 1,000 patient-years, a hazard ratio of 1.97 (95% CI 1.41–2.75).
A subsequent analysis by Matthews and colleagues (Diabetologia, 2019) characterized these events in detail. Most amputations occurred at the level of the toe or metatarsal, and absolute risk was highest in participants with a history of prior amputation or peripheral vascular disease. The mechanism remains unproven; proposed contributors include volume depletion, haemodynamic effects on already compromised perfusion, and chance.
A Different Result in CREDENCE
The CREDENCE trial (Perkovic et al., New England Journal of Medicine, 2019) tested canagliflozin in people with type 2 diabetes and chronic kidney disease. Amputation rates were not significantly different from placebo (hazard ratio approximately 1.11, 95% CI 0.79–1.56). Notably, CREDENCE incorporated enhanced monitoring and temporary interruption of the drug in participants who developed active foot problems, a design feature that may have influenced the result.
Pooled Evidence Across the Drug Class
Lin and colleagues (Cardiovascular Diabetology, 2021) pooled 39 randomized trials, with 15 contributing to the amputation analysis. Overall, SGLT2 inhibitors were associated with a modestly higher odds of amputation (OR 1.23, 95% CI 1.08–1.40). When examined by drug, the increase was statistically significant only for canagliflozin (OR 1.60, 95% CI 1.04–2.46). Estimates for dapagliflozin (OR 1.08, 95% CI 0.85–1.37), empagliflozin (OR 1.07, 95% CI 0.76–1.49), ertugliflozin and sotagliflozin were not significant, although confidence intervals were wide because of few events.
The same analysis found a higher odds of PAD-related events overall (OR 1.21, 95% CI 1.03–1.42), while diabetic foot ulcer showed no significant increase (OR 1.24, 95% CI 0.93–1.64). Meta-regression suggested that greater weight loss and lower baseline diastolic blood pressure were associated with higher amputation risk, whereas age, sex, diabetes duration, renal function and HbA1c reduction were not. The authors concluded that monitoring weight and blood pressure may be a useful precaution in patients at high risk of lower-limb complications, while emphasizing that these findings are hypothesis-generating.
Interpreting the Evidence Clinically
Several points help place these findings in context. First, the absolute risk is low in most patients, and the cardiovascular and renal benefits of this drug class are well established. Second, the signal appears strongest for canagliflozin and may not represent a class-wide effect, though the trials were not designed to compare agents directly. Third, amputation was a secondary or safety outcome in most trials, and ascertainment varied.
The patients in whom caution is most relevant are those with existing PAD, prior amputation, active foot ulceration or neuropathy with deformity. For this group, a thorough foot examination, vascular assessment and attention to hydration status are reasonable elements of care before and during therapy. Regular foot inspection and prompt evaluation of any new wound remain fundamental regardless of medication.
Key Takeaways
The CANVAS Program identified a roughly two-fold higher amputation rate with canagliflozin, which was not replicated in CREDENCE. Pooled analyses show a modest overall increase driven primarily by canagliflozin, with no clear excess for other agents. Risk appears concentrated in people with established lower-limb disease, and weight and blood pressure change may be markers worth monitoring. Ongoing surveillance and real-world data will further clarify whether the signal reflects a true drug effect and in whom.
References
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS Program). N Engl J Med. 2017.
- Matthews DR, Li Q, Perkovic V, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019.
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE). N Engl J Med. 2019.
- Lin C, Zhu X, Cai X, Yang W, Lv F, Nie L, Ji L. SGLT2 inhibitors and lower limb complications: an updated meta-analysis. Cardiovasc Diabetol. 2021;20:91.
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