Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are now central to type 2 diabetes care because of their cardiovascular and kidney benefits. Early in the SGLT2 inhibitor era, however, a signal of increased lower limb amputation raised concern in a population already at high risk of foot complications. Several years of trial and cohort data now allow a more nuanced reading of that signal.
Where the Amputation Signal Began
The concern originated with the CANVAS Program (Neal et al., New England Journal of Medicine, 2017), which compared canagliflozin with placebo in people with type 2 diabetes and high cardiovascular risk. Amputations occurred at a rate of 6.3 versus 3.4 per 1,000 patient-years (hazard ratio 1.97, 95% CI 1.41–2.75), and most involved the toe or metatarsal. The later CREDENCE trial (Perkovic et al., NEJM, 2019), which used enhanced foot-care precautions, found no statistically significant difference (hazard ratio 1.11, 95% CI 0.79–1.56), although it was not designed to settle the question.
What Pooled Analyses Show
A meta-analysis of 39 randomized trials (Lin et al., Cardiovascular Diabetology, 2021) reported a small overall increase in amputation (odds ratio 1.23, 95% CI 1.08–1.40) and peripheral artery disease events (odds ratio 1.21, 95% CI 1.03–1.42), but no significant increase in diabetic foot events (odds ratio 1.24, 95% CI 0.93–1.64). At the level of individual drugs, only canagliflozin showed a statistically significant increase in amputation (odds ratio 1.60, 95% CI 1.04–2.46); dapagliflozin, empagliflozin, ertugliflozin and sotagliflozin did not. The authors noted that greater weight and blood pressure reduction were associated with higher limb complication rates, and they described these associations as hypothesis-generating rather than causal. An earlier meta-analysis in PLoS ONE (2020) reached a similar conclusion: a canagliflozin-specific signal (relative risk 1.59, 95% CI 1.26–2.01) without a consistent class-wide effect, and with heterogeneity that limited firm conclusions.
Real-World Cohort Evidence
Observational data complement the trials, which were not powered for rare limb outcomes. In a Danish nationwide cohort of 74,475 adults with type 2 diabetes (Werkman et al., Cardiovascular Diabetology, 2023), SGLT2 inhibitor use was not associated with a higher risk of amputation compared with sulfonylureas (adjusted hazard ratio 1.10, 95% CI 0.71–1.70) or of diabetic foot ulcer (1.18, 95% CI 0.90–1.55). GLP-1 receptor agonist use was associated with a lower amputation risk (adjusted hazard ratio 0.57, 95% CI 0.39–0.84), without a significant difference in ulcer risk. A post hoc comparison found a higher amputation risk with SGLT2 inhibitors than with GLP-1 receptor agonists (hazard ratio 1.91, 95% CI 1.25–2.92), which the authors suggested may partly explain elevated risks in earlier comparisons. As with all cohort studies, residual confounding by indication cannot be excluded. Notably, a history of peripheral artery disease was associated with a markedly higher amputation risk with either drug class.
Clinical Interpretation
Several points emerge from this body of work. First, the absolute risk of amputation in these trials is low, and any increase must be weighed against demonstrated reductions in heart failure hospitalization and kidney disease progression with SGLT2 inhibitors. Second, the signal appears strongest, if present at all, for canagliflozin and in people with existing peripheral artery disease, prior amputation or active foot ulceration. Third, plausible mechanisms, including volume depletion, reduced perfusion and weight loss, remain unproven. Regulatory labeling for canagliflozin carried a boxed amputation warning for several years; the United States Food and Drug Administration removed it in 2020 after reviewing additional trial data, while retaining a warning about amputation risk in the prescribing information.
Consensus practice is that the foot should be examined before and during therapy, and that people with neuropathy, vascular disease, or a history of ulceration or amputation be identified as higher risk. Therapy may be paused if a foot ulcer, infection, or signs of acute limb ischemia develop, and hydration status should be monitored.
Key Takeaways
The amputation signal with SGLT2 inhibitors arose primarily from canagliflozin in CANVAS, has not been consistently reproduced with other agents, and appears absent in several real-world cohorts. GLP-1 receptor agonists have been associated with lower amputation rates in observational data, though randomized confirmation is lacking. Systematic foot assessment remains the foundation of risk management regardless of the glucose-lowering agent chosen.
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.
- 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, et al. SGLT2 inhibitors and lower limb complications: an updated meta-analysis. Cardiovasc Diabetol. 2021;20:91.
- Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: a systematic review and meta-analysis. PLoS ONE. 2020.
- Werkman NCC, Driessen JHM, Stehouwer CDA, et al. The use of SGLT2 inhibitors or GLP-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations: a nationwide cohort study. Cardiovasc Diabetol. 2023;22:160.
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