Guidance published by the American College of Cardiology (ACC) in 2020 highlights key considerations when using sodium-glucose co-transporter-2 (SGTL2) inhibitors for cardiovascular risk reduction in patients with type 2 diabetes mellitus. It is noted that use of SGLT2 inhibitors should be used in caution in patients with prior amputations, severe peripheral neuropathy, severe peripheral vascular disease, or active diabetic foot ulcers or soft tissue infections. However, supporting evidence for this warning is derived from the CANVAS and CREDENCE trials, primarily related to increased risk of amputation with canagliflozin. Data from the DECLARE-TIMI 58 and DAPA-HF trials did not demonstrate the same risk with dapagliflozin. Similarly, post-hoc analysis of EMPA-REG OUTCOME did not find increased risk of amputation for empagliflozin. [1]
A recent meta-analysis published in 2024 compared the safety and effectiveness among SGLT2 inhibitors. A total of 21 randomized controlled trials (RCTs) were included for analysis in which 51,964 participants were randomized to receive an SGLT2 inhibitor, and 44,232 participants were randomized to receive placebo. Median follow-up time among included RCTs ranged from 3 months to 4.2 years. There was found to be no difference in the risk of limb amputation when comparing empagliflozin or dapagliflozin to other SGLT2 inhibitors. An evaluation of efficacy outcomes or risk of amputation specifically in a subpopulation of patients with active foot infections was not within the scope of this analysis. [2]
A 2022 meta-analysis specifically evaluated the effects of SGLT2 inhibitors on amputation events. A total of 15 RCTs were included with a combined cohort of 63,716 patients. Subgroup analyses for individual SGLT2 inhibitors were conducted in which no significant difference was found in the odds of amputation for dapagliflozin (4 studies; Peto odds ratio [POR] 0.96; 95% confidence interval [CI] 0.65 to 1.43; p= 0.84). Similarly, subgroup analyses for empagliflozin (3 studies) found no significant difference in the odds of amputation (POR 7.39; 95% CI 0.15 to 372.38). Of note, included studies typically did not report history of cardiovascular disease or history of peripheral vascular disease. Additionally, the analysis did not specifically evaluate use of SGLT2 inhibitors specifically in patients with active foot infections. Overall, there does not appear to be an increased odds of amputation with use of SGLT2 inhibitors. [3]
Additional meta-analyses evaluating the risk of amputation and lower limb complications associated with SGLT2 inhibitors are conflicting. A 2020 meta-analysis found no difference in amputation risk in patients exposed to SGLT2 inhibitors in a random effects analysis (risk ratio [RR] 1.28; 95% CI 0.93 to 1.76; p= 0.12), while a significantly increased risk of amputation associated with SGLT2 inhibitor exposure was found in a fixed effects analysis (RR 1.27; 95% CI 1.09 to 1.48; p= 0.003). Notably, subgroup analyses identified there to be an increased risk of amputation associated with use of canagliflozin (RR 1.59; 95% CI 1.26 to 2.01; p= 0.0001) but not with dapagliflozin or empagliflozin. Another 2021 meta-analysis found that the odds of amputation in patients with SGLT2 inhibitor treatment was significantly increased compared to non-SGLT2 inhibitor users (OR 1.23; 95% CI 1.08 to 1.40; p= 0.002). Similarly, subgroup analyses identified canagliflozin to be associated with an increased odds of amputation (OR 1.60; 95% CI 1.04 to 2.46; p= 0.03) but not other SGLT2 inhibitors. [4], [5]
A 2019 review article aimed to provide an overview of the safety profile of SGLT2 inhibitors based on data from clinical trials and postmarketing reports. Regarding lower limb amputations, data from several large cohort studies have indicated an increased risk associated with the use of SGLT2 inhibitors compared to other antihyperglycemic agents. Notably, the CANVAS Program trials demonstrated an approximately twofold increased risk of lower limb amputations with canagliflozin compared to placebo. However, findings from the CREDENCE trial did not showcase a significant difference in lower limb amputation risk between canagliflozin and placebo groups. Meta-analyses of RCTs have revealed that SGLT2 inhibitors as a class were not significantly associated with amputation risk. Additionally, pooled data from observational databases and cohort studies showcased no significant association between canagliflozin use and increased risk of below-knee lower extremity amputation. However, the FDA Adverse Event Reporting System (FAERS) reports up to March 2017 documented 66 cases of amputations associated with SGLT2 inhibitors, with canagliflozin listed in 86% of these cases. Moreover, 36% of all cases exhibited at least one characteristic of diabetic foot syndrome. The authors note the reason for these lower limb amputation events is unknown, and it remains unclear whether this is a class effect of SGLT2 inhibitors. Overall, it is suggested that prior to starting SGLT2 inhibitor treatment, patients should undergo assessments for factors that could potentially increase the risk of foot infection or impaired blood flow, such as peripheral vascular disease, neuropathy, or existing foot ulcers. [6]