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Compared with some type 2 diabetes therapies, SGLT-2 inhibitors may be tied to an increased risk for amputations, researchers found.

In a retrospective cohort study, newly initiated SGLT-2 inhibitors for the treatment of type 2 diabetes were associated with significantly increased risk for lower extremity amputation when compared with older agents including sulfonylureas, metformin and thiazolidinediones (adjusted HR 2.12, 95% CI 1.19-3.77), reported Hsien-Yen Chang, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues.

Point estimates for risk were also numerically higher with "gliflozin" agents compared with newly initiated DPP-4 inhibitors (aHR 1.50, 95% CI 0.85-2.67) or GLP-1 agonists (aHR 1.47, 95% CI 0.64-3.36) although these differences were not statistically significant, the group wrote in .

"These findings are relevant because of how commonly SGLT-2 inhibitors are prescribed, the increased risk of foot and leg amputations with the use of canagliflozin in the CANVAS and CANVAS-R clinical trials, and the importance of this outcome for patients," said the researchers, who also noted that the underlying mechanisms for this increased risk still aren't known.

Based on the outcomes of the CANVAS trials, the SGLT-2 inhibitor canagliflozin (Invokana, Ivokamet, Invokamet XR) carries a boxed warning regarding the increased risk for leg and foot amputation.

"The rate of amputation found by Chang et al is strikingly lower than the rate found in the CANVAS program (6.3 per 1000 person-years), reflecting important differences between the populations in each study," commented Michael Fralick, MD, of Brigham and Women's Hospital in Boston, and two colleagues in an , highlighting how the current study's population was generally younger, and fewer participants had a history of ischemic heart disease, history of amputation, or use of insulin compared with those in CANVAS.

"These differences in baseline comorbidities likely explain, at least in part, why the incidence rate of amputation was much lower than that detected in CANVAS," they suggested.

Interestingly in contrast, the recent OBSERVE-4D study reported new users on canagliflozin didn't have any increased risk for below-knee amputations when compared with other SGLT-2 inhibitors and other classes of antihyperglycemic agents.

Chang and colleagues also found newly initiated SGLT-2 inhibitors were associated with a higher risk for certain other adverse outcomes when compared with older agents:

• Vascular ulcers: aHR 1.34 (95% CI 1.10-1.61)
• Osteomyelitis: aHR 1.44 (95% CI 1.02-2.05)
• Peripheral vascular disease: aHR 1.11 (95% CI 1.02-1.22)

But when compared with DPP-4 inhibitors, SGLT-2 inhibitors were tied to a lowered risk for peripheral vascular disease (aHR 0.88, 95% CI 0.79-0.96), as well as critical limb ischemia (aHR 0.76, 95% CI 0.64-0.89). Rates of the latter were also lower for newly initiated of gliflozins when compared with GLP-1 agonists (aHR 0.79, 95% CI 0.65-0.79).

The analysis included 953,906 individuals with type 2 diabetes who appearing in the Truven Health MarketScan Commercial Claims and Encounters database. This group included 39,869 patients who were on newly initiated SGLT-2 inhibitor therapy -- the majority of whom were taking canagliflozin (n=28,036), followed by dapagliflozin (Farxiga; n=8,647), and empagliflozin (Jardiance; n=3,186). Individuals who had experienced an amputation were excluded from the analysis. At baseline, hypertension and use of statins was more common among individuals prescribed SGLT-2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists compared with older types of therapies.

"The study by Chang et al helps to contextualize the risk in a relatively low-risk patient population, but does not settle the debate," expressed the commentators, stating how it's still unclear if this elevated amputation risk is attributed to a class effect with SGLT-2 inhibitors.

"Until more data are available, the results of CANVAS provide the greatest evidence that canagliflozin is associated with an increased risk of amputation and should influence our prescribing accordingly," Fralick's group recommended.