Real-world analysis found no amputation risk with canagliflozin for treating type 2 diabetes

Canagliflozin is the first sodium-glucose co-transporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes.1 Although canagliflozin offers benefits such as reductions in body weight, blood pressure, and risk for hypoglycemia,2 the US Food and Drug Administration (FDA) has included a black box warning regarding an increased risk of leg and foot amputation with canagliflozin.3 Promisingly, a recent real-world analysis of more than 700,000 patients found no link between canagliflozin and amputations.4 The findings were presented at the American Diabetes Association (ADA) 2018 Scientific Sessions.4

The CANagliflozin cardioVascular Assessment Study (CANVAS), a cardiovascular outcome trial for this medication, has previously reported an increased rate of lower extremity amputations in the primary and secondary prevention cohorts.5 There was a two-fold excess risk for below-knee amputations in patients receiving canagliflozin, but the absolute risk was low (6.3 cases/1,000 patient-years; the risk for placebo was 3.4 cases/1,000 patient-years).6

“The vast majority of the US population with diabetes who haven’t had prior amputations and don’t have those kinds of risks – and particularly in those with clinical cardiovascular disease where the benefits are huge – that’s the population where we really just have to help [clinicians] feel comfortable with the idea that the benefits far, far, far outweigh the risks,” said Dr. Robert H. Eckel, MD, professor of medicine at the University of Colorado Anschutz Medical Campus, US.6

OBSERVE-4D was a large comprehensive analysis that analyzed de-identified patient-level data from 4 large US administrative claims database.7 It compared the risk of hospitalization for heart failure and below-knee lower extremity (BKLE) amputation among 142,000 new users of canagliflozin, 110,000 new users of SGLT2 inhibitors, and 460,000 new users of non-SGLT2 inhibitors, with median treatment exposure less than 6 months.7

Two primary time-at-risk periods were evaluated.7 On-treatment period evaluated the risk during the period in which an individual is exposed to the drug and intent-to-treat period evaluated the overall risk after initiating treatment.7 The estimate for BKLE amputation with canagliflozin vs non-SGLT2i was 0.75 (95% CI: 0.40-1.41) in the on-treatment analysis and 1.01 (95% CI: 0.93-1.10) in the intent-to-treat analysis.7 These demonstrated no increased risk of BKLE amputation in patients receiving canagliflozin.7

Consistent with the findings in CANVAS, the OBSERVE-4D also found reduction in hospitalization for heart failure (HHF) with canagliflozin.7 The meta-analytic HR estimate of HHF with canagliflozin compared to non-SGLT2 inhibitor was 0.39 (95% CI: 0.26-0.60; p=0.01) in the on-treatment analysis.7 “The SGLT2 inhibitor class is exceptionally promising,” said Dr. John B. Buse, director of the Diabetes Center at the University of North Carolina School of Medicine in Chapel Hill, US. “Probably 60% to 70% of patients with type 2 diabetes will die of either cardiovascular disease, heart failure or kidney failure, and this class of drugs has been shown to reduce those outcomes substantially.8

Dr. Buse acknowledged that the low number of patients with more than 6 months of follow-up is a limitation and further study will be required to fully investigate the issue.7 “I think in the highest-risk patients [for amputation] … you really have to think about it twice. But for people with prior cardiovascular disease, and particularly people with prior heart failure, I think the benefit is enormous,” Dr. Buse concluded. “It's a matter of balancing perceived risks and perceived benefits.”7,9


1. FDA Approves Invokana. 2018 (Accessed July 18 2018, at

2. Karagiannis T, Bekiari E, Tsapas A. Canagliflozin in the treatment of type 2 diabetes: an evidence-based review of its place in therapy. Core Evid. 2017;12:1-10.

3. FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). 2018 (Accessed July 19 2018, at

4. Ryan PB, Buse JB, Schuemie MJ, et al. Canagliflozin (CANA) vs. Other Antihyperglycemic Agents on the Risk of Below-Knee Amputation (BKA) for Patients with T2DM—A Real-World Analysis of >700,000 U.S. Patients. American Diabetes Association (ADA) 2018 Scientific Sessions. June 22-26, 2018; Orlando, Florida, US. Abstract 4-LB.

5. Mahaffey KW, Neal B, Perkovic, et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events. Circulation. 2018;137:323-334.

6. New Study Finds No Link Between Canagliflozin and Amputation. Medscape. 2018 (Accessed July 17, 2018, at

7. Ryan PB, Buse JB, Schuemie MJ, et al. Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab. 2018.

8. OBSERVE-4D: No amputation risk with canagliflozin in type 2 diabetes. Healio. 2018 (Accessed August 22, 2018, at

9. No Greater Amputation Risk with Canagliflozin in T2D Patients. Medpagetoday. 2018 (Accessed August 22, 2018, at

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