Future Clinical Trials And Investigations Need To Clarify Whether This Amputation Drug Injury Could Be A Class Effect Of All SGLT2 Inhibitors
During this year we have written several times about the still developing drug safety issue of lower limb amputations linked to Invokana use:
What still is not clear to drug regulators and medical researchers, however, is the so-called "mechanism of injury" which explains how and why there is an increased risk of lower limb amputations for patients using Invokana. Further, it remains uncertain whether this serious side effect may be associated with Farxiga, Jardiance, and other diabetes drugs known as Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors.
These precise concerns were addressed in a recent Commentary piece, "CANVAS: Straight Talk Needed on Amputation Risk", by Harpreet S. Bajaj, MD, MPH, which was published on the Medscape website:
Since the US Food and Drug Administration announced its black-box warning earlier this year for [Invokana (canagliflozin)], many of us have been concerned about the amputation risk observed with this drug in the CANVAS trial (hazard ratio [HR], 1.97 compared with placebo). Despite the overall positive cardiovascular, heart failure, and kidney disease-related benefits seen with canagliflozin, a key clinical concern among prescribing clinicians such as me relates to predictive factors for amputations, and whether this risk correlates with the other treatment-related adverse effects observed (eg, volume depletion and hemoconcentration).
I expected further data clarifications surrounding this issue at the 1-hour CANVAS session at the European Association for the Study of Diabetes (EASD) 2017 meeting, held in September in Lisbon. But I was disappointed; no new data related to amputations from the CANVAS program were shared.
During the presentation, the discussants did include a prepublication meta-analysis of the CANVAS and EMPA-REG OUTCOMES trial programs. As a reminder, a previously published post hoc analysis from the latter cardiovascular outcomes trial had suggested no increase in amputations with [Jardiance (empagliflozin)]. The new meta-analysis slides show an increased risk for amputation with combined data from the two sodium/glucose cotransporter 2 (SGLT2) inhibitors ([Invokana (canagliflozin)] and [Jardiance (empagliflozin)]), with a significant HR of 1.44.
So, how are we supposed to interpret this discrepancy?
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That October 2017 Medscape article closes with a good idea about how to approach this drug safety issue going forward:
Moreover, to clarify whether the amputation harm could be a class effect of SGLT2 inhibitors, a thorough collection of prospective data on amputations and other foot-related complications should be required of all ongoing and future long-term trials within the class (eg, DAPA-CKD, DAPA-HF, and DECLARE with [Farxiga (dapagliflozin)]; EMPEROR-Preserved and EMPEROR-Reduced with [Jardiance (empagliflozin)]; and VERTIS CV with ertugliflozin [a SGLT2 inhibitor which has not been approved by the FDA, yet]).
Of course, we will continue to monitor the medical literature to learn more about how and why there is an increased risk of amputations involving toes, feet, and legs in patients using Invokana -- and perhaps Farxiga, Jardiance, and other SGLT2 inhibitors used as diabetes drugs.
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