Going Into 2019 The Issue Of These Amputations Being An SGLT2 Inhibitors Drug Class Side Effect Remains Open To Debate
A year-and-a-half ago we wrote this article, "Invokana - Amputation Side Effect Gets 'Black-Box Warning' On Revised Drug Label Issued In July 2017".
As we pointed out therein, this Invokana label change was previewed by "FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)" document was issued on May 16, 2017.
Since that time there has been a mix of opinions expressed in the medical literature about whether or not lower limb amputations are a side effect of the sodium-glucose co-transporter-2 (SGLT2) inhibitors class of diabetes drugs -- which includes Farxiga and Jardiance -- or limited only to Invokana and Invokamet.
This ongoing discussion, or controversy, is the subject of this December 5, 2018 piece, "The SGLT2 Inhibitor-Amputation Link", by medical news reporter Judy George.
That piece includes an "Expert Critique" item from the Endocrine Reading Room -- a collaboration of MedPage Today and the Endocrine Society -- from which we get this introduction to this still developing drug safety issue:
[T]he following article addresses the higher rate of lower limb amputations observed with the agent canagliflozin in the CANVAS randomized control trial, which was not seen in the randomized control trials for other agents in its class. Not surprisingly, the risk was highest in patients with pre-disposing risk factors, such as a history of amputation or peripheral vascular disease, but the statistical and clinical significance was not trivial. However, these findings were not replicated in the OBSERVE 4-D meta-analysis of four observational databases, which may be due to the differences in populations studied as further discussed below. Yet another analysis of a real-world setting found that the risk of amputation was higher for the new use of the SGLT2i as a class overall (compared with the new use of sulfonylureas, metformin, and thiazolidinediones), albeit the observed difference was smaller than that seen in CANVAS. Overall, it appears that more data is needed before making definitive conclusions, particularly given the relatively rare event rate of amputations. However, a consensus that emerged among the researches associated with all the aforementioned studies was that clinicians should use particular caution when considering the use of the SGLT2i class in any patient with pre-existing risk factors for amputation.
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Moving on to the December 2018 MedPage Today piece by reporter Judy George, there is this consideration of the amputations side effect issue:
There are several reasons why questions about SGLT2 inhibitors and amputations aren't resolved, said Michael Fischer, MD, MS, of Harvard Medical School.
"One challenge in assessing this risk is that amputations are relatively rare events," Fischer explained.
Although the Johns Hopkins analysis [which showed that starting treatment with SGLT2 inhibitors was tied to a significantly greater risk of amputations compared with new use of sulfonylureas, metformin, and thiazolidinediones (HR 2.12)] included a large number of patients treated with SGLT2 inhibitors, there were only 18 total amputations observed in that study, he noted.
"In addition, the patients in this observational study had a lower burden of illness and were followed for less time than the patients in the randomized controlled trial where this amputation risk was initially detected," Fischer pointed out. "These differences in population also make it harder to determine whether there is indeed an increased risk of amputation."
In observational studies, patients are not randomly assigned to treatment as they are in randomized controlled trials, Fischer added. "Patient characteristics that influence which diabetes treatment they receive may be correlated with their risk of amputation -- in either a positive or negative direction -- limiting our ability to accurately identify associations between a drug exposure and a clinical outcome," he said.
For Fischer, the results from the randomized controlled CANVAS trial remain "the most reliable evidence that we have so far on the risk of amputation, and should be factored into clinicians' prescribing decisions."
It seems fair to say that the SGLT2 inhibitors drug class amputations side effect issue remains open to debate.
Over the past couple of years we have been contacted by patients who had lower limb amputations while using Farxiga, Jardiance, and other diabetes medicines in the SGLT2 inhibitors drug class other than Invokana and Invokamet. We are evaluating those amputation cases and possible drug injury lawsuits against the responsible pharmaceutical companies.
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