Jardiance Seemingly Not Associated With Amputations Per Reexamination Of Drug Company Funded EMPA-REG OUTCOME® Trial Data
In April 2016 the European Medicines Agency (EMA) warned that Invokana and Invokamet were linked to an increased risk of amputations, especially of the toes.
Ever since then we have been monitoring the medical literature concerning the risk of lower limb amputations and drugs in the sodium glucose cotransporter 2 (SGLT2) inhibitor class, such as canagliflozin (Invokana / Invokamet), empagliflozin (Jardiance / Glyxambi / Synjardy), and dapagliflozin (Farxiga / Xigduo / Qtern).
On November 13, 2017 Boehringer Ingelheim published on their website this press release, "Jardiance® reduced risk of cardiovascular death in adults with type 2 diabetes and peripheral artery disease". Therein, we found this excerpt concerning lower limb amputations:
These results, from a post-hoc analysis of the landmark EMPA-REG OUTCOME® trial, were shared as an oral presentation on behalf of Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) at the American Heart Association® (AHA) Scientific Sessions 2017 in Anaheim, Calif. and simultaneously published online [as a Research Letter: "Cardiovascular Outcomes and Safety of [Jardiance (Empagliflozin)] in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME"] in the AHA’s journal, Circulation....
Overall side effects and serious side effects were balanced between the Jardiance [(empagliflozin)] and placebo groups in adults with and without peripheral artery disease. In the group with peripheral artery disease, lower-limb amputations occurred in 5.5 percent of those treated with Jardiance and 6.3 percent of those treated with placebo. In the group without peripheral artery disease, lower-limb amputations occurred in 0.9 percent of those treated with Jardiance and 0.7 percent of those treated with placebo….
On that same date, the medical journal Diabetes Care made available online a "Publish Ahead of Print" version of this brief article, "[Jardiance (Empagliflozin)] and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial".
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It includes this apparent "soft" disclaimer about the findings of those medical researchers whose names were displayed next to the article title.
We acknowledge the inherent limitations of manually identifying [lower limb amputation (LLA)] and performing post hoc analyses. A dedicated case report form was not used in the EMPA-REG OUTCOME trial as there was no concern regarding an increased risk of amputation with [Jardiance (empagliflozin)] before or during the trial. We are confident that the reporting and systematic retrieval processes employed were thorough.
Furthermore, and perhaps significantly, at the end of this Diabetes Care article text appears the following note:
Acknowledgments. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Elizabeth Ng of FleishmanHillard Fishburn, London, U.K., during the preparation of this paper.
We point out that there is a similar Acknowledgments note concerning the involvement of FleishmanHillard Fishburn at the end of the earlier-mentioned Circulation Research Letter, also.
A week later, on November 20, 2017, this headline caught our attention, "[Jardiance (empagliflozin)] does not increase amputation risk". This relatively short piece, published on the Healio IN THE JOURNALS PLUS website, reported on the above Diabetes Care article.
That Healio report was followed by this November 27, 2017 Medscape story, "No Signal for Amputation With [Jardiance (Empagliflozin)] in EMPA-REG" which, despite the favorable title, included this cautionary part:
[D]octors are clearly still concerned about this and whether it represents a class effect of SGLT2 inhibitors or is specific to [Invokana (canagliflozin)].
Commenting on the topic in a recent perspective for Medscape Medical News, Harpreet Bajaj of Mount Sinai Hospital, University of Toronto, Ontario, said: "To reassure us of the benefit/harm balance with [Invokana (canagliflozin)], we clinicians need more data-mining from CANVAS and additional long-term randomized controlled trials."
This Medscape story did not indicate whether Dr. Bajaj thought the Boehringer Ingelheim press release, the Diabetes Care article, or the Healio piece alleviated his own concerns, at least, about lower limb amputations possibly being associated with other SGLT2 inhibitors, like Jardiance and Farxiga.
However, that statement by Dr. Bajaj was immediately followed by this sub-headline for the next part of the November 27 Medscape story: Inherent Limitations in Manually Identifying Lower-Limb Amputations.
Now, we take you back to this past June and an article, "Invokana Shown to Have Heart Benefits, but Elevated Amputation Risks", which was posted on our Drug Safety Developments blog. Only five months ago a leading expert in diabetes medicine made this observation:
John Buse, the chief of endocrinology at UNC - Chapel Hill provided his opinion on the matter, "Personally, I would much rather have a small heart attack than lose a toe... And I think I would much rather have a big heart attack than lose a leg.” He anticipates a significant debate, saying that the benefits and harms are most likely "over- and under-estimated in each study." [emphasis added]
In closing, it appears there needs to more medical research done on the risk of lower limb amputations for patients who use the increasing popular diabetes medicines in this SGLT2 inhibitors drug class, which includes Invokana and Jardiance as well as Farxiga.
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