Earlier Invokana Lower Limb Amputation Reports Are Being Followed By Farxiga And Jardiance Amputation Cases Now
There is new medical evidence which suggests the hypovolemic effect of sodium-glucose cotransporter 2 (SGLT-2) inhibitor diabetes drugs might explain the increased risk of lower limb amputations associated with Invokana and Invokamet. In May 2017 the FDA mandated new safety warnings be added to the drug labels for Invokana and Invokamet, including a "Black-Box Warning" about leg, foot, and toes amputations.
Moreover, this new medical evidence indicates that these lower limb amputations may be a "drug-class" side effect for all of the SGLT-2 inhibitor diabetes drugs which have been approved by the FDA to date:
- Xigduo XR
These new findings were presented in October 2018 at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting by Ronan Roussel, MD, PhD, chief of the endocrinology, diabetes, and nutrition department at Group Hôpital Bichat, AP-HP, Paris, France, in Abstract OP-02.
We get the following explanation of this increased risk of amputation for Jardiance and Farxiga as well as Invokana and other similar diabetes drugs from this October 2, 2018 medical news report, "SGLT2 Inhibitor-Amputation Link in Diabetes -- Is it Hypovolemia?":
The mechanism behind the finding of an increased risk of lower-limb amputation in patients taking [Invokana (canagliflozin)] in the Canagliflozin Cardiovascular Assessment Study (CANVAS) has been much debated. Findings from observational trials of [Invokana (canagliflozin)] have conflicted regarding the amputation risk, and the effect hasn't been seen with other SGLT2 inhibitors.
But, assuming the amputation risk is a class effect, one theory about the mechanism is that the reduction in plasma volume from SGLT2 inhibitors could lead to decreased perfusion, especially in patients who already have reduced lower limb perfusion. "If true, we hypothesized that diuretics would show a similar safety profile," Roussel explained.
In fact, he noted, a few previous retrospective studies have shown an association between diuretic use and lower-limb amputation (Pharmacoepidemiol Drug Saf. 2004;13:139-146).
In the current study, after propensity matching and adjustment for multiple confounders, Roussel and colleagues found a doubling of risk for amputation with diuretic use.
"This is a strong signal," he told Medscape Medical News in an interview, adding that the data suggest diuretics should be used with caution in patients who are at increased risk for amputation, such as those with critical ischemia.
Regarding his extrapolation to SGLT2 inhibitors, he emphasized that the new findings are merely "hypothesis-generating" and not conclusive. However, "If this observation [is accurate], it's probably a class effect," he said....
[Roussel] concluded, "The hypovolemia hypothesis could provide an explanation for the increased risk of lower limb amputation observed with SLGT2 inhibitors."
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From another article about this new medical research, "EASD 2018: Diuretics Linked With Greater Amputation Risk in Type 2 Diabetes -- May help explain risk of amputations with SGLT-2 inhibitor in CANVAS", we get this additional information:
“This study was based on the hypothesis that amputation warnings found in the CANVAS trial could be driven by the diuretic effect of SGLT-2 inhibitors,” Louis Potier, MD, with Assistance Publique - Hôpitaux de Paris (AP- HP) in France told Elsevier’s PracticeUpdate. “This is, to our knowledge, the first study so far to propose a mechanistic explanation for this unexpected outcome.”
For the prospective, observational cohort study known as SURDIAGENE, 1074 patients with type 2 diabetes were enrolled between 2002 and 2012 and followed-up until the onset of lower-limb events, death, or December 31, 2015. The primary outcome measure was the first occurrence of a lower-limb event, defined as a composite of lower-limb amputation and lower-limb revascularization....
“In the light of our primary hypothesis of diuretic-induced effect for amputations observed in CANVAS, we assume that volume depletion could lead to hypoperfusion of the distal extremities and then trigger amputations,” said Dr. Potier. “However, this assumption remains speculative; we do not have enough data in our study to support this hypovolemia hypothesis. … Further studies with careful assessment of volemic status are needed to address this question.”
As background, some diabetic patients at the highest risk of amputations are those with peripheral arterial disease or foot ulcers.
Given the increasing medical evidence that lower limb (leg, foot, toes) amputations are a drug-class side effect of SGLT-2 inhibitors, we continue to investigate amputation drug injury cases for patients using Invokana, Farxiga, Jardiance, and similar newer diabetes medications.
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