November 2018: The BMJ Medical Journal Publishes New SGLT2 Diabetes Drug Observational Study
Diabetes drugs in the sodium-glucose cotransporter 2 (SGLT2) inhibitors class are associated with twice the risk for lower limb amputations relative to certain other diabetes medicines, according to a new observational study published by The BMJ medical journal in November 2018.
Noteworthy is that Farxiga (dapagliflozin) and Jardiance (empagliflozin) accounted for 99% of SGLT2 inhibitor use in this study which involved 2013–2016 data from Swedish and Danish registries.
However, in the US only a third SGLT2 inhibitor, Invokana (canagliflozin), has a drug label warning for increased amputation risks, and it is a so-called "Black-Box" warning pursuant to an FDA mandate issued in May 2017.
By comparison, the European Medicines Agency (EMA) warned about a potential increased risk of lower limb amputations (mostly affecting the toes) in patients taking any of the SGLT2 inhibitors, including Farxiga and Jardiance as well as Invokana, in February 2017.
It is this BMJ article, "Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study", which reports about Farxiga and Jardiance being associated with a two-times increased risk for amputations of toes, feet, and legs. From the Abstract for this medical journal article:
Results Use of SGLT2 inhibitors, as compared with [ glucagon-like peptide 1 (GLP1) receptor agonists], was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91)....
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In more detail, from the Discussion part of this November 2018 medical journal article:
The twofold increase in risk of lower limb amputation associated with the use of SGLT2 inhibitors observed in our study is in line with the findings from the CANVAS Program, which randomised patients with high cardiovascular risk to [Invokana (canagliflozin)] or placebo. Importantly, our results were consistent in patients with and without cardiovascular disease and with and without peripheral arterial disease or previous amputation; the event rates, however, were substantially higher in the subgroups with such history. A pooled analysis of clinical trials of [Farxiga (dapagliflozin)] was underpowered to assess lower limb amputations, and no imbalance in this outcome in patients receiving [Jardiance (empagliflozin)] versus placebo was observed in the EMPA-REG OUTCOME trial. Whether the increase in lower limb amputations is a class effect for SGLT2 inhibitors, or specific to individual drugs, needs further study.... [Footnotes omitted.]
For some commentary on this recent BMJ medical journal article concerning Farxiga and Jardiance, we turn to this November 15, 2018 HealthDay News report, "Certain Diabetes Meds Tied to Higher Odds for Amputation":
[Dr. Kevin Pantalone, an endocrinologist with the Cleveland Clinic] and [Dr. David Lam, an assistant professor of medicine, endocrinology, diabetes and bone disease at the Icahn School of Medicine at Mount Sinai in New York City] said one potential way that SGLT2 inhibitors might increase amputation risk is due to the way they work in the body.
Many people who are diabetic have poor circulation in their legs and feet, and these drugs cause people to excrete more urine to lower their blood sugar, the doctors said.
"You could potentially get more dehydrated if your blood sugars are very elevated," Lam said. "Because of the decrease in blood volume, it's decreasing overall blood flow and that might be compromising someone who's already at risk for having poor blood circulation to their lower extremities. It could be making an existing problem worse."
The conflicting results between this observational study and previous clinical trials means doctors will have to take a patient-by-patient approach, Pantalone and Lam said.
We will continue to monitor the drug safety issue of lower limb amputations for patients using Farxiga and Jardiance, in particular, as well as watch for a possible new FDA warning about an increased risk of amputations covering all SGLT2 inhibitor diabetes drugs, not just Invokana.
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