No Signal for Amputation With Empagliflozin in EMPA-REG

November 27, 2017

A post hoc analysis of the landmark EMPA-REG cardiovascular outcomes trial with the sodium glucose cotransporter 2 (SGLT2) empagliflozin (Jardiance, Boehringer Ingelheim) in patients with type 2 diabetes and established cardiovascular disease has found no evidence of an increased risk of lower-limb amputation with the drug vs placebo.

The study, led by Silvio Inzucchi, MD, of Yale University, New Haven, Connecticut, has been published in Diabetes Care.

Concern about a possible association of SGLT2 inhibitors and increased risk of lower-limb amputation, primarily of the toe, first arose from interim data from a trial with a different agent in the class, canagliflozin (Invokana, Janssen Pharmaceuticals), from the Canagliflozin Cardiovascular Assessment Study (CANVAS) last year, which led to a warning on the labels of all SGLT2 inhibitors by the European Medicines Agency, as it determined that it wasn't possible to exclude other SGLT2 inhibitors from the alert.

In contrast, the US Food and Drug Administration has mandated a boxed warning relating to the amputation risk only for canagliflozin specifically.

In the full presentation of the CANVAS data, at the ADA meeting in June this year, the results confirmed an overall doubling in the risk for amputations between those taking canagliflozin vs placebo (6.3 vs 3.4 cases per 1000 patient-years; hazard ratio [HR], 1.97).

But overall, canagliflozin still reduced cardiovascular events by 14% and cut the rate of renal decline by 40% in this large outcomes trial, and the investigators maintained that, even with the amputation signal, the benefit/risk profile of canagliflozin was favorable.

Yet doctors are clearly still concerned about this and whether it represents a class effect of SGLT2 inhibitors or is specific to 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 canagliflozin, we clinicians need more data-mining from CANVAS and additional long-term randomized controlled trials."

Inherent Limitations in Manually Identifying Lower-Limb Amputations

EMPA-REG OUTCOMES randomized 7020 patients with type 2 diabetes and established cardiovascular disease to receive placebo or empagliflozin (10 mg/day or 25 mg/day) plus standard care for 3.1 years.

The results were the first to show, in 2015, that a diabetes drug offered cardiovascular benefit beyond mere glucose lowering, with empagliflozin producing a 38% relative risk reduction in cardiovascular mortality and a 32% risk reduction in all-cause mortality. The following year, the FDA approved the drug for the new indication of improving survival in adults with type 2 diabetes and cardiovascular disease.

When EMPA-REG was conducted, there was no inkling of any association of this SGLT2 inhibitor drug class with amputation, so these were not systematically reported.

And at the time of the presentation of the CANVAS data, Dr Inzucchi told Medscape Medical News that there was no signal for amputation in EMPA-REG with empagliflozin vs placebo.

Now he and his colleagues have published the details of their post hoc assessment of EMPA-REG for amputation.

They note in their new paper that "any hospital admission during EMPA-REG was to be reported as a serious adverse event [SAE]," with investigators asked to provide a detailed narrative in each case.

So they went back and identified lower-limb amputations via a systematic search of these SAEs, as well as looking for them in a number of other ways.

"All cases identified were medically reviewed to confirm a lower-limb–amputation event," they note.

Overall, lower-limb amputations were identified in 131 patients: 88 patients treated with empagliflozin (1.9%) and 43 (1.8%) treated with placebo.

The incidence rate was 6.5 per 1000 patient-years in both groups.

In the analyses of time to first event, the risk of lower-limb amputation was similar between empagliflozin pooled and placebo (HR, 1.00).

And results were similar with empagliflozin 10 mg (HR, 0.96) and empagliflozin 25 mg (HR 1.04).

The findings were also consistent across subgroups by established amputation risk (such as history of smoking, diabetic foot, diabetic neuropathy, and peripheral artery disease).

"We acknowledge the inherent limitations of manually identifying lower-limb amputation 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 before or during the trial," they explain.

Yet "we are confident that the reporting and systematic retrieval process employed were thorough. Empagliflozin was not associated with an increased risk of lower-limb amputation compared with placebo in EMPA-REG OUTCOME," they reiterate.

EMPA-REG OUTCOME was funded by the Boehringer Ingelheim and Eli Lilly Alliance. Dr Inzucchi has consulted for Boehringer Ingelheim, AstraZeneca, Merck, Intarcia Therapeutics, Lexicon Pharmaceuticals, Janssen, Sanofi, Novo Nordisk, and vTv Therapeutics. Disclosures for the coauthors are listed in the paper.

Diabetes Care. Published online November 13, 2017. Article

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