Empagliflozin Particularly Effective in 'Vulnerable' Diabetes Subgroup

Marlene Busko

November 28, 2017

ANAHEIM, CA — In the subgroup of "vulnerable" patients with type 2 diabetes who also have peripheral artery disease (PAD), the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) reduced cardiovascular mortality, hospitalization for heart failure, and renal disease progression, without increasing the risk of lower-limb amputation, researchers report[1].

Dr Subodh Verma

Dr Subodh Verma (University of Toronto, ON) presented these findings from a subgroup analysis of the EMPA-REG OUTCOME trial in a late-breaking trial session November 13, 2017 at the American Heart Association 2017 Scientific Sessions, and the study was simultaneously published as a research letter in Circulation.

Patients with PAD are "an extremely vulnerable population of patients," Verma told theheart.org | Medscape Cardiology. This analysis showed "profound reductions in cardiovascular mortality" in patients with type 2 diabetes and PAD, he said.

Moreover, although patients with PAD are at higher risk of lower-leg amputations, "importantly, there was no signal of increased risk of amputation," assigned discussant Dr Renato D Lopes (Duke University, Durham, North Carolina) noted in his summary.

This is in contrast to the increased risk of amputation seen with another SGLT2 inhibitor, canagliflozin (Invokana, Janssen), in type 2 diabetes patients in the CANVAS trial.

"CANVAS and EMPA-REG leave us excited that a new class of drugs is associated with less cardiovascular disease risk; then there's this confusion [related to] this difference in rates of adverse events in terms of amputation [in CANVAS] vs no amputation with EMPA-REG," session comoderator Dr Robert H Eckel (University of Colorado School of Medicine, Aurora) told theheart.org | Medscape Cardiology.

One in Five EMPA-REG Patients Had PAD

EMPA-REG OUTCOMES randomized 7020 type 2 diabetes patients with a history of 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.

The history of CVD required for enrollment into the trial could include PAD, and one in five patients (21%) fell into this category—defined as having had limb angioplasty, stenting, or bypass surgery; leg or foot amputation; significant peripheral artery stenosis; or with an ankle-brachial index <0.9.

In this new analysis, the researchers aimed to investigate the effects of empagliflozin by PAD status. They compared four groups of patients: those with PAD or without PAD who received placebo or empagliflozin.

Across the four groups, patients had a similar mean age (64) and about 72% were male.

They had a mean BMI of 31 kg/m2 and a mean HbA1c of 8.1%. About half had an eGFR between 60 and 90 mL/min/1.73 m2 and a quarter had eGFR <60 mL/min/1.73 m2.

Not surprisingly, patients with PAD were more likely to be current and former smokers, Verma noted. They were also less likely to have a history of MI or stroke and less likely to use lipid-lowering medications (74% vs 82%).

Over a mean follow-up of 3.1 years, patients who received empagliflozin as opposed to placebo had a lower risk of cardiovascular mortality, all-cause mortality, hospitalization for heart failure, and new or worsening nephropathy—whether or not they had PAD.

Reduction in Risk of Outcome, Empagliflozin vs Placebo (%)*

Outcome All patients (%) Patients with PAD (%) Patients without PAD (%)
CV death 38 43 36
All-cause death 32 38 30
HF hospitalization 35 44 32
New or worsening nephropathy 39 46 37
*Among patients in the EMPA-REG OUTCOME trial, over a mean follow-up of 3.1 years


Substantial Reductions in CV Death and HF With Empagliflozin in PAD

Twenty-nine patients with type 2 diabetes and PAD would need to be treated with empagliflozin for 3.1 years to prevent one cardiovascular death, the researchers report.

This contrasts with the figure from the overall EMPA-REG trial, in which 39 patients would need to be treated with empagliflozin during a 3-year period to prevent one death.

"There's a profound and precocious separation of curves for the outcome of cardiovascular death . . . in people with and without PAD at baseline," Verma said, adding that it was important to put the absolute risk reduction "into context of other interventions that we use in secondary prevention."

"In patients with PAD, there was a 3% absolute risk reduction of cardiovascular death in those who received empagliflozin vs placebo (7.5% vs 4.5%), with a hazard ratio of 0.57."

In patients without PAD, there was a 2% absolute risk reduction of this outcome in those who received empagliflozin vs placebo (5.5% vs 3.5%; hazard ratio 0.64).

Similarly, there was a 2.2% absolute reduction in risk of hospitalization for heart failure in patients with PAD who received empagliflozin, which was twice the absolute risk reduction in patients without PAD who received empagliflozin.

And importantly these gains were achieved without any increase in lower-limb amputation, he stressed.

Rates of lower-limb amputation were 5.5% and 6.3% in patients with PAD who received empagliflozin or placebo, respectively, and 0.9% and 0.7% among patients without PAD who received empagliflozin or placebo, respectively—consistent with the overall EMPA-REG OUTCOME trial, which found no excess risk of amputation with empagliflozin.

"These data have important translational implications for risk-reduction approaches in patients with type 2 diabetes and PAD," the researchers conclude.

The EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim and Eli Lilly Diabetes Alliance. Verma has received research grants and/or speaking honoraria from Boehringer Ingelheim/Eli Lilly, AstraZeneca, Janssen, Merck, and Amgen. Disclosure for  the coauthors are listed in the paper.

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