Empagliflozin Benefits in EMPA-REG Explored in Diabetics Initially With or Without Heart Failure

Marlene Busko

November 16, 2015

ORLANDO, FL — Patients with type 2 diabetes and established CVD who received the antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Lilly/Boehringer Ingelheim), as opposed to placebo, had a reduced risk of being hospitalized for heart failure or dying from CVD during a median follow-up of 3.1 years. The finding was strongest in patients without heart failure at baseline[1]. The finding is noteworthy in part because associated heart failure has been a concern, justified or not, with some other diabetes medications.

Dr Silvio Inzucchi

In these high-risk patients, empagliflozin resulted in a "consistent benefit" in these outcomes, Dr Silvio E Inzucchi (Yale University School of Medicine, New Haven, CT) said, presenting these findings from a prespecified secondary analysis of the EMPA-REG OUTCOME trial at the American Heart Association (AHA) 2015 Scientific Sessions.

Unlike the gasps and applause that greeted him when he presented the trial's primary outcome results at the European Association for the Study of Diabetes (EASD) 2015 Meeting in Stockholm in mid-September, the audience reaction this time was more measured. The trial had also been published at about the time of its EASD presentation [2].

The principal findings showed that compared with patients who took placebo, those who were randomized to empagliflozin had a 38% (P<0.001) reduced risk of CV death and a 35% P=0.002) reduced risk of hospitalization for HF, at a median follow-up of 3.1 years.

In the current secondary analysis, the 90% of patients who were free of heart failure at study entry showed a steep and significant drop in HF hospitalizations during the trial. There was also a drop in HF hospitalizations with active therapy in the minority who had HF at baseline, but it failed to reach significance.

"I think metformin is likely to remain our first-line oral therapy for patients with type 2 diabetes," Dr Donald M Lloyd-Jones (Northwestern University Feinberg School of Medicine, Chicago, IL), cochair at an AHA press briefing, told heartwire from Medscape. "There is an alphabet soup of diabetes medications," with multiple agents that effectively lower blood glucose and reduce patients' risk of retinopathy, nephropathy, and neuropathy.

However, "it was . . . unexpected that [empagliflozin], as reported recently [at the EASD meeting and] in the New England Journal of Medicine [has an] effect on CV death and other CV events." This is still an early stage of research, he cautioned, and it is not known how the drug exerts its CV effects and whether there is a class effect. "But [this] could be a game changer, because we would love to have [antidiabetic] medications that not only control blood sugar but also reduce death and [other] hard events," he said.

First CV Outcomes Trial in this Drug Class

Until now, none of the antiglycemic medications has also been shown to improve HF outcomes, Inzucchi explained. "We've actually been searching decades for a diabetes medicine that will not only lower blood glucose but also reduce cardiovascular complications," he said in a press briefing. "And I would remind you that based on the 2008 FDA guidance to industry, all new diabetes medications need to be tested for cardiovascular safety before being allowed on the market," he added.

EMPA-REG OUTCOME is the first published, large CV-outcome trial of an SGLT-2 inhibitor.

As previously described, the trial randomized 7028 adult patients who had type 2 diabetes and established CVD to receive 10 mg/day or 25 mg/day empagliflozin or placebo. The CVD included prior MI (46.6%), CABG (24.8%), stroke (23.3%), and peripheral artery disease (PAD) (20.8%).

The patients were also required to have an HbA1c level between 7% and 10%, body-mass index (BMI) <45, and, because the drug exerts its effects via the kidney, estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2.

"Importantly, study medication was given upon a backdrop of standard care—antihyperglycemia therapy, as well as other evidence-based cardiovascular therapies such as statins, ACE inhibitors, and aspirin," Inzucchi stressed.

Spotlight on HF Outcomes

The current analysis dove deeper into the heart-failure outcomes in the trial.

The risk of hospitalization for HF or CV death was consistently significantly lower in patients who received empagliflozin vs placebo, in subgroup analyses related to age, kidney function, and medication use (ACE inhibitors/angiotensin receptor blockers [ARBs], diuretics, beta-blockers, or mineralocorticoid-receptor antagonists).

Overall, the patients who received empagliflozin had a 34% reduced risk of being hospitalized for HF or dying from CV causes and a 39% reduced risk of being hospitalized for or dying from HF.

Risk of Hospitalization or Death, Empagliflozin vs Placebo

Outcome HR (95% CI) P
Hospitalization for HF or CV death 0.66 (0.55–0.79) <0.00001
Hospitalization for or death from HF 0.61 (0.47–0.79) <0.00001

Most patients (90%) did not have HF at baseline.

In the patients without HF at baseline, "as you might expect, [HF] hospitalizations were relatively small in number" (1.8% of patients on the study drug and 3.1% of patients on placebo), said Inzucchi. There was a statistically significant 41% reduced risk of HF hospitalization in patients without HF at baseline on the study drug vs placebo (HR 0.59, 95% CI 0.43–0.82).

In the smaller number of patients who did have HF at baseline, the rate of hospitalizations for HF was much higher (10.4% of patients on the study drug and 12.3% of patients on placebo). But in this case, the difference between patients on the study drug vs placebo was not statistically significant (HR 0.75, 95% CI 0.48–1.19).

The results were similar when the analysis was repeated for the combined outcome of hospitalization for HF or CV death.

"Not surprisingly," adverse events were more common in sicker patients with baseline HF; genital infections, a well-known adverse event in drugs that increase glucose in the urine, were three times more common in those patients, said Inzucchi.

"I think these are very compelling data, but early days," said Lloyd-Jones.

Inzucchi receives research grants from Genzyme and honoraria from Boehringer Ingelheim, Merck Sharp & Dome, Sanofi, Amgen, and Genzyme, and he is a consultant on advisory boards for Boehringer Ingelheim, Sanofi, and Amgen. Disclosures for the coauthors are listed in the abstract. Lloyd-Jones has no relevant financial relationships.

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