EMPA-REG: Empagliflozin Cut Heart Failure Hospitalizations, CV Death in High-Risk Diabetes Patients

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Empagliflozin has cardiovascular benefits for patients with type 2 diabetes.
Empagliflozin has cardiovascular benefits for patients with type 2 diabetes.

ORLANDO, Fla. — When added to standard of care, the sodium glucose cotransporter (SGLT2) inhibitor empagliflozin appeared to reduce heart failure hospitalizations and cardiovascular (CV) death in patients with type 2 diabetes and high CV risk. This benefit was consistent for both patients with and without heart failure at baseline, according to data from the EMPA-REG OUTCOME trial.

“For this outcome, the hazard ratio (HR) was 0.63 for those with no heart failure at baseline — a 37% relative risk reduction — and 0.72 for those with heart failure at baseline — a 28% relative risk reduction. However, our statistical test determined that these 2 values were not different,” said study investigator Silvio Inzucchi, MD, who is a professor of medicine and medical director of the Yale Diabetes Center at Yale University School of Medicine in New Haven, Connecticut.

Cardiovascular disease is a major problem in patients with diabetes, and while lowering blood sugar is important, it does little to reduce the risk for CV events on its own.

“We've actually been looking for decades for a medication that will not only lower blood glucose but also lower cardiovascular risk,” he said during a press conference.

Dr Inzucchi, who presented the results at the American Heart Association Scientific Sessions, noted that clinicians have been waiting for the results from this first-in-class, large CV outcomes trial involving an SGLT2 inhibitor because, in addition to lowering blood glucose, SGLT2 inhibitors have modest benefits on blood pressure and weight.

“The question is could SGLT2 inhibitors, specifically empagliflozin, finally be the drug category that reduces cardiovascular complications?”

Dr Inzucchi and his colleagues recently reported the initial results of EMPA-REG OUTCOME at the European Association for the Study of Diabetes (EASD) meeting in Stockholm. Data have also been published in the New England Journal of Medicine.

Relative Risk Reductions in CV Outcomes

The study included 7020 patients with type 2 diabetes and established CVD from 42 countries at 590 sites who were randomly assigned to empagliflozin 10 mg (n=2333), 25 mg (n=2345), or placebo (n=2342), given against the backdrop of standard of care.

At baseline, mean HbA1c was 8.1%, mean BMI was 30.6, and 71.5% of the patients were men. More than 99% had a prior history of CVD, with 46.6% having experienced a previous myocardial infarction (MI), 24.8% having undergone CABG, 23.3% having experienced a previous stroke, and 20.8% having peripheral arterial disease.

The primary outcome was major adverse cardiac events, defined as a composite of nonfatal MI, nonfatal stroke, or CV death. 

According to the data, empagliflozin reduced MACE by 14% (hazard ratio [HR]=0.86; 95.02% CI, 0.74-0.99).

However, the most striking outcome, said Dr Inzucchi, was the 38% relative risk reduction in CV mortality in patients randomly assigned to either dose of empagliflozin (HR=0.62; 95% CI, 0.49-0.77). He also noted that the relative risk reduction for hospitalization for heart failure was 35% in favor of those randomly assigned to empagliflozin (HR=0.65; 95% CI, 0.50-0.85).

Patients With vs Without Heart Failure at Baseline

For this presentation, Dr Inzucchi said the researchers expanded their inquiry into heart failure outcomes, reporting that the relative risk for a composite of hospitalization for heart failure or CV death was reduced by 34% for those assigned to empagliflozin (HR=0.66; 95% CI, 0.55-0.79). Additionally, relative risk for hospitalization or death from heart failure was reduced by 39%, favoring empagliflozin (HR=0.61; 95% CI, 0.47-0.79).

The researchers also compared outcomes in patients with (10%) and without heart failure at baseline (90%). Hospitalizations for heart failure were relatively small in number, but the HR of 0.59 was significant in patients without heart failure at baseline in the empagliflozin groups (95% CI, 0.43-0.82). For those with heart failure at baseline, the HR was 0.75 (95% CI, 0.48-1.19), also favoring empagliflozin.

In terms of hospitalization for heart failure or CV death in patients with vs those without heart failure at baseline, the HRs were 0.63 (95% CI, 0.51-0.78) and 0.72 (95% CI, 0.50-1.04), respectively, with empagliflozin.

“SGLT2 inhibitors have an osmotic diuretic effect, and therefore the improvement in heart failure outcomes makes some mechanistic sense. However, we did not expect the rapidity of the effect nor its magnitude,” Dr Inzucchi told Endocrinology Advisor

“As for the CV death outcome, the results are not easily explained at all. Empagliflozin does reduce blood glucose without increasing the risk of hypoglycemia, while also reducing blood pressure and body weight, but these effects would not be expected to have such an impressive effect by themselves. Perhaps combining these effects with mild diuresis is the explanation.”

However, he noted that this is speculative, and more studies are warranted to better understand the benefits of empagliflozin demonstrated in this trial.

Among the patients in the trial, there was high usage of evidence-based CV therapies, such as statins, renin-angiotensin system (RAS) blockers, and aspirin, he added.

“I personally think that empagliflozin should be considered a leading second-line agent after metformin in patients with established CVD. Whether this applies to any SGLT2 inhibitor is not yet known. Right now, we have data on empagliflozin, and we'll need to wait for the results of CANVAS and DECLARE before we know whether canagliflozin and dapagliflozin have a similar effect,” said Dr Inzucchi.

“I think endocrinologists should care about these results because they represent the first time that any glucose-lowering drug has demonstrated unequivocally improved CV outcomes in a high-risk population. We've been searching for this for decades. Time after time, it appeared that no matter what we did from a glycemic standpoint, we could not substantially decrease CV event rates. But, perhaps now we can,” said Dr Inzucchi.

References

  1. Inzucchi SE, Wanner C, Lachin JM, et al; for the EMPA-REG Outcome Investigators. LBCT.02 - Decreasing the Global Burden of Disease: Breakthroughs in Prevention. Empagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus at High Cardiovascular Risk. Presented at the American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL.
  2. Zinman B, Wanner C, Lachin JM, et al; for the EMPA-REG Outcome Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;doi:10.1056/NEJMoa1504720.
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