More CV Benefits of Empagliflozin Revealed: Cuts Deaths, Hospitalization for Those With or Without Heart Failure

The cardioprotective benefits of the SGLT2 inhibitor empagliflozin, first reported in September, were amplified Monday when it was reported that the diabetes therapy cut heart failure hospitalization and cardiovascular (CV) deaths for patients whether or not they had heart failure at baseline.

More details from the EMPA-REG OUTCOME trial, a long-term CV trial involving 7020 patients, were reported this morning at the Scientific Sessions of the American Heart Association in Orlando, Florida. Silvio Inzucchi, MD, professor of medicine and director of the Yale Diabetes Center, discussed the findings at a press conference ahead of the session.¹

As Inzucchi explained, FDA now required CV outcomes trials for innovative diabetes and obesity medications, after several incidents that required blockbusters to be pulled from the market. While regulators are chiefly interested in whether drugs carry any long-term safety risks, researchers want to know if drugs can offer multiple benefits.

“There are now 12 different types of medication to lower blood glucose,” Inzucchi said, explaining that metformin remains the foundation for treating type 2 diabetes, but there’s debate what to do after that. For years, he said, “We’ve been searching for a therapy to not only lower blood glucose but also reduce cardiovascular complications.”

New of the CV benefits of empagliflozin stunned the scientific community when they were reported in the New England Journal of Medicine on September 17, 2015, and presented at the European Association for the Study of Diabetes in Stockholm, Sweden. As Inzucchi repeated Monday, the drug was shown to reduce CV-related deaths by 38% and death from any cause by 32%.²

Monday’s results stood in sharp contrast to the disappointing outcome of Sunday’s report on liraglutide. In the FIGHT trial, (Functional Impact of GLP-1 for Heart Failure Treatment), the glucagon-like peptide receptor agonist did its job in controlling blood sugar—and produced weight loss in patients with diabetes—but did not improve clinical stability or pumping action of the heart in patients with advanced heart failure.³

The unique mechanism of action of the sodium glucose co-transporter-2 inhibitor (SGLT2) plays a role in its cardioprotective benefit, Inzucchi explained. Like other drugs in this class, empagliflozin reduces renal glucose absorption by expelling it through the urine, resulting in significant reductions in glycated hemoglobin (A1C), weight loss, and reductions in blood pressure without increases in the heart rate.

A separate abstract being presented at the sessions on another SGLT2 inhibitor, canagliflozin, will highlight that drug’s benefits in improving blood pressure.⁴ There has been speculation that the cardioprotection results for empagliflozin will apply to other drugs in the SGLT2 class, but Inzucchi sounded a word of caution on this point. In other drug classes, researchers have been “burned” by assuming that a benefit found in the first drug would extend to others.

“It’s tempting to say it should be a class effect,” he said, noting that CV trials are under way for canagliflozin and dapagliflozin, which should be completed in the next 2 to 3 years. “So we’ll find out.”

Results. In the study, 7020 patients were randomized to receive 10 mg (n=2345) or 25 mg (n=2342) doses of empagliflozin or placebo (n=2333). The study drug was given in addition to standard of care. Study participants had type 2 diabetes and established CV disease, as well as a body mass index of 45 or less, A1C of 7% to 10%, and eGFR of at least 30 mL/min/1.73 m² (MDRD); as Inzucchi explained, the drug’s mechanism requires a basic level of renal function.

Nearly all patients (99.2%) had a history of CV disease: myocardial infarction 46.6%, coronary artery bypass grafting 24.8%, stroke 23.3%, and peripheral arterial disease 20.8%.

With its primary outcome already reported, today’s presentation focused narrowly on the differences between patients with heart failure at baseline and those without. Patients with heart failure (HF) at baseline taking placebo (n=244) were more likely to have adverse events (AEs), severe AEs, hospitalization for heart failure, and deaths than those with HF taking the study drug (n=462). The same was true with those who did not have heart failure at baseline (n=2089 taking placebo, n=4225 taking study drug); this group accounted for more trial participants.

In the chief measure of hospitalization for heart failure or CV death, among patients with baseline HF, 75 of 462 on the study drug had an event, while 49 of 244 on placebo had an event for a hazard ratio (HR) of 0.72 (0.50-1.04, 95% CI). Of the patients who did not have baseline HF, 190 of 4225 on the study drug had an event, while 149 of 2089 on placebo had an event for an HR of 0.63 (0.51-0.78, 95% CI).

Although it wasn’t known at the time, Inzucchi hinted at the empagliflozin results in June at the American Diabetes Association Scientific Sessions. Serving as a commentator on results of the CV outcomes trial of lixisenatide, which did not show a risk or a benefit, he said that if a diabetes drug were to show a cardioprotective effect, it would have achieved “the holy grail.”

References

1. Inzucchi S, Wanner C, Lachin JM, et al. Empagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus at high cardiovascular risk. Presented at the American Heart Association Scientific Sessions; Orlando, Florida; November 9, 2015; abstract 20238.

2. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes [published online September 17, 2015]. N Engl J Med. 2015; doi:10.1056/NEJMoa1504720.

3. Margulies KB, Anstrom KJ, Givertz MM, et al. A randomized trial of liraglutide for high-risk heart failure patients with reduced ejection fraction. Presented at the American Heart Association Scientific Sessions; Orlando, Florida; November 8, 2015; abstract 20102.

4. Townsend R, Machin I, Jen Ren J. Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment of canagliflozin in patients with type 2 diabetes mellitus and hypertension. Presented at the American Heart Association Scientific Sessions; Orlando, Florida, November 10, 2015; abstract T 2095.