Empagliflozin Improves Cardiac Function, Exercise Capacity in Nondiabetic HFrEF

In patients with heart failure and reduced ejection fraction (HFrEF) who don’t have diabetes, empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) has broad effects on cardiac structure and function, exercise capacity, and quality of life, the small, single-center EMPATROPISM trial shows.

The findings, presented during the virtual American Heart Association 2020 Scientific Sessions and published online in the Journal of the American College of Cardiology, provide some mechanistic information to explain the benefits seen in larger trials of sodium-glucose co-transporter 2 (SGLT2) inhibitors—initially developed for the treatment of type 2 diabetes—in patients with HFrEF, regardless of diabetes status.

Specifically, LV end-diastolic and end-systolic volumes declined to a greater extent in the empagliflozin versus placebo group, LV mass was reduced, and peak oxygen consumption, 6-minute walk distances, and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores improved.

“So it’s not that you inhibit the progression of heart failure, but you can even regress the process,” Juan Badimon, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), principal investigator of EMPATROPISM, told TCTMD. “SGLT2 inhibition seems to be an alternative to the treatment of heart failure patients independently of whether there are or there are not diabetics.”

EMPATROPISM

When the trial was initially designed, consideration was not yet being given to using the SGLT2 inhibitors in patients without diabetes, but Badimon’s group had already seen promising results in a nondiabetic porcine model of heart failure. Since then, results of EMPEROR-Reduced with empagliflozin and DAPA-HF with dapagliflozin (Farxiga; AstraZeneca) have demonstrated a wide range of clinical benefits in HFrEF patients with and without diabetes. The results indicate that the improvements in clinical outcomes with these agents are not only related to reductions in hyperglycemia.

It’s not that you inhibit the progression of heart failure, but you can even regress the process. Juan Badimon

EMPATROPISM might help explain what else is contributing. For the single-center study, the investigators enrolled 84 nondiabetic patients (mean age 62 years; 36% women) who had NYHA class II or III heart failure, an LVEF below 50% (average 36%), and stable symptoms on medical therapy for the past 3 months. They were randomized to empagliflozin or placebo for 6 months.

The primary endpoint was change in LV volumes through 6 months as assessed by cardiac magnetic resonance imaging. Compared with placebo, empagliflozin led to greater reductions in LV end-diastolic volume (-25.1 vs -1.5 mL) and LV end-systolic volume (-26.6 vs -0.5 mL; P < 0.001 for both).

In addition, LV mass declined by 17.8 g in the empagliflozin group and increased by 4.1 g in the placebo group, whereas LVEF improved by 6% with active treatment and declined slightly, by 0.1%, with placebo (P < 0.001 for both). Empagliflozin improved both peak oxygen consumption during cardiopulmonary exercise testing (by 1.1 mL/min/kg) and 6-minute walk distance (by 81 m), outcomes that worsened in the placebo group. Moreover, KCCQ score increased by an average of 21 points (from 67.7 to 88.3) in the empagliflozin arm and by only 2 points (from 71.8 to 73.6) in the placebo arm.

“Reversing LV remodeling is an important factor in reducing mortality and morbidity in patients with heart failure,” the authors write in their paper. “In fact, short-term benefits on LV remodeling are associated with longer-term outcome improvements. Importantly, the ameliorated LV remodeling demonstrated in EMPATROPISM parallels the improvement in outcomes observed with DAPA-HF and EMPEROR-Reduced.”

Active treatment also led to improvements in oxygen uptake efficiency slope and LV sphericity (P < 0.001 for both) and a decline in plasma NT-proBNP (11.5% decrease with empagliflozin vs an 8.5% increase with placebo; P = 0.01).

In terms of safety, there were three serious adverse events with empagliflozin—one malignant ventricular tachycardia and two new cardiac device implants. That compares with eight in the placebo group—one CV death, one case of worsening heart failure, two new cardiac device implants, and two cases each of ventricular fibrillation and pleural effusion.

Reassurance for Prescribing Physicians

Commenting for TCTMD, Radha Gopalan, MD (Banner – University Medicine Heart Institute, Phoenix, AZ), credited the investigators for using MRI to measure changes in cardiac function and volumes with empagliflozin treatment.

That provides useful information for physicians considering prescribing the drug, he said, because what they want to know three main things: how the medication works, whether it improves disordered organ function, and how it affects clinical outcomes. The focus has typically been on the third factor because that’s what patients are most interested in, Gopalan said. But, he added, “as a clinician, you want to understand the mechanisms and what it does to the disordered organ. So for me, understanding a drug and how it affects the organ and whether it improves the organ function itself, in addition to the clinical outcomes, is way more reassuring in selecting medications.”

For me, understanding a drug and how it affects the organ and whether it improves the organ function itself, in addition to the clinical outcomes, is way more reassuring in selecting medications. Radha Gopalan

Asked whether he would expect to see similar findings with the other SGLT2 inhibitors, Badimon said it’s not clear in the absence of head-to-head trials. However, he postulated that the results seen in EMPATROPISM represent a class effect.

Speaking to the clinical implications, he said a mechanistic study like this provides information complementary to that obtained from the larger outcomes trials. “This really is showing you how these drugs work and that what we have seen in the clinical trials is not a fluke. It is real. Because what you do is you regress all the symptomatology associated with heart failure,” Badimon said.

He predicted that “this class of drugs is here to stay and very soon they will be used practically in all heart failure patients, independently of glycemic status, at least for the patients with reduced ejection fraction.” Additional studies are needed in patients with preserved ejection fraction, he said.