Treatment with empagliflozin in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF) may bring about significant improvements in left ventricular (LV) volumes, LV mass, and LV systolic function, as well as in functional capacity and quality of life (QoL), according to results from the Are the “Cardiac Benefits” of Empagliflozin independent of Its Hypoglycemic Activity (EMPA-TROPISM) trial.
The findings, which were published in the Journal of the American College of Cardiology, strongly support the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the treatment of these patients, according to EMPA-TROPISM researchers.
Empagliflozin is an antihyperglycemic agent, classified as a sodium glucose cotransporter-2 inhibitor (SGLT2i), that is approved for the treatment of type 2 diabetes. Previous large clinical trials have documented the early and significant benefits of SGLT2i treatment in patients with diabetes and HFrEF.
“In patients with type 2 diabetes, sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce the risk of hospitalization for heart failure by 30% to 35% and improve cardiac outcomes. The recent clinical trials DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) have expanded these heart failure benefits of SGLT2i to the realm of patients with HFrEF,” according to Carlos G. Santos-Gallego, MD, of Mount Sinai Hospital, New York City, and fellow researchers.
In this single-site, double-blind, placebo-controlled study, these researchers randomized 80 nondiabetic patients (mean age: 62 years; 64% male; 50% Hispanic/Latino) with HFrEF to treatment with empagliflozin (10 mg/d) or placebo for 6 months. They sought to assess the efficacy of empagliflozin on left ventricular (LV) function and volume, functional capacity, and QOL.
At baseline, patients underwent clinical assessment, anthropometric measurements, 6-minute walk test (6MWT), and the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Their cardiac function was assessed with cardiac MRI, and maximal exercise capacity via cardiopulmonary exercise testing (CPET). At baseline, 88% of patients were concomitantly being treated with beta-blockers, 75% with statins, 65% with antiplatelet therapy, and 55% with loop diuretics. Patients were assessed at 5 visits over 6 months.
After 6 months, empagliflozin was associated with significant reductions in LV end-diastolic volumes compared with placebo (−25.1 vs −1.5 ml, respectively; P˂ 0.001) and LV end-systolic volume (−26.6 vs −0.5 ml; P˂ 0.001), as well as with reductions in LV mass (−17.8 v 4.1 g, respectively; P ˂ 0.001) and LV sphericity, and improved LVEF (6.0 vs 3.9; P˂ 0.001).
Empagliflozin also led to significant improvements in peak O2 consumption compared with placebo (1.1 vs −0.5 ml/min/kg, respectively; P=0.017), oxygen uptake efficiency slope (111 vs −145; P ˂ 0.001), and 6MWT (81 vs −35 m; P ˂ 0.001), and QoL (21 vs 2; P ˂ 0.001).
“The main findings of the EMPA-TROPISM trial are that empagliflozin administration to nondiabetic HFrEF patients is associated with reverse LV remodeling, reduction in LV volume, decrease in LV hypertrophy, improvement in LVEF, and a less spherical LV with less pronounced architectural remodeling, as compared with placebo,” wrote Santos-Gallego et al.
“Of utmost importance, empagliflozin-treated patients exhibited improvement in functional capacity (using both maximal exercise in CPET and submaximal exercise in 6MWT) and increase in QoL compared with the placebo arm. Our observations suggest that SGLT2i could become a new therapeutic strategy for the treatment of HFrEF patients independently of their diabetic status,” they concluded.
Lee R. Goldberg, MD, of The University of Pennsylvania, Philadelphia, explained the importance of studies like EMPA-TROPISM in unearthing new uses for older treatments.
“Nearly every therapeutic agent has effects that are beyond their initially intended targets. When these effects are negative, we refer to them as adverse or side effects, but when they are beneficial, we refer to them as pleiotropic effects. Pleiotropic effects are usually unanticipated and typically are not among the pre-specified observations in the initial clinical trials of therapeutics under investigation. Within cardiology, both adverse events and pleiotropic events have been observed either ending the widespread use of a compound or intervention or substantially expanding or spawning a new therapeutic class. This is the story of the SGLT2 inhibitors. SGLT2 inhibitors are a newer class of drugs where novel and unexpected pleiotropic effects have substantially expanded their role well beyond the initial intended population,” Goldberg wrote in an accompanying editorial.
He also commented on the value of these results from Santos-Gallego and colleagues:
“Documenting positive cardiac structural change induced by this class of drugs validates the previously observed improvements in cardiovascular outcomes. Positive left ventricular remodeling has been associated with improved outcomes in HFrEF across a variety of pharmacological and device interventions. The fact that positive remodeling was seen in addition to appropriate background neurohormonal blockade is remarkable as most of these agents, themselves, promote positive remodeling. These observations, therefore, are another piece in the puzzle of understanding the mechanism of SGLT2 inhibitor action on myocardial and vascular structure and function,” he wrote.
Goldberg added, however, that limitations of this study include the effects of ventricular loading conditions and intravascular volume on cardiac MRI measurements of LV function measurement and volumes, the infrequent use of loop diuretics by these patients, and the large number of patients who did not complete cardiopulmonary exercise testing.
Santos-Gallego and colleagues noted that other limitations of the EMPA-TROPISM study include the small number of patients and the inclusion of only those with HFrEF.
Nevertheless, Goldberg concluded, these results add to what is known about SGLT2 inhibitors and their beneficial effects on cardiac function.
“The story of the ongoing development of the SGLT2 inhibitor class continues to unfold. The surprising pleiotropic effects that have led to improved cardiovascular morbidity and mortality will likely be the most impactful for this class of agents. Improvements in the structure and function of the myocardium validate the outcomes trials and shed some light on potential mechanisms of action,” he concluded.
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The SGLT2 inhibitor, empagliflozin, was effective in improving left ventricular (LV) volumes, mass, and systolic function, as well as functional capacity and quality of life in patients with heart failure with reduced ejection fractions (HFrEF).
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Researchers of the EMPA-TROPISM study concluded that their results “strongly support” the use of SGLT2 inhibitors in the treatment of HFrEF.
E.C. Meszaros, Contributing Writer, BreakingMED™
This study was supported by Boehringer Ingelheim.
Santos-Gallego reported no disclosures.
Goldberg has received research grants and consulting fees from Respircardia and consulting fees from Abbott.
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Topic ID: 74,3,730,3,187,192,925
