SGLT2 inhibitors may confer cardio-renal benefits through a central mechanism involving the reduction of epicardial adipose tissue (EAT), researchers proposed following a secondary analysis of the EMPA-TROPISM trial.
Nondiabetic study participants with heart failure with reduced ejection fraction (HFrEF) saw improvements on several cardiac MRI parameters after 6 months of empagliflozin (Jardiance) therapy atop standard medications:
- Reduced epicardial fat (EAT volume -5.14 mL vs -0.75 mL with placebo, P<0.05) and subcutaneous adipose tissue (-5.33 cm2 vs +9.13 cm2, P<0.05)
- Improvement in myocardial fibrosis (extracellular volume -1.25% vs +0.24%, P<0.01), with reductions in both matrix volume and cardiomyocyte volume
- Normalization of arterial stiffness (pulsed wave velocity -0.58 cm/s vs +0.60 cm/s, P<0.01)
Furthermore, these imaging findings were accompanied by a significant reduction in inflammatory biomarkers on proteomic analysis, reported Juan José Badimon, PhD, and colleagues of Icahn School of Medicine at Mount Sinai in New York City, in JACC: Heart Failure.
“These improvements in cardiovascular structure and function shed new light on potential additional mechanisms of action involved in the benefits of SGLT2 inhibition in patients with HFrEF regardless of their glycemic status. These data therefore reinforce the use of SGLT2 inhibitors in the treatment of patients with HFrEF independent of their diabetic status,” they concluded.
EAT, the visceral fat deposit under the visceral layer of the pericardium, is closely associated with inflammation, cardiovascular disease, and obesity, as well as coronary and myocardial function, according to Badimon’s group.
“This analysis suggests a potential central role of changes in EAT which further generates the promise of beneficial effects of SGLT2 inhibitors on other cardiac conditions, such as heart failure with preserved ejection fraction or atrial fibrillation,” commented Wilfried Mullens, MD, PhD, and Pieter Martens, MD, PhD, both of Ziekenhuis Oost-Limburg and University Hasselt in Genk, Belgium.
“The EAT shares a common blood supply with the myocardium, and no structures such as fascia separate the EAT from the myocardium. As a consequence, EAT-derived proinflammatory adipokines have a direct paracrine effect on the myocardium and have been shown to negatively influence cardiomyocyte function,” they noted in an accompanying editorial.
The large DAPA-HF and EMPERIOR-Reduced trials had proven that dapagliflozin (Farxiga) and empagliflozin, respectively, improve cardiovascular outcomes in HFrEF regardless of diabetes.
In the hunt for the mechanism underpinning such cardioprotection, the EMPA-TROPISM investigators reported that empagliflozin use in nondiabetic HFrEF patients is associated with normalizations in left ventricular (LV) volume, LV hypertrophy, and LV ejection fraction, as well as improvements in cardiopulmonary functional capacity and quality of life.
They had previously found that empagliflozin shifts myocardial metabolism from glucose to other more energy-efficient metabolites in a pig study.
All in all, it appears that “the glycosuric effects of SGLT2 inhibitors, in addition to inducing a negative caloric balance, alter the ratio of glucagon and insulin, leading to enhanced lipolysis. This results in a reduction of EAT, which is probably paralleled by a reduction in proinflammatory adipokines,” according to Mullens and Martens.
In addition, SGLT2 inhibitors have important diuretic effects that may contribute to their overall cardio-renal benefits, the pair said. “The long-term reduction in filling pressure with the use of an SGLT2 inhibitor would likely result in decongestion of the interstitium of the myocardium,” they explained.
EMPA-TROPISM investigators had 84 patients randomized to 6 months of empagliflozin 10 mg once a day or placebo. Participants had a mean age of 61.9, and 36% were women.
Patients underwent cardiac MRI at baseline and after 6 months.
In addition to the imaging findings, empagliflozin use was associated with greater reductions in weight, BMI, and waist circumference at the end of the study.
Badimon and colleagues acknowledged that their study was performed at a single center and limited by a small sample.
The editorialists criticized the use of T1 mapping alone to calculate interstitial myocardial fibrosis. “T2 mapping could have provided valuable information, because of changes in myocardial water content, about whether the observed changes in myocardial mass are related,” they suggested.
Moreover, it is unclear how sensitive the study findings are for missing data, according to Mullens and Martens.
The study was supported by a grant from Boehringer Ingelheim.
Badimon had no disclosures.
Mullens and Martens reported serving on advisory boards for AstraZeneca and Boehringer Ingelheim.