Empagliflozin effects on cardiac remodeling: re-shaping the future of heart failure prevention

KEYWORDS:

• Empagliflozin
• cardiac remodeling
• type 2 diabetes
• diabetic cardiomyopathy
• heart failure
• cardiotoxicity

We read with interest the paper by Garcia-Ropero et al. [1] reporting improved speckle-tracking echocardiography findings in a non-diabetic porcine model of ischemic heart failure (HF) following the administration of empagliflozin 10 mg/day for 2 months compared with placebo. The authors [1] conclude that the results ‘may be related to a mitigation of adverse cardiac remodeling following ischemia reperfusion injury’ [1]. We would like to support their important findings with some relevant literature that probably could not be cited and discussed within the limitations of an original research paper [1].

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), has been reported to exert cardiorenal benefits [2–7]. Regarding its effects on cardiac remodeling, other animal studies have produced similar results. For example, empagliflozin (10 mg/kg/day) significantly improved cardiac parameters [i.e. ejection fraction (EF), fractional shortening, myocardial infarct size, heart weight] and protected from myocardial fibrosis and hypertrophy, in both non-diabetic and diabetic rats, 8 weeks after the induction of a myocardial infarction (MI) [8]. In non-diabetic mice with HF, treatment with empagliflozin (10 mg/kg/day) for 2 weeks resulted in maintaining stable cardiac systolic function by preventing EF reduction [9]. Empagliflozin-induced improvements in left ventricular (LV) structure (LV mass, dilatation and sphericity) and function (EF), as well as enhancement of myocardial work efficiency via the use of ketone bodies for energy production, were also reported in non-diabetic pigs [10]. Furthermore, administration of empagliflozin (10 mg/kg/day) for 4 weeks in diabetic rats led to significantly smaller LV end-diastolic diameters and shorter QT intervals, as well as to improved electrophysiological characteristics, Ca²⁺ regulation, Na⁺/hydrogen-exchanger and late Na⁺ currents [11]. These findings support a protective effect of empagliflozin against diabetic cardiomyopathy [11].

Empagliflozin may also preserve atrial function and prevent the incidence of atrial fibrillation (AF). In a rat diabetic model, empagliflozin (10 or 30 mg/kg/day, for 8 weeks) ameliorated left atrial electrical and structural remodeling parameters (i.e. interstitial fibrosis, diameter and mitochondrial biogenesis), the extent of attenuation being greater in the high-dose compared with the low-dose empagliflozin group [12]. Furthermore, the inducibility of AF incidence, as well as mitochondrial respiratory function and membrane potential were also improved by empagliflozin (non-significantly in the low-dose group and significantly in the high-dose group) [12].

Anticancer drugs may exert cardiotoxicity. In this context, within 6 weeks, empagliflozin attenuated doxorubicin-induced cardiotoxic effects in terms of preventing the deterioration of both systolic and diastolic LV function (assessed by EF, fractional shortening, E/Eʹ, longitudinal and circumferential strain) as well as the development of myocardial fibrosis in a non-diabetic mice model [13]. Further research is warranted in this field.

With regard to human data, Kang et al. [14] found that human cardiac myofibroblasts (in culture), in response to empagliflozin administration, were smaller, with fewer and shorter extensions, and with attenuated cell-mediated extracellular matrix remodeling; these benefits were greater with increasing concentrations of empagliflozin (0.5, 1 and 5 μmol/L). In this study [14] empagliflozin also significantly suppressed the gene expression of profibrotic markers (such as fibronectin, connective tissue growth factor, collagen and matrix metalloproteinases). These findings suggest a direct impact of empagliflozin on both phenotype and function of human cardiac myofibroblasts by preventing adverse cardiac remodeling [14]. Furthermore, in the EMPA-HEART CardioLink-6 trial, involving 97 patients with type 2 diabetes and coronary heart disease, empagliflozin 10 mg/day therapy for 6 months significantly reduced LV mass indexed to body surface area compared with placebo [15]. The ongoing Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction (EMMY) trial is evaluating the impact of empagliflozin on cardiac remodeling, as well as pre- and afterload reduction in both diabetic and non-diabetic patients with acute MI [16]. The results of this trial will further enlighten the cardioprotective mechanisms of empagliflozin.

The abovementioned data are of clinical importance taking also into consideration the recently published results of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) [17]. In this trial, empagliflozin (10 mg/day), for a median of 16 months, significantly (p < 0.001) reduced the primary endpoint [i.e. a composite of hospitalization for worsening heart failure (HHF) or cardiovascular death] by 25%, as well as HHF by 30%. The rate of the decline in estimated glomerular filtration rate was also reduced (absolute between-group difference: 1.73 ml/min/1.73 m²/year; p < 0.001) compared with placebo in 3,730 HF patients with reduced EF (i.e. ≤40%), irrespective of the presence or absence of diabetes [17].

Declaration of interest

NK has given talks, attended conferences and participated in trials sponsored by Astra Zeneca, Bausch Health, Boehringer Ingelheim, Elpen, Mylan, Novo Nordisk, Sanofi and Servier.

KK has given talks, attended conferences, acted as a consultant and participated in trials sponsored by Astra Zeneca, Boehringer Ingelheim, Eli-Lilly, Elpen, MSD, Novo Nordisk, Sanofi and Servier.

VK has given talks, attended conferences and participated in trials sponsored by Astra Zeneca, Boehringer Ingelheim, Elpen, Sanofi and Servier.