Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial

Abstract

BackgroundAsymptomatic left ventricular (LV) dysfunction is highly prevalent in type 2 diabetes patients. Unlike the other hypoglycemic drugs, SGLT2 inhibitors have shown potential benefits for reducing cardiovascular death and risk factors, aside from lowering plasma glucose levels. With this study we aim at determining whether the treatment with empagliflozin is associated with an improvement in LV functions in diabetic patients with asymptomatic LV dysfunction against Sitagliptin, which is presumably neutral on myocardial function. To determine changes in LV systolic and diastolic functions we will use speckle-tracking echocardiography, a novel sensitive, non-invasive, bedside method allowing the calculation of LV global longitudinal strain (GLS), an index of myocardial deformability, as well as 3D echocardiography, which allows a better evaluation of LV volumes and mass.MethodsThe EMPA-HEART trial will be a phase III, open label, active-controlled, parallel groups, single centre, exploratory study conducted in Pisa, Italy. A cohort of 75 diabetic patients with normal LV systolic (2D-Echo EF > 50%) and renal (eGFR sec MDRD > 60 ml/min/1.73 mq) functions and no evidence of valvular and/or ischemic heart disease will be randomized to either Empagliflozin 10 mg/die or Sitagliptin 100 mg/die. The primary outcome is to detect a change in GLS from baseline to 1 and 6 months after treatment initiation. The secondary outcomes include changes from baseline to 6 months in 3-D Echocardiography EF, left atrial volume and E/E′, VO2max as measured at cardiopulmonary test, cardiac autonomic function tests (R–R interval during Valsalva manoeuvre, deep-breathing, lying-to-standing), and the determination of a set of plasma biomarkers aimed at studying volume, inflammation, oxidative stress, matrix remodelling, myocyte strain and injury.DiscussionSGLT2 inhibitors might affect myocardial functions through mechanisms acting both directly and indirectly on the myocardium. The set of instrumental and biohumoral tests of our study might actually detect the presence and entity of empagliflozin beneficial effects on the myocardium and shed light on the mechanisms involved. Further, this study might eventually provide information to design a clinical strategy, based on echocardiography and/or biomarkers, to select the patients who might benefit more from this intervention. Trial registration EUDRACT Code 2016-0022250-10

<p>Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence</p>

“…31 Other RCTs investigating the effects of SGLT2i on LV remodelling in patients with T2D and HF are currently ongoing. 32,33 A RCT exploring cardiac effects of SGLT2i using impedance cardiography showed that 12 weeks of treatment with dapagliflozin had no significant effects on cardiodynamic parameters related to blood flow (stroke volume, cardiac output, cardiac index), systolic function (ejection fraction, acceleration and velocity indexes, systolic time ratio), circulatory function (systemic vascular resistance index), and fluid status (thoracic fluid content), compared to placebo. 34 Several possible mechanisms have been suggested to explain the beneficial effect of SGLT2i on cardiovascular outcomes, but not yet formally proven.…”

Impact of Diabetes Mellitus on Left Ventricular Longitudinal Function of Patients with Non-Ischemic Dilated Cardiomyopathy

“…Thus, GLS-guided management using antihyperglycemic drugs as well as cardioprotective drugs for DCM patients with T2DM at a given stage of HF, may be able to prevent progression to later HF stages and offer new insights into the management of DCM patients with T2DM. In fact, prospective studies are currently being conducted to examine the association of antihyperglycemic drugs such as sodium-glucose cotransporter 2 inhibitors or dipeptidyl peptidase-4 inhibitor with GLS in T2DM patients [32][33][34].…”

The effects of sodium‐glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions

“…There are currently ongoing clinical studies that are also utilizing cardiac magnetic resonance imaging to assess the effects of SGLT2 inhibitors on cardiac structure and function, as shown in Table . In addition, studies utilizing speckle‐tracking echocardiography for the measurement of global longitudinal strain and three‐dimensional echocardiography for more accurate quantification of LV structure in people with diabetes and normal LV ejection fraction are underway . Although these studies also involve a relatively small cohort of participants, they will be able to provide useful insights and hypotheses for further larger studies to be conducted in this area.…”