Study design and participants
This was a prospective observational study conducted in a single-centre in Jerez de la Frontera (Spain). Patients were recruited from the endocrinology outpatient department. Fifty-two consecutive diabetic patients with at least 18 years of age and glycated haemoglobin level between 6.5% and 10.0% were prospectively included between November 2019 and April 2020. The exclusion criteria were: a history of type 1 diabetes mellitus, current SGLT2 inhibitor or glucagon-like peptide receptor agonist use, an estimated glomerular filtration rate < 45 ml/min/1.73 m2, acute coronary syndrome the last 2 months, previous cardiac surgery, pregnant women, New York Heart Association IV symptoms of heart failure, greater than moderate valvular disease, or suboptimal echocardiographic acoustic window.
Clinical decisions on medical management were made by the referring physician based on clinical data and co-morbidities at baseline visit, according to current recommendations .
Data collection and follow-up
Clinical, anthropometric, analytical and echocardiographic assessments were performed at baseline and after 6 months of follow-up. Arterial blood pressure was also estimated during the initial visit. According to the prescribed treatment at this point, patients were classified into SGLT2 inhibitors group or control group. The same sonographers, who were blinded to clinical data, baseline echocardiographic data and prescribed treatment, performed both echocardiographic examinations.
The primary outcome endpoint was the change in ventricular remodelling and function between initial and follow-up echocardiographic assessment.
Standard echocardiographic examination
Two-dimensional transthoracic echocardiographic and Doppler studies were obtained with clinical ultrasound machines equipped with 2.5 to 3.5 MHz transducers (iE33 Phillips Medical Systems, The Best, The Netherlands). All tests were conducted by two experienced sonographers, who were blinded to the clinical data and prescribed treatment. Baseline echocardiographic examination was performed during the first 7 days after inclusion to the study.
Left ventricular chamber dimension and wall thicknesses were measured, and left ventricular mass was calculated according to the American Society of Echocardiography guidelines . Left ventricular hypertrophy (LVH) was defined as indexed left ventricular mass of 95 g/m2 or greater for women and 115 g/m2 or greater for men . The relative wall thickness (RWT) was calculated as the ratio of posterior wall thickness/left ventricular diastolic radius, independently of the presence of LVH. A ratio of 0.42 or greater indicated concentric left ventricular geometry. End-diastolic and end-systolic left ventricular volumes were estimated and left ventricular ejection fraction (EF) was assessed by the modified Simpson’s Biplane Method. To assess diastolic function, the following mitral Doppler pulse and tissue Doppler variables were measured: early (E) and late (A) diastolic filling velocity, E/A ratio, septal (septal e’) and lateral (lateral e’) early mitral annular tissue velocity. We also calculated the E/e’ ratio.
According to LVVi (cut off value 75 mL/m2), LVMi (cut off value 115 g/m2 in men and 95 g/m2 in women), and RWT, patients were classified into 8 geometric patterns. Normal ventricle was considered as normal LVMi, normal LVVi, and RWT between 0.32 and 0.42. Dilated and hypertrophied ventricles were classified, according to RWT, as eccentric hypertrophy (RWT < 0.32), mixed hypertrophy (RWT > 0.42), or dilated hypertrophy (RWT 0.32–0.42). Nondilated ventricles with RWT > 0.42 are categorized as having concentric remodelling or concentric hypertrophy, based on the value of LVMi. Dilated ventricles with normal LVMi and RWT < 0.32 are described as eccentric remodelling. Patients were classified into 8 geometric remodelling patterns according to the end-diastolic left ventricular volume (LVV) (cut-off value 75 ml/m2), LVH and RWT  (Figure 1).
Myocardial strain was measured using Speckle Tracking echocardiography. To assess LV, longitudinal strain the endocardial and epicardial borders were traced in the apical two-, three- and four-chamber echocardiographic view on an end-diastolic frame. The software then automatically divided the myocardium into 17 segments. Peak systolic strain was estimated for each segment, and then GLS was calculated from the average of the 17 segments values. All images were stored electronically and LV strain was analyzed off-line with 2D Speckle Tracking software (QLab 10).
Data were expressed as mean ± standard deviation for continuous variables, and were compared using the unpaired t-test. Categorical variables were expressed as percentages and were compared using chi-square analysis or the Fisher exact test. Comparison of variables between baseline and 6 months after treatment were made using the paired test or Wilcoxon signed-rank test. Comparisons between changes in indexed LVM, GLS and other continuous variables were calculated by Pearson correlation.
Analyses followed an intention-to-treat approach, where all the patients were included in their corresponding group according to the initial prescribed treatment.
Differences were considered significant at p values<0.05. For data analysis, the statistical program SPSS version 20.0 (SPSS Inc., Chicago, Illinois) was used.