ELUCIDATE Trial: A Single-Center Randomized Controlled Study

Abstract

Background: Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, is an epochal oral antidiabetic drug that improves cardiorenal outcomes. However, the effect of early dapagliflozin intervention on left ventricular (LV) remodeling in patients with type 2 diabetes free from cardiovascular disease remains unclear.

Methods and results: The ELUCIDATE trial was a prospective, open-label, randomized, active-controlled study that enrolled 76 patients with asymptomatic type 2 diabetes with LV ejection fraction ≥50%, randomized to the dapagliflozin 10 mg/day add-on or standard-of-care group. Speckle-tracking echocardiography-based measurements of the cardiac global longitudinal strain were performed at baseline and 24 weeks after treatment initiation. Patients who received dapagliflozin had a greater reduction in LV dimension (1.68 mm [95% CI, 0.53-2.84]; P=0.005), LV end-systolic volume (5.51 mL [95% CI, 0.86-10.17]; P=0.021), and LV mass index (4.25 g/m^2.7 [95% CI, 2.42-6.09]; P<0.0001) compared with standard of care in absolute mean differences. Dapagliflozin add-on therapy led to a significant LV global longitudinal strain increment (0.74% [95% CI, 1.00-0.49]; P<0.0001) and improved LV systolic and early diastolic strain rates (0.27/s [95% CI, 0.17-0.60]; and 0.11/s [95% CI, 0.06-0.16], respectively; both P<0.0001) but not in global circumferential strain. No significant changes were found in insulin resistance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, or other biomarkers at 6 months after the dapagliflozin administration.

Conclusions: Dapagliflozin add-on therapy could lead to more favorable cardiac remodeling accompanied by enhanced cardiac mechanical function among patients with asymptomatic type 2 diabetes. Our findings provide evidence of the efficacy of dapagliflozin use for the primary prevention of diabetic cardiomyopathy.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871621.

Keywords: clinical trial; dapagliflozin; echocardiography; sodium–glucose cotransporter 2 inhibitors; type 2 diabetes; ventricular remodeling.

Figure 1. Study flow diagram.

Numbers of participants who were initially screened, randomized, and included in the final analysis (A). An illustration of GLS (right panel) and LVSR (left panel) measured using tissue Doppler imaging (B). eGFR indicates estimated glomerular filtration rate; GLS, global longitudinal strain; HbA_1c, glycated hemoglobin; HOMA‐IR, homeostatic model assessment of insulin resistance; LVMi, left ventricular mass index; LVSR, left ventricular strain rate; and NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.

Figure 2. Connected dot plots of LV mass index (A), GLS (B), LVSRe (C), and LVSRs (D).

Each line represents an individual experiment (N=38 in each group). The starting and end points are the performance of week 0 and week 24, respectively. GLS indicates global longitudinal strain; LV, left ventricular; LVMi, left ventricular mass index; LVSRe, left ventricular strain rate during early diastole; LVSRs, left ventricular strain rate during systole; and SOC, standard of care.

Figure 3. Changes in secondary outcome measures are shown over 6 months between groups.

(A) Change in fasting blood glucose; (B) change in glycated hemoglobin; (C) change in homeostatic model assessment of insulin resistance; (D) change in body mass index; (E) change in systolic blood pressure; and (F) change in hemoglobin. Bars represent the median with interquartile range (quartile 1–quartile 3). GLS indicates global longitudinal strain; LVMi, left ventricular mass index; LVSRe, s⁻¹, left ventricular strain rate during early diastole; LVSRs, s⁻¹, left ventricular strain rate during systole; and SOC, standard of care.