Effect of Empagliflozin on Cardiac Function, Adiposity, and Diffuse Fibrosis in Patients with Type 2 Diabetes Mellitus

Abstract

Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, significantly improves cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that empagliflozin might have beneficial effects on cardiac function, structure, adiposity, and myocardial diffuse fibrosis. This prospective study enrolled 35 patients (48.6% men, age 63.5 ± 9.7 years) with type 2 diabetes mellitus (T2DM) from June 1, 2017, to November 31, 2018. The patients received an SGLT2 inhibitor (empagliflozin 25 or 12.5 mg/d) for 6 months in addition to stable oral hypoglycaemic treatment. All patients underwent cardiac magnetic resonance imaging (CMRI) before and after empagliflozin treatment. Left ventricular (LV) function and structure were quantified using cine CMRI. Cardiac adiposity was defined based on pericardial fat and intracardiac triglyceride contents, whereas myocardial diffuse fibrosis was indicated by extracellular volume (ECV). The statistical significance of parameter changes was assessed using paired t-test and stepwise multiple linear regression. There were no significant differences in LV function and structure changes. Cardiac adiposity and diffuse fibrosis indices were also not different before and after empagliflozin treatment. Concerning clinical parameters, only a significant decrease in systolic blood pressure (by 6.4 mmHg) was observed (p = 0.013). Stepwise multiple linear regression revealed that worse baseline MRI parameters were associated with better improvements. Intracardiac triglyceride content decrease was inversely associated with baseline intracardiac triglyceride content (p < 0.001). Pericardial fat changes were negatively correlated with baseline pericardial fat (p < 0.001) and ECV changes (p = 0.028). ECV changes were inversely associated with baseline ECV (p < 0.001), baseline LV ejection fraction (p < 0.001), and LV mass index changes (p = 0.020). This study demonstrated that 6 months of empagliflozin treatment did not significantly improve the LV function, structure, adiposity, and diffuse fibrosis in patients with T2DM. Further, the beneficial effects of empagliflozin treatment might be more evident in patients with worse baseline LV substrate and structure.

A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study

“…Moreover, myocardial triglyceride content was unaffected despite its baseline value being higher in our subjects than in healthy Japanese subjects [ 37 ] or patients with left ventricular hypertrophy [ 38 ]. This result is consistent with that of a previous one-arm study showing that 6 months of empagliflozin treatment did not impact myocardial triglyceride content [ 45 ]. Considering that no clinical studies have assessed the effect of DPP-4 inhibitors on myocardial triglyceride content or compared the effects of SGLT2 inhibitors and DPP-4 inhibitors on cardiac lipid levels, this is the first study to show that SGLT2 inhibitors and DPP-4 inhibitors do not affect pericardial fat accumulation or myocardial triglyceride content at the early-stage of T2DM.…”

Sodium glucose cotransporter‐2 inhibitor was associated with an improvement in left ventricular systolic function in patients with type 2 diabetes mellitus with impaired left ventricular systolic function

“…The discrepancy between our findings and those of previous studies might be attributed to the different study populations and increased severity of baseline heart function impairment in our study (27% of patients with an impaired baseline LVEF <50%). Nevertheless, our results are in accordance with the recent study showing that patients with T2DM with worse baseline characteristics benefit more from the SGLT2i treatment 17 . Recently, the subgroup analysis of the DECLARE–TIMI 58 indicated that SGLT2i with dapagliflozin reduced the risk of cardiovascular death or heart failure hospitalization to a greater extent in 671 patients with reduced baseline LVEF (LVEF <45%) than in those without reduced LVEF.…”

“…Nevertheless, our results are in accordance with the recent study showing that patients with T2DM with worse baseline characteristics benefit more from the SGLT2i treatment. 17 Recently, the subgroup analysis of the DECLARE-TIMI 58 indicated that SGLT2i with dapagliflozin reduced the risk of cardiovascular death or heart failure hospitalization to a greater extent in 671 patients with reduced baseline LVEF (LVEF <45%) than in those without reduced LVEF. This difference was driven by large reductions in cardiovascular death and all-cause mortality in patients with reduced LVEF.…”

Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study

“…showed that improvement of diastolic function could be mediated by reduced spontaneous diastolic sarcoplasmic reticulum calcium release, independently of changes in cardiac ketone metabolism [ 39 ]. Our results are consistent with the open-label trial of Hsu et al ., who found no effect of 6 months of empagliflozin treatment on LV function, pericardial myocardial fat, myocardial fibrosis or LV mass [ 34 ]. Likewise, this study reported no effect of empagliflozin on myocardial triglyceride content at 12 weeks.…”