Left Ventricular Mass Reduction and Empagliflozin

Empagliflozin significantly lowered LVMi, systolic blood pressure, and diastolic blood pressure in patients with CAD and type 2 diabetes. 

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been established to provide cardiovascular benefit in type 2 diabetes patients, including being shown to reduce hospitalization in patients who have heart failure. A previous study found that the use of empagliflozin was associated with decreased left ventricular mass (LVM) indexed to baseline body surface area (LVMi). LVM is a strong predictor for cardiovascular events. Therefore, this study was conducted due to the EMPA-REG OUTCOME cohort to determine the effects of empagliflozin on LVM regression.   

This study (EMPA-HEART) was a double-blind, placebo-controlled, randomized investigator–initiated clinical trial. Patients had to have known type 2 diabetes, coronary artery disease (CAD), which included a history of myocardial infarction, and prior coronary  revascularization with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery (except having surgery in the last two months), an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m, and had been stable on antihyperglycemic agents (except for SGLT2i, glucagon-like peptide 1 receptor agonist, and saxagliptin) for two months preceding enrollment. Patients with heart failure (left ejection fraction of <30% and a New York Heart Association IV) were excluded.  Baseline visits included clinical and anthropometric assessments along with cardiac magnetic resonance imaging (cMRI). A 24- hour ambulatory blood pressure monitor was fitted to subjects. Subjects (97) were randomized to either 6-months of 10 mg empagliflozin daily or placebo in addition to standard of care. Subjects were followed-up for three visits over six months. The primary outcome was the change in LVMi from baseline to 6 months. The secondary outcome was the changes in LV end-diastolic volume (LVEDV) and -systolic (LVESV) volume and indexed to baseline BSA [LVEDVi and LVESVi, respectively]), LVEF and NT-proBNP. Regarding statistical analysis, ANCOVA was used for primary outcome analysis and NT-proBNP analysis. Additional sensitivity analysis was performed for baseline characteristics, alternative LVMi definitions, duration of treatment, scan quality, and LV hypertrophy presence.   

A total of 90 participants had data available for them. The mean duration of diabetes was over ten years; 94% of the patients were on metformin, and 25% were on insulin. About 80% of the patients had angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), lipid-lowering therapies, and antiplatelet therapies. Regarding the reduction of LVMi over six months, the adjusted difference was -3.4 g/m2 (-5.9, -0.8; P=0.01) from baseline in the empagliflozin group. No significant difference was observed in LVEF, LVESV, LVEDV, LVESVi, or LVEDVi. Subjects with a baseline of LVMi >60g/m2 showed greater LVMi regression (Pinteraction=0.007). Regarding systolic and diastolic blood pressure, there was an adjusted difference of – 6.8 (-11.2, -2.3 mmHg; P=0.003) in systolic blood pressure and -3.2 (-5.8, -0.6 mmHg; P=0.016) in diastolic blood pressure in the empagliflozin group after the six months. No significant difference was observed regarding heart rate or NT-proBNP. Regarding hematocrit, the adjusted difference was 2.3% (1.1%, 3.6%; P=0.0003) in the empagliflozin group. No cardiovascular events or deaths have occurred in the 6-month follow-up period.   

In conclusion, empagliflozin showed a significant reduction in LVMi and blood pressure (systolic and diastolic) in patients who had established CAD with type 2 diabetes. The mechanism of reducing LVMi is yet to be understood. Future studies should focus on establishing whether the addition of empagliflozin can produce benefit in patients with type 2 diabetes but without established CAD and larger sample size. The study’s limitations include small sample size, short follow-up period, possible confounding of medication changes during the study, higher male composition, exclusion of patients with chronic kidney disease, and recent heart failure exacerbations.  

Practice Pearls:  

• The addition of empagliflozin significantly lowered left ventricular mass indexed to baseline body surface area (LVMi), systolic blood pressure, and diastolic blood pressure in patients who had established coronary artery disease and type 2 diabetes; these patients were treated with guideline–driven therapies such as ACEi/ARB, antilipidemics, and antiplatelets.    
• Empagliflozin did not affect NT-proBNP levels and significantly increased hematocrit levels.    
• These data can be used to understand further the cardiovascular benefits that SGLT2 inhibitors provide for patients.   

Verma, Subodh, et al. “Effect of Empagliflozin on Left Ventricular Mass in Patients with Type 2 Diabetes and Coronary Artery Disease: Circulation, 2019  

Nour Salhab, Pharm.D. Candidate, USF College of Pharmacy