Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. While it has been theorized that SGLT2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine if SGLT2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Methods: Between April 2021 and January 2022, 169 individuals, 40-80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomized to empagliflozin (10 mg/day; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area (BSA) as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to baseline BSA and LV ejection fraction. Results: Among the 169 participants (141 men [83%], mean age 59.3 ± 10.5 years), baseline LVMi was 63.2 ± 17.9 g/m 2 and 63.8 ± 14.0 g/m 2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group vs. placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1,1.5 g/m 2 ) (P=0.74). Median baseline (IQR) NT-proBNP was 51 pg/mL (20, 105 pg/mL) and 55 pg/mL (21, 132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin vs. placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mmHg (-5.2, 2.6 mmHg) (P=0.52), 0.69 mmHg (-1.9, 3.3 mmHg) (P=0.60) and -6.1 pg/mL (-37.0, 24.8 pg/mL) (P=0.70) for systolic blood pressure, diastolic blood pressure and NT-proBNP, respectively. No clinically meaningful between group differences in LV volumes (diastolic and systolic indexed to baseline BSA) or ejection fraction were observed. No difference in adverse events was noted between the groups. Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, SGLT2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04461041clinicaltrials.gov Identifier: NCT04461041.