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

Abstract

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

Vascular regenerative cells in cardiometabolic disease

“…Notably, empagliflozin treatment also increased the frequency of circulating ALDH hi SSC low CD133 + cells previously associated with cardioprotective function. In the subsequent EMPA-HEART-2 study, conducted in individuals without T2D but with CV risk factors, empagliflozin for 6 months also induced a significant increase in ALDH hi SSC low CD133 + progenitor cells, and an increase in ALDH hi SSC mid CD163 + pro-vascular monocyte precursors and decreased ALDH hi SSC mid CD86 + CD163 − pro-inflammatory monocyte precursors [48,49 ▪▪ ,50]. This data indicated that SGLT2i therapy, independent of T2D status, mediated a beneficial increase in VR progenitor cell content.…”

SGLT2 Inhibitors’ Cardiovascular Benefits in Individuals Without Diabetes, Heart Failure, and/or Chronic Kidney Disease: A Systematic Review

“…Similar findings have been observed in individuals without DM. Connelly and colleagues’ RCT showed that 6‐month treatment with empagliflozin did not significantly reduce left ventricular mass index to body surface area in individuals without T2DM and significant HF ( p = .74) 63 . The follow‐up period and sample size may be inadequate to find significant changes.…”

“…Connelly and colleagues' RCT showed that 6-month treatment with empagliflozin did not significantly reduce left ventricular mass index to body surface area in individuals without T2DM and significant HF (p = .74). 63 The follow-up period and sample size may be inadequate to find significant changes. Given that approximately 25% of the patients in this trial had HF, we did not include it in the systematic review.…”

Impact of dapagliflozin on cardiac remodelling in patients with chronic heart failure: The DAPA‐MODA study

“…31 However, in a recent randomized controlled trial that involved patients at risk of HF, without diabetes or HF, empagliflozin did not demonstrate any significant impact on LV remodelling. 32 It has been suggested that cardiac anti-remodelling effects of SGLT2 inhibitors are particularly significant in patients with HF. 5 The DAPA-MODA study showed that dapagliflozin improved cardiac geometry by reducing LV dimensions and mass (−14%), leading to mild improvements in systolic function.…”

“…Indeed, in type 2 diabetic patients and LV hypertrophy, but not HF, dapagliflozin was associated with a reduction in LV mass 31 . However, in a recent randomized controlled trial that involved patients at risk of HF, without diabetes or HF, empagliflozin did not demonstrate any significant impact on LV remodelling 32 . It has been suggested that cardiac anti‐remodelling effects of SGLT2 inhibitors are particularly significant in patients with HF 5 .…”