Effect of SGLT2 Inhibitors on Cardiac Structure Remodeling and Function

After years of attempted and failed therapies for heart failure, the introduction of SGLT2 inhibitors has been a significant breakthrough in the treatment of a disease that remains a massive public health challenge. SGLT2 inhibitors are guideline-directed medical therapy for patients with heart failure irrespective of diabetic status. While randomized controlled trials such as EMPEROR-Reduced and DAPA-HF have shown that SGLT2 inhibitors reduce all-cause mortality and cardiovascular death, the exact mechanisms behind these results are not well established. It is not known whether the SGLT2 inhibitors have an impact on the mechanism of adverse cardiac remodeling (ACR) seen in patients with heart failure. It is also not known whether the proposed mechanisms are a class effect or differ between SGLT2 inhibitors. This meta-analysis by Fan and Guo seeks to identify a link between the use of specific SGLT2 inhibitors and imaging parameters associated with ACR.

The authors analyzed 15 randomized controlled trials comprising 1343 patients, measuring the effect of SGLT2 inhibitors on echocardiographic and MRI measurements of cardiac structural remodeling. They found that in comparison to patients on non-SGLT2 inhibitor regimens, patients taking an SGLT2 inhibitor had improved heart rates, left atrial volume index, left ventricular mass index, left ventricular end systolic volume, E/e’ ratio, and ejection fraction. In comparison to other SGLT2 inhibitors, empagliflozin had a more significant impact on these measurements.

This study suggests that SGLT2 inhibitors are associated with reversal of ACR as measured by cardiac imaging. While this adds to the body of evidence linking these medications to parameters associated with heart recovery, examination of the forest plots demonstrates only modest changes in mean difference between groups. Parameters of congestion (pro-BNP and left ventricular end diastolic volume) were unchanged. There are likely competing mechanisms of benefit in heart failure, including improved energetics and ionic homeostasis in the myocardium, autophagy, and altered adipokine regulation. The suggestion that empagliflozin may be superior to other SGLT2 inhibitors in reversing cardiac remodeling is intriguing, but only hypothesis-generating given that it is derived from a subgroup analysis. Long term data from patients taking SGLT2 inhibitors will be essential in determining the significance and degree of alterations in cardiac remodeling and whether these effects differ between approved drugs in class.