How should we monitor the cardiovascular benefit of sodium–glucose cotransporter 2 inhibition?

Abstract

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are increasingly prescribed for the treatment of patients with type 2 diabetes to reduce the risk of cardiovascular events, including heart failure (HF). The mechanisms by which SGLT2 inhibitors reduce such risk are likely to be independent of diabetes status and improvement of glycemic control. In this commentary, based on recent mediation analyses of cardiovascular outcome trials with SGLT2 inhibitors, we discuss the prognostic role of a well-known HF-related biomarker, amino-terminal pro-B-type natriuretic peptide (NT-proBNP), in patients receiving SGLT2 inhibitors. Interestingly, the NT-proBNP concentration had a relatively small impact on the SGLT2 inhibitor-associated benefit on HF events, suggesting a limited value in measuring NT-proBNP concentrations to monitor effects on cardiovascular outcomes after initiation of SGLT2 inhibitor therapy. Instead, clinical factors, such as body weight and volume status, were prognostic for cardiovascular outcomes. As shown in some biomarker studies, short-term SGLT2 inhibitor treatment significantly improved volume and HF-related health status, despite the absence of a significant change in NT-proBNP concentration. Given the early and continuous risk reduction in HF events seen in the cardiovascular outcome trials with SGLT2 inhibitors, changes in these fundamental clinical parameters after initiation of SGLT2 inhibitor therapy, independent of NT-proBNP, could be more prognostic and could represent key determinants to identify responders or non-responders to SGLT2 inhibitors for cardiovascular outcomes. Thus, this commentary highlights the clinical importance of establishing how clinicians should monitor patients initiating SGLT2 inhibitor therapy to predict the expected cardiovascular benefit. Further detailed investigations and discussion to better understand this ‘‘black box’’ are urgently warranted.

Effect of canagliflozin on N-terminal pro-brain natriuretic peptide in patients with type 2 diabetes and chronic heart failure according to baseline use of glucose-lowering agents

“…Interestingly, a recent mediation analysis in the Canagliflozin Cardiovascular Assessment Study (CANVAS) program reported that the decrease in NT-proBNP concentration caused by treatment with a SGLT2 inhibitor was associated with a relatively small reduction in the risk of HF-related events [ 34 ]. Therefore, there is an urgent need to establish reliable markers for predicting or monitoring the cardiovascular benefits of SGLT2 inhibitors [ 35 ]. In this regard, changes in some fluid volume parameters indicative of a hemodynamic effect of SGLT2 inhibition are likely to be associated with clinical benefits [ 34 , 36 ].…”

Type 2 Diabetes and Myocardial Infarction: Recent Clinical Evidence and Perspective

“…Moreover, SGLT2 inhibitors have been used to treat patients with T2DM to reduce the risk of CV events, including HF, and it is clear that the mechanism by which SGLT2 inhibitors reduce this risk may not be directly related to improved diabetic status and glycemic control. In addition, short-term use of SGLT2 inhibitors significantly improved volume load and symptoms in HF patients with concomitant T2DM; however, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, which are traditionally used to assess HF severity, did not improve significantly, suggesting that we need to explore meaningful biomarkers that can monitor and evaluate the effect SGLT2 inhibitors for HF treatment in the future ( 55 ), in order to provide scientific evidence for in-depth understanding of the many unknowns of SGLT2 inhibitors.…”

Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts

“…Thus, the reduction of adverse cardiovascular outcomes suggests that SGLT2i may have plausible class effects on cardiorenal outcomes. Therefore, several theories of the mechanism of action of SGLT2i in heart failure have been postulated [11,12]. First, SGLT-2i could affect cardiovascular risk factors, such as improving the metabolic profile; reducing plasma glucose levels, blood pressure, and body weight; and modifying the lipid profile.…”