Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF

Abstract

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), yet underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between SGLT2i treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry-based profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis (PCA)-defined metabolite clusters that changed differentially with treatment, and also examined the relationship between change in metabolite clusters with change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Models were adjusted for relevant clinical covariates, and nominal p<0.05 with FDR-adjusted p-value<0.10 were used to determine statistical significance. Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short/medium-chain acylcarnitine PCA metabolite clusters compared with placebo (nominal p=0.01, FDR-adjusted p-value=0.08 for both clusters). However, ketosis (Β-hydroxybutyrate levels > 500 μM), was infrequently achieved (3 [2.5%] in dapagliflozin arm vs. 1 [0.9%] in placebo arm), and supraphysiologic levels were not observed. Conversely, increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in KCCQ scores (i.e. worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of SGLT2i in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with SGLT2i in patients with HFrEF. Reassuringly, only physiologic levels of ketosis were observed. Additionally, we identified several metabolic biomarkers associated with adverse HFrEF outcomes.

SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism

“…11 In addition, β-hydroxybutyrate suppresses the activation of the NLRP3 inflammasome, 12 inducing anti-inflammatory activity. Therefore, the metabolic switch toward KB metabolism seems adaptive and can act as a metabolic stress defense Selvaraj et al 1 shed more light on this hypothesis of SGLT2 inhibitor-induced metabolic switch and improved energetics. DEFINE-HF is a randomized, placebo-controlled trial investigating the effect of dapagliflozin on biomarkers, symptoms, and functional status in HFrEF.…”

“…However, the mechanisms of benefit of SGLT2 inhibitors on HF are not completely understood. In this issue of Circulation , Selvaraj et al 1 shed more light on the effect of SGLT2 inhibitors on myocardial energetic and fuel metabolism by leveraging targeted metabolomics in blood samples of the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction).…”

“…5,7 A previous study with targeted metabolomics had already hinted at increased FFA use. 13 The importance of the present analysis 1 involves its randomized, placebo-controlled trial design with a large sample size specifically in HFrEF (whereas the previous study 13 involved before-after intervention, no placebo arm, individuals with type 2 diabetes, and only 25 patients).…”

Pathophysiology and Management of Heart Failure in the Elderly

“…85 In the DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) trial, targeted metabolomics revealed that dapagliflozin affected key metabolic pathways involved in the pathogenesis of HFrEF, including ketone and fatty acid metabolism. 86 Similarly, empagliflozin use was associated with a lower risk of cardiovascular mortality and HF hospitalization than the placebo. 87…”

The Therapeutic Role of SGLT-2 Inhibitors in Acute Heart Failure: From Pathophysiologic Mechanisms to Clinical Evidence with Pooled Analysis of Relevant Studies across Safety and Efficacy Endpoints of Interest

“…However, other trials have documented that SGLT-2 inhibitors do not modify myocardial glucose uptake [44]. In the chronic HF setting, both experimental and human data have supported that SGLT-2 inhibitors shift myocardial fuel utilization from glucose towards the consumption of free fatty acids, ketone bodies and branched-chain amino acids, without an increase in the risk for significant ketosis, thus improving myocardial energetics, LV remodeling and function [45,46]. However, it remains unclear whether such an effect can be translated into significant clinical benefit for patients with acute HF.…”