SGLT2 inhibitor dapagliflozin treats heart failure with preserved ejection fraction via the SIRT1/PGC-1α pathway

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated clinical benefits in heart failure with preserved ejection fraction (HFpEF), yet the underlying mechanisms remain poorly defined. Given that mitochondrial dysfunction represents a central feature of HFpEF pathophysiology, we investigate whether modulation of mitochondrial homeostasis contributes to the cardioprotective effects of dapagliflozin. Using a Dahl salt-sensitive rat model of HFpEF, we find that dapagliflozin markedly improves diastolic function and attenuates cardiac hypertrophy, fibrosis, and apoptosis. These beneficial effects are accompanied by significant restoration of mitochondrial structure and function. Consistently, in an in vitro HFpEF model, dapagliflozin enhances mitochondrial respiratory capacity in cardiomyocytes, indicating a direct mitochondrial regulatory effect. Mechanistically, integrative transcriptomic and experimental analyses identify the SIRT1/PGC-1α/Mitofusin-2 (Mfn-2) signaling axis as a critical pathway suppressed in HFpEF but reactivated following dapagliflozin treatment. Activation of this pathway promotes mitochondrial biogenesis and improves mitochondrial dynamics, thereby preserving cardiomyocyte homeostasis. Collectively, our findings reveal that dapagliflozin exerts cardioprotective effects in HFpEF by restoring mitochondrial homeostasis through the SIRT1/PGC-1α/Mfn-2 axis, providing mechanistic insight into SGLT2i-mediated benefits and highlighting mitochondrial regulation as a potential therapeutic strategy for HFpEF.

1. Introduction

Heart failure (HF), characterized by its complexity and heterogeneity, is a major global health concern [1]. Heart failure with preserved ejection fraction (HFpEF, EF ≥50%) accounts for approximately half of all HF cases, significantly impacting quality of life and increasing healthcare burdens [2]. With the aging global population, HFpEF is expected to become the most prevalent form of HF [3]. Despite its increasing incidence, effective treatment options remain limited. However, recent clinical trials on sodium-glucose cotransporter 2 inhibitors (SGLT2is) have provided promising therapeutic prospects [4–7].

Dapagliflozin, an SGLT2 inhibitor, is a novel antidiabetic drug that has demonstrated unexpected benefits for HFpEF patients [8]. The DELIVER trial reported an 18% reduction in cardiovascular death or worsening heart failure in HFpEF patients, along with a significant improvement in the quality of life and extended event-free survival [8]. The PRESERVED-HF trial showed that dapagliflozin rapidly improved symptoms and physical activity in HFpEF patients within 12 weeks, although its precise molecular mechanism remains unclear [9]. The risk factors of HFpEF include diabetes, obesity, hypertension, and aging [10], with mitochondrial dysfunction being a common pathological feature. Therefore, investigating the role of mitochondria in HFpEF, particularly in mitochondrial biogenesis pathways, represents a promising research direction [11].