The landscape of novel antidiabetic drugs in diabetic HFpEF: relevant mechanisms and clinical implications

Abstract

As a heterogeneous syndrome, heart failure with preserved ejection fraction (HFpEF) has become the leading form of heart failure worldwide. Increasing evidence has identified that diabetes mellitus (DM) increases the risk of HFpEF. Worse still, the coexistence of both diseases poses a great threat to human health by further worsening the cardiovascular system and accelerating the progression of diabetes. Although several studies have indicated that the novel antidiabetic drugs, including sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase 4 inhibitors (DPP4i) provide the cardiovascular benefits in T2DM patients with HFpEF, the elaborated roles and mechanisms are not fully understood. In this review, we summarize the state-of-the-art evidence regarding the epidemiology and pathophysiology of diabetic HFpEF, and the landscape of the novel antidiabetic drugs in the treatment of diabetic HFpEF, as well as discuss the relevant mechanisms, aiming to broaden the understanding of diabetic HFpEF and gain new insight into the treatment of this disease.

Keywords: DPP4i; GLP-1 RA; HFpEF; SGLT2i; T2DM.

Fig. 1

The pathophysiology of DM with HFpEF. DM patients are accompanied with endothelial function injury, abnormal fatty acid metabolism and dysregulation of glucose metabolism. Among them, endothelial function injury leads to coronary microvascular dysfunction, myocardial fibrosis and sustained increase of ventricular filling pressure; abnormal fatty acid metabolism contributes to myocardial lipotoxicity, oxidative stress, and mitochondrial dysfunction; dysregulation of glucose metabolism results in an increase in reactive oxygen species (ROS), the activation of inflammatory pathways and reduction of cardiac energy efficiency, which ultimately prompts the development of HFpEF

Fig. 2

The mechanisms of novel antidiabetic drugs in diabetic HFpEF via inflammation, oxidative stress and lipotoxicity. Novel antidiabetic drugs could reduce inflammation, oxidative stress, apoptosis and lipotoxicity, by activating several signaling pathways, including AMPK/mTOR, AMPK/PGC-1α, Sirt1/AMPK, or by inhibiting certain signaling pathways, such as JAK/STAT, RhoA/ROCK, mTOR/HIF-1α and ROCK/PPARα pathway, ultimately improving diabetic HFpEF

Fig. 3

The relevant mechanisms of the novel antidiabetic drugs in diabetic HFpEF through mitochondrial dysfunction, autophagy and ferroptosis. Novel antidiabetic drugs mitigated mitochondrial dysfunction and ferroptosis, as well as promoted autophagy by activating Xc⁻/GSH/GPX4 axis and SIRT3-mediated autophagic pathway, or by inhibiting TGF-β/Smad pathway, ultimately improving diabetic HFpEF