Potential mechanisms responsible for cardioprotective effects of sodium-glucose co-transporter 2 inhibitors

Abstract

Diabetes mellitus currently affects over 350 million patients worldwide and is associated with many deaths from cardiovascular complications. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs with cardiovascular benefits beyond other antidiabetic drugs. In the EMPA-REG OUTCOME trial, empagliflozin significantly decreases the mortality rate from cardiovascular causes [38% relative risk reduction (RRR)], the mortality rate from all-causes (32% RRR) and the rate of heart failure hospitalization (35% RRR) in diabetic patients with established cardiovascular diseases. The possible mechanisms of SGLT-2 inhibitors are proposed to be systemic effects by hemodynamic and metabolic actions. However, the direct mechanisms are not fully understood. In this review, reports concerning the effects of SGLT-2 inhibitors in models of diabetic cardiomyopathy, heart failure and myocardial ischemia from in vitro, in vivo as well as clinical reports are comprehensively summarized and discussed. By current evidences, it may be concluded that the direct effects of SGLT-2 inhibitors are potentially mediated through their ability to reduce cardiac inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ionic dyshomeostasis.

Keywords: Diabetes mellitus; Heart; Sodium–glucose co-transporter 2 (SGLT-2) inhibitors.

Fig. 1

Potential mechanisms responsible for cardioprotective effect of SGLT-2 Inhibitors. From current evidence from both in vitro or ex vivo experiments, SGLT-2 inhibitors have been demonstrated that they could have direct cardiac effects on inflammation [63], oxidative stress [65], and ionic dyshomeostasis [116]. Although the effects of SGLT-2 inhibitors on the attenuation of apoptosis and mitochondrial dysfunction could be direct cardiac effects [59, 62, 64], they have not been proved by either in vitro or ex vivo experiments. Italics indicate the mechanisms have not been proved by either in vitro or ex vivo experiments. SGLT-2 sodium–glucose co-transporter 2, NLRP3 nucleotide-binding oligomerization domain-like receptor 3, IL interleukin, STAT3 signal transducer and activator of transcription 3, ERS endoplasmic reticulum stress, Bcl-2 B cell chronic lymphocytic leukemia/lymphoma-2, Bax Bcl-2-associated X, PGC1-α peroxisome proliferator-activated receptor gamma coactivator 1-alpha, CPT1 carnitine palmitoyltransferase 1, ROS reactive oxygen species, NHE Na⁺/H⁺ exchange, [Na⁺]_c cytoplasmic Na⁺ concentration, [Ca²⁺]_c cytoplasmic Ca²⁺ concentration, [Ca²⁺]_m mitochondrial Ca²⁺ concentration, SERCA2a sarcoplasmic endoplasmic reticulum Ca²⁺-ATPase, I/R ischemic/reperfusion