Benefits of SGLT2 Inhibitor: Preventing Heart Failure and Beyond.

Main cause of death and the costliest complications in diabetic patients are highly associated with cardiovascular disease. Specifically, type 2 diabetes mellitus (T2DM) is a risk factor for developing heart failure (HF).

Sodium glucose cotransporter 2 (SGLT2) inhibitors have emerged as oral anti-diabetic drugs that reduce cardiovascular death or major adverse events in patients with diabetes. In the non-diabetic context, dapagliflozin and phlorizin did not reduce the infarct size; however, they attenuated oxidative stress and cardiac fibrosis after myocardial infarction (MI).1) Moreover, Canagliflozin Cardiovascular Assessment Study (CANVAS) also reported that canagliflozin reduced HF hospitalizations compared to placebo and the reductions in HF hospitalizations were more pronounced in patients with a history of HF.2)

Pre-specified secondary analysis of Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOM) showed that empagliflozin reduced new-onset HF and hospitalization with HF.3) In a rat metabolic syndrome model with pre-diabetes, empagliflozin reduced cardiac hypertrophy and fibrosis.4) In the EMPA-HEART CardioLink-6 study, treatment with empagliflozin resulted in a great reduction in cardiac mass and increased left ventricular ejection fraction.5) Moreover, empagliflozin was also shown to improve diastolic function and ameliorate cardiac hypertrophy and fibrosis in a mouse model with obesity.6) Recently, empagliflozin was reported to improve cardiac function in non-diabetic rats with left ventricular dysfunction after MI. Empagliflozin attenuated myocardial oxidative stress by reductions in advanced oxidation protein product and nicotinamide adenine dinucleotide phosphate oxidase 2, therefore, cardiac fibrosis and oxidative damage to mitochondrial DNA were reduced.7) These overall studies implicated that empagliflozin effectively attenuated left ventricular remodeling in patients with T2DM with HF.

How can inhibition of SGLT2 lead to such a striking cardioprotective effects in HF? The mechanisms of SGLT2 inhibitors contain inhibiting renal glucose reabsorption, improving insulin sensitivity and beta cell function. One of the possible explanations is that empagliflozin increases the plasma concentration of ketone bodies, which may improve efficiency of myocardial energy metabolism, and increases cardiac uptake of ketone bodies in HF patients compared with controls.8) Ketone bodies such as acetoacetate and β-hydroxybutyrate (βOHB) are alternative energy substrate in ischemic myocardium. Intriguingly, βOHB upregulates oxidative stress resistance factors, including forkhead box O3a (FOXO3a). In a pressure-overloaded HF mouse model, βOHB was elevated in response to oxidative stress in cardiomyocytes. Furthermore, βOHB upregulated superoxide dismutase 2 (SOD2) and catalase, both of which are targets of FOXO3a, and could contribute to cardioprotective effects.9)

In this issue of the Korean Circulation Journal, Oh et al.10) observed the cardioprotective effect of empagliflozin in both acute and chronic doxorubicin-induced HF models. More importantly, βOHB, increased in the blood by empagliflozin treatment, was identified as a critical mediator to reduce cardiomyocyte apoptosis, suppress the generation of intracellular reactive oxygen species, and improve mitochondrial function.10) A recent study demonstrated the modulation of circulating ketone levels may represent a novel therapeutic for treatment of HF. In HF patients, application of βOHB exerted beneficial cardiac effects in a dose-dependent manner without safety issues.11)

The understanding of how SGLT2 inhibitor might work is critical for future acceptance by clinicians to consider patients with high risk of developing HF. Overall, this novel avenue of research may set a new direction to SGLT2 inhibitor for promoting reverse remodeling in the failing heart.