Sodium glucose cotransporter 2 inhibitors: mechanisms of action in heart failure

Abstract

Diabetes is a key independent risk factor in the development of heart failure (HF) and a strong, adverse prognostic factor in HF patients. HF remains the primary cause of hospitalisation for diabetics and, as previous studies have shown, when HF occurs in these patients, intensive glycaemic control does not directly improve the prognosis. Recent clinical studies assessing a new class of antidiabetic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT2is) showed some unexpected beneficial results. Patients treated with SGLT2is had a significant decrease in both cardiovascular (CV) and all-cause mortality and less hospitalisations due to HF compared to those given a placebo. These significant clinical benefits occurred quickly after the drugs were administered and were not solely due to improved glycaemic control. These groundbreaking clinical trials' results have already changed clinical practice in the management of patients with diabetes at high CV risk. These trials have triggered numerous experimental studies aimed at explaining the mechanisms of action of this unique group of drugs. This article presents the current state of knowledge about the mechanisms of action of SGLT2is developed for the treatment of diabetes and which, thanks to their cardioprotective effects, may, in the future, become a treatment for patients with HF.

Keywords: Cardiovascular diseases; Diabetes; Heart failure; Sodium-glucose cotransporter 2 inhibitors.

Fig. 1

Mechanism of action of SGLT2is. The basic mechanism of action of SGLT2is is to inhibit the active transport of glucose by SGLT2 in the luminal surface of the S1 segment of the proximal renal tubule which is linked to Na⁺ transport maintained by its active extrusion. The latter process takes place with the participation of Na⁺/ATPase of the cell membrane. Under normal circumstances, in the glomeruli of the kidneys, large quantities, about 180 g/day, of glucose are constantly filtering into the primary urine. Then, it is reabsorbed in the proximal tubule with the participation of SGLT2 (90%) and to a lesser extent with the participation of SGLT1 (10%). SGLT2is significantly reduce glucose reabsorption from primary urine at the level of the proximal tubule and thus induce glucosuria, lowering plasma glucose concentration in a mechanism independent of insulin. Simultaneously with glucosuria, SGLT2 inhibitors intensify the excretion of sodium, which is cotransported with glucose and which, in turn, causes an increase in osmotic diuresis. This unique mechanism of SGLT2is action results in numerous non-glycaemic effects throughout the body. SGLT1 sodium-glucose cotransporter-1, SGLT2 sodium-glucose cotransporter-2, SGLT2is sodium-glucose cotransporter-2 inhibitors

Fig. 2

Disruption to the regulation of sodium and calcium concentrations in cardiomyocyte in HF. The intracellular regulation of both Ca²⁺ and Na⁺ concentration levels is disrupted in HF. Ca²⁺ and Na⁺ concentrations in the cardiomyocyte cytoplasm are significantly increased at this time. The transport of Ca²⁺ to SR with the participation of SERCA is interrupted. In addition, the loss of Ca²⁺ from SR by RYR increases. The increase in cytoplasmic Na⁺ concentration in cardiomyocytes in HF occurs, mainly, due to excessive SGLT1 expression, increased Na⁺ influx by Late I_Na and increased NHE and SMIT1 activity. The cytoplasmic Na⁺ overload observed in HF causes an increase in Ca²⁺ efflux from the mitochondria to the cytosol, which is mediated by NCLX. The intra-mitochondrial Ca²⁺ concentration is thus reduced, which causes the inhibition of the Ca²⁺ dependent upregulation of dehydgrogenases in the TCA cycle. This leads to a fall in NADH and NADPH production. Reducing the amount of NADH causes a decrease in ATP production and reducing the amount of NADPH results in disruption to the mitochondrial antioxidant defence system. SGLT2is have the ability to inhibit NHE and SMIT1 and thereby reduce the influx of sodium into cardiomyocyte increase during HF, decrease during HF. HF heart failure, SR sarcoplasmic reticulum, SERCA sarco/endoplasmic reticulum Ca²⁺-ATPase, RYR ryanodine receptors, SGLT1 sodium-glucose cotransporter-1, NHE sarcolemmal Na⁺/H⁺ exchanger, SMIT1 sodium–myoinositol cotransporter-1, Late I_Na late Na⁺ current, NKA Na⁺/K⁺ ATPase, NCX sarcolemmal Na⁺/Ca²⁺ exchanger, NCLX mitochondrial Na⁺/Ca²⁺ exchanger, MCU mitochondrial Ca²⁺ uniporter, TCA tricarboxylic acid cycle, NAD⁺ nicotinamide adenine dinucleotide (oxidised), NADH nicotinamide adenine dinucleotide (reduced), NADP⁺ nicotinamide adenine dinucleotide phosphate (oxidised), NADPH nicotinamide adenine dinucleotide phosphate (reduced), FAD flavin adenine dinucleotide (oxidised), FADH₂ flavin adenine dinucleotide (reduced), ETC electron transport chain, e⁻ electron, ATP adenosine triphosphate, ADP adenosine diphosphate, SGLT2is sodium-glucose cotransporter-2 inhibitors