Sodium/glucose cotransporter 2 (SGLT2) inhibitors have gained momentum in the last few years due to their therapeutic effectivity and the potential to reduce cardiovascular (CV) risks in type 2 diabetes [1, 2, 3].
The mechanisms involved in the improved risk profile observed seem to be a combination of several factors, including blood pressure reduction, increased sodium excretion, weight reduction and improved heart function .
SGLT2 inhibitors have consistently showed significant risk reduction of hospitalisation due to heart failure (HF), an observation that has been confirmed in the three major studies with these substances [1, 2, 3]. Moreover, the contribution of this effect is largely responsible for the improved CV risk shown in those studies.
A sub-analysis of the CANVAS trial showed that the risk reduction was greater in patients with history of heart failure . This observation has been confirmed in the studies with empagliflozin and dapagliflozin, shaping the starting point of additional studies in patients with HF without diabetes, with the possibility of extending the therapeutic indications of SGLT2 inhibitors. An example of this is the DAPA-HF trial, in which the effect of dapagliflozin on heart failure was investigated . This double blind, placebo controlled study included subjects with heart failure and ejection fraction below 40%. The primary outcome was a composite of worsening heart failure or cardiovascular death. A reduction in the primary outcome was confirmed in the dapaligliflozin group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). These results confirmed that subjects with HF without diabetes also benefited from SGLT2 inhibition.
SGLT2 inhibitors block the reabsorption of glucose and sodium in the proximal tubule, stimulating the osmotic diuresis effect . As a consequence, there is great reduction in the osmotic gradient between the tubular fluid and the interstitium, reducing the consequent absorption of water. The symptoms and signs of HF are largely a consequence of fluid accumulation in the interstitium, which leads to peripheral and pulmonary congestion. This is the reason why one of the aims in the treatment of HF is the reduction of fluid accumulation, and this is also why one of the cornerstones of HF treatment is the use of diuretics.
The diuretic effect of SGLT2 inhibitors appears valuable for subjects with reduced ejection fraction and tendency to volume overload. Data from experimental procedures suggest that SGLT2 inhibitors provide a great reduction in interstitial fluid volume, controlling effectively congestion . Importantly, the benefits for HF outcomes in the CANVAS trial appeared early after starting the treatment, also suggesting that the main mechanisms were the volume reduction and the hemodynamic effects . It seems that the maintenance of the renal function and the control of volume overload also help HF. Possibly, the use of ketone bodies as the substrate for myocardial energy generation might also contribute to the benefits observed.
Data seem to be conclusive and the benefits of the SGLT2 inhibition for HF are being confirmed. Having entered the market not long ago, SGLT2 inhibitors have changed the paradigms for treatment, not only in diabetes, but also in HF.