References

As shown in the previous talk, the treatment reduction of CV death by the SGLT2 inhibitor empagliflozin was significant and this occurred almost immediately after the start of therapy. These findings were very unexpected, according to Professor Sattar. In his presentation, he explained the thoughts about the proposed mechanism of action of empagliflozin before, and after the EMPA REG trial (10).

SGLT2 inhibitors were known to lower BP and arterial stiffness and to reduce sympatic nervous system activity, albuminuria, weight, visceral adiposity, oxidative stress, triglyceride, HDL and LDL levels, uric acid and most importantly, glucose and insulin levels. However, previously nothing was known about the haemodynamic benefits of empagliflozin. So what makes empagliflozin superior to other SGLT2 inhibitors regarding CV mortality reduction?

According to Sattar, this cannot be explained by the drop in haemoglobulin A1c levels, as this was comparable with that seen in other trials with SGLT2 inhibitors. Furthermore, it probably was neither a result of glucose reduction nor an effect of any other known associated mechanism. Furthermore, it does not look like an athero-thrombotic benefit, since there were no clear benefits observed for MI and stroke. In contrast, the pattern of change in HF and CV death by empagliflozin suggests an effect on the vascular system. Cardiac pre- and afterload may be reduced and renal function may be affected, which can thereby reduce extracellular fluid volume and cardiac pre-load. Moreover, it may effect cardiac metabolism such that the systolic and

diastolic function are enhanced.

*The observed CV benefit of empagliflozin is not just a diuretic effect*

More specifically, it is postulated that empagliflozin has a renal effect that improves hemodynamic factors and will then have a secondary benefit on the heart. This is proposed as follows: as SGLT2 inhibitors will block the reabsorption of glucose by the renal glomeruli, also sodium reabsorption will become blocked. Herein, glucose and sodium blood levels are lowered but sodium delivery is increased in the macula densa. In turn, this results in urinary excretion. Besides excretion, this also leads to restoration of the tubuloglomerular feedback and subsequent afferent

arteriole constriction. In diabetic patients, this normalises pressure in the glomeruli as well as the glomerular filtration rate.

However, regarding heart function, enhanced urinary excretion may decrease intravascular and extracellular fluid volume. This is indeed true as increased haematocrit values and reduced systolic blood pressures were observed during the EMPA REG OUTCOME trial. The consequences of decreased fluid volumes are a reduced cardiac pre- and afterload, increased myocardial oxygen supply and perhaps still unknown improved cardiac mechanisms. Also a reduced heart stress will improve systolic and diastolic dysfunction, and the likelihood of pulmonary congestion is reduced. Less cardiac stretch may lower the risk of fatal arrhythmic death. Remarkably, many risk factors of diabetic patients are associated with increase in body fluid and may thereby particularly increase the risk for HF.

The observed beneficial effect of empagliflozin is not just a diuretic effect. For example, the diuretic furosemide increases distal tubular sodium concentrations and will not normalise proximal tubular sodium reabsorption and thereby arterial constriction. BP reduction itself can also contribute to risk reduction of HF. Studies have shown that even a modest reduction in BP can yield quite a reduction in HF. In the SPRINT trial11, in which diuretics were used, BP was strongly decreased and the frequency of HF was reduced. However, in the EMPA REG trial, BP-lowering was

not as substantial. This means that BP itself reduces HF risk, but that this only partly explains the decreased risk of HF observed in the EMPA REG trial.

To conclude, the CV benefit of empagliflozin is probably predominantly due to its haemodynamic effects. However, it is not just a diuretic result but reduced glucose levels, weight loss and a better renal function probably also contribute to the treatment benefits.

References