Sympathomodulatory effects of sodium–glucose transporter-2 inhibitors in the kidneys and beyond

Sodium–glucose transporter-2 (SGLT-2) inhibitors have been introduced for the treatment of type 2 diabetes. At present, several compounds are registered. The SGLT transporters are located within the kidneys in the proximal tubules. Glucose is freely filtered by the glomerulus. Under normal conditions, SGLT transporters are responsible for the total reabsorption of glucose from the filtrate. The SGLT-2 couples sodium to glucose reabsorption and accounts for approximately 90% of glucose reabsorption and the SGLT-1 is responsible for the remaining 10%. Pharmacological blockade of the SGLT-2 effectively reduces plasma glucose. In a meta-analysis of 45 clinical trials, including over 11 000 patients SGLT-2 inhibitors reduced glycated hemoglobin by 0.79% [1]. Another meta-analysis shows large effects on relevant clinical endpoints, including cardiovascular outcomes and death [2]. Also the compounds affect relevant renal endpoints [3]. The modest improvement in glycemic control does not seem to be able to fully explain the magnitude and rapid onset of the effect on clinical endpoints. So, interest is increasing on what the effects of these inhibitors really are. Several effects, other than that on glycemic control, have been proposed. Clinical trials showed significant body weight reductions as compared to placebo. Osmotic diuresis, but also reduction in body fat mass, may account for this effect. Several trials have documented a modest reduction in both SBP and DBP. Both the osmotic diuresis and the reduction in sodium reabsorption, resulting in a decreased intravascular volume without increase in heart rate, are likely to contribute in that respect. Finally, SGLT-2 inhibitors induce a modest glomerular filtration rate decline within the first weeks of treatment. The presumed reduction in glomerular hyperfiltration is caused by an increase in afferent arteriolar tone, resulting in a reduction in intraglomerular pressure. Most studies have shown a substantial reduction in proteinuria. Current information on these effects was recently reviewed elsewhere [4]. In this issue of the Journal, Matthews et al.[5] present an interesting set of data. Their studies provide experimental evidence that: noradrenaline upregulates in-vitro SGLT-2 protein expression in human proximal tubule cells and in-vivo SGLT-2 inhibition reduced expression of tyrosine hydroxylase not only in the kidneys but also in the heart of mice on high-fat diet (representing a model for glucose intolerance). Tyrosine hydroxylase is used as a marker of sympathetic activation. So, this set of data provides evidence on a mechanism by which sympathetic overactivity may affect glucose metabolism, an association which has been known for years. It is tempting to speculate that the other way around could also be possible, that is that reduction of sympathetic activity improves glucose metabolism. For instance, some data suggest that renal denervation improves glucose tolerance/insulin sensitivity [6,7]. Another study could not confirm such an effect [8]. It is now clear that with the first generation of renal denervation devices, a highly variable and often incomplete denervation is obtained. The potential importance of renal denervation effects other than blood pressure reduction, suggests additional studies on the effects of renal denervation on glucose tolerance/insulin sensitivity should be done using the newer devices. The second set of findings suggests that variables of sympathetic activity are lowered by SGLT-2 inhibitor not only in the kidneys but also in the heart. This is very interesting information for several reasons. Type 2 diabetes is usually associated with increased sympathetic activity [9]. There is strong evidence to suggest that, as it happens in hypertension [10], this adversely affects cardiovascular and kidney prognosis in type 2 diabetes (and in other disease conditions) and that reduction is beneficial. Reduction of increased sympathetic activity may also help to understand the various effects of SGLT-2 inhibitors on the kidneys. Matthews et al.[5] showed that tyrosine hydroxylase staining in animals on high-fat diet was high but was reduced by SGLT-2 inhibition to levels comparable to those present in animals on regular chow. Also kidney noradrenaline levels were substantially reduced. It seems worth investigating whether a higher dose would even further reduce this. It is generally thought that SGLT-2 is uniquely expressed in the kidneys, whereas SGLT-1 is also active in other organs. So the present findings seem to suggest that this idea needs to be adjusted or modified, as they show that the high levels of tyrosine hydroxylase in the heart of mice on high-fat diet are partially reduced by SGLT-2 inhibition. Also tissue noradrenaline levels are reduced, although not significantly. In some way, SGLT-2 inhibition appears to affect heart tissue, at least in this experimental setting. It is certainly worth studying this effect in more detail. Subsequently and parallel to further experimental studies, studies in humans should address the hypothesis that SGLT-2 inhibition reduces sympathetic overactivity not only to the kidneys but also toward other organs, including the heart and systemic vasculature, using methodologies such as assessment of sympathetic nerve activity by microneurography and noradrenaline spillover techniques [11]. Different doses should be studied. The interaction with commonly used medication in this type of patients, especially renin–angiotensin system blockers needs to be taken into account. Given the separate mechanisms, it seems appropriate to hypothesize that effects occur separate from each other. Indeed, available clinical evidence shows that SGLT-2 inhibitors have their effects when added to standard treatment. Could this sympathoinhibitory effect of SGLT-2 inhibitors be of relevance in other disease conditions, also characterized by sympathetic overactivity, such as heart failure and renal insufficiency? At this stage, that question is difficult to answer. In type 2 diabetes, SGLT-2 is upregulated, so it may not be surprising that reduction of this upregulation has a detectable effect. Heart failure and kidney failure are often characterized by subtle dysregulation of glucose metabolism. It seems worth to evaluate what the effects are of SGLT-2 inhibition in disease conditions without overt dysregulation of glucose metabolism. In sum, the present experimental studies add relevant new information to the present understanding of possible mechanisms through which SGLT-2 inhibitors exert their beneficial effects in type 2 diabetes, apart from improving glucose levels per se. The present studies should be considered as a start of a series of forthcoming studies, both experimental and clinical, which address these mechanisms in more detail. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.