Sodium Glucose Cotransporter-2 Inhibitors Protect The Cardiorenal Axis: Update On Recent Mechanistic Insights Related To Kidney Physiology Ⅱ

5. SGLT2 inhibition: changes in kidney physiology driving cardiovascular outcomes? 

As stated above, the beneficial effects of SGLT2 inhibition on 3- MACE as well as heart failure outcomes were largely unexpected. Not surprisingly, the mechanism(s) that drive(s) these CV benefits are uncertain and have led to a wide range of hypotheses that have been reviewed elsewhere (e.g. [41,49,50]). A central hypothesis is based on SGLT2 inhibitor-induced volume contraction, as mediation analyses from the EMPAREG OUTCOME study showed that hematocrit was the best predictor for CV benefit [51]. Increased hematocrit has been proposed to serve as a marker for plasma volume. In line, it was shown using radioactively labeled albumin, that dapagliflozin increased plasma volume [52]. The theory is that this volume contraction is secondary to increased natriuresis. Two earlier studies indeed showed a transient, but small increment in urinary sodium excretion following SGLT2 inhibition, however, there was control for dietary sodium intake [53,54]. In healthy volunteers with a fixed sodium diet (110 mmol/day), dapagliflozin induced a small transient (day 1; 20 mmol) increment in natriuresis, which was much lower than the sodium excretion induced by bumetanide [55], a drug that is not known to increase hematocrit. A limitation here was uncontrolled fluid intake and low compliance to sodium tablets which can cause nausea and vomiting. In people with heart failure, two studies showed minimal effects of SGLT2 inhibition on markers of sodium homeostasis. Griffin et al. reported increments in fractional sodium excretion (24 h urine not collected, no fixed sodium intake) [56], while in contrast no change in 24 h sodium excretion was shown by Mordi et al. In the latter study, an increment in urinary volume was observed, however, this is difficult to interpret as sodium and fluid intake was not monitored [57]. In the recent DAPASALT study, people with T2D and normal kidney function were given a standardized diet (150 mmol/day), and urinary volume and natriuresis were carefully monitored using multiple 24 h urine collections [58]. Dapagliflozin overall did not change 24-hour urine and sodium excretion, although a small increment in sodium excretion was seen in the first day of treatment. Glucose excretion on the other hand was strongly increased while increased fractional lithium excretion confirmed inhibition of proximal tubular function. Plasma volume was not significantly decreased during treatment but was increased following cessation. Despite these minor effects on natriuresis and plasma volume, systolic blood pressure was reduced by 6 mmHg, indicating that other factors mediate SGLT2 inhibitor-induced blood pressure reduction. 

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The kidneys are able to adapt to (drug-induced) changes in tubular physiology enabling them to maintain sodium and water balance. From that point of view, it is unlikely that SGLT2 inhibitors lead to prolonged urinary sodium and water loss. Although there is ongoing inhibition of proximal tubular function and glycosuria, urinary volumes are mostly kept constant through a number of mechanisms. First, SGLT2 inhibitors activate RAAS resulting in distal sodium retention, second, SGLT2 inhibitors reduce free water clearance and increase copeptin secretion and third, may conserve water through urea metabolism [43,59]. Clinical observations that raise questions marks with volume contraction by SGLT2 inhibitor treatment and its effect on CV outcomes include (1) no influence of baseline eGFR on CV effects [23,24,60] and (2) and the only mildly lower NT-proBNP concentrations that are observed during SGLT2 treatment also seem to play a minor role [61]. Indeed several other mechanisms have been proposed to underlie the beneficial CV effects of SGLT2 inhibitor treatment, such as mitochondrial dysfunction, reduced oxidative stress, reduced activity of sodium-hydrogen exchanger isoform 3 (NHE3) and altered myocardial substrate metabolism [62]. An additional interesting observation is that despite reductions in blood pressure and debated hemoconcentration, there is no reciprocal heart rate increment with SGLT2 inhibition. Mechanistically, this may be caused by inhibition of SLGT2 of the sympathetic nervous system as shown in elegant rodent studies [63]. This may set the SGLT2 drugs apart from conventional diuretics. 

To summarize, the role of changes in kidney sodium handling induced by SGLT2 inhibitors remains enigmatic, in particular its contribution to CV protection that is observed with SGLT2 inhibition. A factor herein is the lack of larger studies that have measured (not estimated) plasma volumes and have conducted rigorous trials where sodium balance is measured across different populations such as heart failure and DKD patients. The reasons why hematocrit is elevated during SGLT2 treatment is currently unclear and could also relate to erythropoiesis as discussed above. 

6. Areas of ongoing research 

Several clinical trials are currently ongoing with respect to SGLT2 inhibition. An important question is how SGLT2 inhibition combines with other (potential) kidney protective agents. In the conducted outcomes trials, SGLT2 inhibitors were initiated on top of the RAAS blockade. Therefore, the interaction between these drugs remains poorly studied. Two studies have recently been completed in people with type 1 and type 2 diabetes which investigated the interactions between RAAS blockers and SGLT2 inhibitors [NCT04238702; NCT02632747] (Table 2). In addition, the novel mineralocorticoid receptor antagonist (MRA) finerenone was recently shown in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial, to reduce CKD progression in people with type 2 diabetes [64]. However, MRA has the side effect of hyperkalemia, limiting its use. In this light, it is interesting to note that SGLT2 inhibitors lower the risk for hyperkalemia, without inducing hypokalemia risk [65]. The interaction between finerenone and SGLT2 inhibitors is currently ongoing to assess their combined clinical effects and safety profile. 

In recent years, the glucagon-like peptide (GLP-1) receptor agonists, which lower blood glucose levels through stimulation of insulin secretion, reduction of glucagon production, reduction of gastric emptying, and increased satiety, have been shown to reduce albuminuria in people with type 2 diabetes [66]. The current FLOW study [NCT03819153] is ongoing to investigate the effects of GLP-1 receptor agonists on kidney outcomes in people with type 2 diabetes, many of which will also be treated with SGLT2 inhibitors, allowing to study their interaction. 

Finally, endothelin-receptor agonists (ERA) have been shown to improve kidney outcomes, however, at the expense of increased fluid retention, edema and congestive heart failure [67]. It may be hypothesized that SGLT2 inhibitors could partly offset these effects of ERA treatment. This is currently under investigation [NCT04724837]. Thus, the above-indicated studies will help to understand whether (1) combination therapies of SGLT2 inhibition and other kidney protective drugs have additive value and (2) may provide an enhanced safety profile through opposing effects on factors such as flood regulation. 

Regarding mechanistic studies, CROCODILE [NCT04074668] is ongoing to investigate renal oxygenation, perfusion and consumption, as well as insulin sensitivity and mitochondrial function in patients with type 1 diabetes and healthy controls. To further investigate the mechanisms of renal damage in type 1 diabetes, renal biopsies are performed. The ongoing ROCKIES study [NCT04027530] will provide insight into the role of renal hypoxia in the diabetic kidney and will assess the effects of SGLT2 inhibition on renal tissue oxygenation and oxygen consumption, as well as a change in intrarenal hemodynamics and perfusion in type 2 diabetic patients (Table 2).  

The ongoing ATTEMPT trial [NCT04333823] will assess renal mechanistic effects of SGLT2 inhibition on the early onset manifestations and progression of diabetes complications in adolescents with type 1 diabetes. The ADAPT trial [NCT04794517] is ongoing to assess whether dapagliflozin ameliorates hyperfiltration and reduces proteinuria as compared to placebo, in patients with non-diabetic CKD (stage IV CKD) and proteinuria (0.5 g/24 h) (Table 2). 

Table 2 Ongoing clinical trials with SGLT2 inhibition. 

7. Conclusions

In conclusion, SGLT2 inhibitors have acquired a central role in the treatment of type 2 diabetes, chronic kidney disease including diabetic kidney disease, and heart failure with reduced ejection fraction. This is driven by the large cardiovascular and kidney outcome trials conducted in the past few years which have shown surprisingly beneficial results on cardiovascular outcomes (3-point MACE), end-stage kidney disease, hospitalization for heart failure, and cardiovascular mortality in people with and without diabetes. The mechanisms underlying these benefits have been extensively investigated, but still remain incompletely understood. Concerning the kidney protective effect of SGLT2i in people with diabetes, several mechanistic studies indicate that a correction of kidney hyperfiltration owing to postglomerual vasodilation in adults with type 2 diabetes following SGLT2i accounts for the protective effect. Another focus of research is the possible alleviation of kidney hypoxia by SGLT2 inhibition, in addition to small beneficial systemic effects. With regards to the cardiac protective effect, it has been long hypothesized that a plasma volume contraction following natriuresis was most likely to be the underlying mechanism. Recent studies carefully scrutinizing this topic have however raised doubts with respect to this concept and future mechanistic trials may shed further light on the mechanism of actions of these drugs. In the meantime, patients with cardiovascular and/or renal disease benefit from these agents in clinical practice. 

References

[1] Alicia RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017;12(12):2032–45.  

[2] National Kidney F. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60(5):850–86. 

[3] Muskiet MH, Tonneijck L, Smits MM, Kramer MH, Heerspink HJ, van Raalte DH. Pleiotropic effects of type 2 diabetes management strategies on renal risk factors. Lancet Diabetes Endocrinol 2015;3(5):367–81. 

[4] Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358(6):580–91. 

[5] Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013;24(2):302–8. 

[6] Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomized, double-blind, controlled trial. Lancet 2008;372(9638):547–53. 

[7] Lewis EJ, Lewis JB, Greene T, Hunsicker LG, Berl T, Pohl MA, et al. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am J Kidney Dis 2011;58(5):729–36. [

8] Packham DK, Wolfe R, Reutens AT, Berl T, Heerspink HL, Rohde R, et al. Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy. J Am Soc Nephrol 2012;23(1):123–30.

[9] de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369(26):2492–503. 

[10] Wilding JP. The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors. Metabolism 2014;63(10):1228–37. 

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