REGROUP: Renohemodynamic Effects empaGliflozin in vaRiOUs Populations

Worldwide, diabetic kidney disease (DKD) is the most common cause of chronic and end stage kidney disease. Large-sized prospective randomized clinical trials indicate that intensified glucose and blood pressure control, the latter especially by using agents that interfere with the renin-angiotensin-aldosterone system (RAS), halts the onset and (particularly) the progression of DKD, in both type 1 Diabetes Mellitus (T1DM) and type 2 Diabetes Mellitus (T2DM) patients. However, despite the wide use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), a considerable amount of patients develop DKD (20-40%), indicating an unmet need for renoprotective therapies as DKD largely causes the increased mortality risk from cardiovascular disease (CVD) in people with diabetes.

Sodium-glucose linked transporters (SGLT-2) inhibitors are a relatively novel glucose-lowering drug for the treatment of T2DM as they lower plasma glucose levels by blocking renal glucose reabsorption. In addition, these agents exert pleiotropic actions beyond glucose control. As such, SGLT-2 inhibitors decrease proximal sodium reabsorption, reduce blood pressure, body weight and uric acid. In large trials and likely through these pleiotropic effects, SGLT2 inhibitors reduce cardiovascular mortality, hospitalization for heart failure and reduce end stage kidney disease. At this point in time, the renoprotective mechanisms involved with SGLT-2 inhibition still remain speculative, though a consistent finding is that SGLT-2 inhibitors reduce estimated eGFR after first dosing, which is reversible after treatment cessation. This "dip" indicates a renal hemodynamic phenomenon reminiscent of the RAS blockers and is thought to reflect a reduction in intraglomerular pressure.

The mechanisms of this observation have only been partially investigated by us and others. From studies in peolpe with T1DM it is hypothesized that SGLT-2 inhibition increases sodium chloride delivery to the macula densa, which in turn augments the afferent arteriolar resistances, known as tubuloglomerular feedback (TGF), consequently reducing glomerular (hyper)filtration and hydrostatic pressure. Recently a trial has been conducted in humans with T2DM to investigate if this also holds true in these patients. Suprisingly, this study showed that the renohemodynamic actions of SGLT-2 inhibition in T2DM are not due to afferent vasoconstriction but rather efferent vasodilation [van Bommel/van Raalte Kidney International 2019 in press]. The investigators realized that the SGLT-2 associated dip in eGFR remains insufficient understood. The increase in sodium excretion following SGLT-2 inhibition peaks at day 2-3 after which it normalizes. It is unknown whether this drop in eGFR is related to this peak in sodium excretion, as the drop remains after normalization of sodium excretion. Therefore it might be possible that glucosuria, by inducing osmotic diuresis, is the main driver of the reduction in intraglomerular pressure more than sodium, since SGLT-2 inhibitors cause persisting glucosuria.

Furthermore, it is known that SGLT-2 induced glucosuria and possibly sodium excretion is dependent of renal function and HbA1c and consequently is diminished in people with CKD or without T2DM. However, the renoprotective effects in T2DM are also observed in patients with impaired kidney function and seem statistically independent of glucose levels. Until now it has not been investigated whether or not the SGLT-2 induced eGFR alterations occur in people with CKD with or without T2DM. It is clinically relevant to understand the renal hemodynamics of SGLT-2 inhibitors in these populations since then it is possible to interpret the results from the ongoing trials in people with CKD without T2DM, such as EMPA-KIDNEY and DAPA-CKD.

Recently, potential mediators of renal arterole tone, such as adenosine, have been measured to gain more insight into mechanisms of SGLT-2 inhibitor-induced changes in renal hemodynamics. Adenosine is known to augment preglomerular arteriolar resistance. Adenosine was significantly increased after SGLT-2 inhibition, as was also observed in patients with type 1 diabetes. However, it can also induce postglomerular vasodilation via A2aR activation in the presence of RAS blockade. One study in T1DM rats has shown that increased adenosine generation by the macula densa in response to SGLT-2 inhibition suppresses hyperfiltration, as the improvements in preglomerular arteriolar resistance were abolished after adenosine antagonist administration. To date, this has not been investigated in T2DM humans. Therefore, this trial will assess TGF responses with and without adenosine blockade by caffeine.