Renohemodynamic Effects of Combined empagliflOzin and LosARtan
Condition: Diabetes Mellitus, Type 2; Diabetic Kidney Disease
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Worldwide, diabetic kidney disease (DKD) is the most common cause of chronic and end stage
      kidney disease. In parallel with the ever-increasing rates of obesity and type 2 diabetes
      (T2D), the incidence of DKD is expected to further increase in the coming years. DKD is a
      multi-factorial condition, involving pathophysiological factors such as chronic
      hyperglycemia, obesity, systemic- and glomerular hypertension, dyslipidemia, oxidative stress
      and pro-inflammatory cytokines. 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 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,
      indicating an unmet need for renoprotective therapies. Sodium-glucose linked transporters
      (SGLT-2) inhibitors are a relatively novel glucose-lowering drug for the treatment of T2DM.
      These agents seem to exert pleiotropic actions 'beyond glucose control'. SGLT-2 inhibitors
      decrease proximal sodium reabsorption and decrease glomerular pressure and albuminuria in
      type 2 diabetes. In addition, SGLT-2 inhibitors reduce blood pressure and body weight. 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 potential renoprotective effects and mechanisms of
      combination therapy of SGLT-2 inhibitors and RAS inhibitors have not been sufficiently
      detailed in human type 2 diabetes. Therefore, the current study aims to explore the
      underlying mechanism of the improved renal hemodynamics and mechanistics of mono- and
      combination therapy with an SGLT-2 inhibitor and a RAS inhibitor on renal physiology in
      metformin and/or SU-treated T2DM patients.
    

Detailed description: 
      Diabetic kidney disease (DKD), characterized by reduced whole-kidney glomerular filtration
      rate (GFR) and/or urinary protein leakage, is a feared complication of type 2 diabetes
      (T2DM). With severe consequences such as endstage kidney disease (ESKD) and renal death, and
      strongly linked to cardiovascular (CV) morbidity and mortality, optimal treatment of DKD is
      vital. Still, even with multifactorial treatment of renal risk factors, including
      hyperglycemia, hypertension, obesity, dyslipidemia and albuminuria, residual risk remains
      high worldwide. Since the introduction of blockers of the renin-angiotensin-aldosterone
      system (RAS), no other renoprotective drug for T2D has been successfully developed,
      highlighting the need for novel strategies or new therapeutic drugs to improve renal outcome
      in T2DM.

      In this regard, the introduction of the sodium glucose cotransporter (SGLT)2 inhibitors has
      been met with great enthusiasm. Designed to inhibit glucose reabsorption in the proximal
      tubule they induce glycosuria which indeed reduces hyperglycemia. More importantly, these
      drugs have shown remarkable benefits on CV disease and renal outcome in large CV safety
      trials in T2DM patients with high risk of or established atherosclerotic cardiovascular
      disease (CVD) as well as in patients with DKD. The first of these trials, the EMPAgliflozin
      cardiovascular outcome event trial in type 2 diabetes mellitus patients-Removing Excess
      Glucose (EMPA-REG OUTCOME), was reported in 2015 and demonstrated, next to risk reductions in
      CV outcomes, impressive reductions in the prespecified secondary renal outcome. In two
      subsequently reported CV safety trials conducted with canagliflozin (CANVAS-Program) and
      dapagliflozin (DECLARE-TIMI 58), these promising results indicating renal benefit were
      further strengthened. Recently, the results of a dedicated placebo-controlled trial with
      canagliflozin (CREDENCE) in DKD patients were reported. The study was terminated early due to
      overwhelming beneficial effects. Yet, at this point in time, the renoprotective mechanisms
      involved with SGLT2 inhibition still remain speculative, though a consistent finding is that
      SGLT2 inhibitors reduce estimated GFR 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. From studies in
      rodent models of type 1 diabetes (T1DM) and humans with type 1 diabetes it is hypothesized
      that SGLT2 inhibition leads to urinary sodium excretion by inhibiting in the proximal tubule,
      which influences renal hemodynamics through a mechanism known as tubuloglomerular feedback.
      In short, reduced sodium reabsorption at the level of the proximal tubule leads to increased
      sodium chloride delivery at the downstream located macula densa, which in turn increases
      afferent arteriolar resistance and reduces glomerular (hyper)filtration and hydrostatic
      pressure. In the recent RED trial (NCT02682563) the investigators assessed whether this is
      also true in T2DM patients. Suprisingly, this study showed that the renohemodynamic actions
      of SGLT2 inhibition in T2DM are not due to afferent vasoconstriction but rather efferent
      vasodilation. This is also the proposed working mechanism of inhibitors of the RAS system in
      T2DM, although dedicated studies in humans are scarcely done. Indeed, people with T2DM that
      do not respond to RAS blockers in terms of albuminuria reduction, also do not respond to
      SGLT2 inhibitor treatment.

      Consequently, several questions remain regarding the combination of SGLT2 and RAS inhibitors.
      Especially with the recent results of CREDENCE, it is very likely that the combination of
      these agents will become standard of care in patients with T2DM and DKD. Both agents dilate
      the postglomerular arteriole, which might lead to relevant interactions or even synergistic
      effects. Since the majority of the population in the cardiovascular outcome trials used RAS
      inhibition, it is known that the renoprotective effect of SGLT2 inhibition is present with
      concurrent RAS inhibition. However, to what extend these agents interact and which of the
      various complex pathways involved in blood pressure and plasma volume control are affected by
      mono or combination therapy with these agents is unknown. It is important to emphasize that
      in the large trials, RAS blockade was not randomized and that the participants not on RAS
      blockade were small in numbers, making additional analyses on this topic difficult.

      In conclusion: Despite multifactorial treatment approaches, residual risk for the development
      and progression of DKD remains high, and novel therapies or strategies to halt renal burden
      in T2DM are urgently needed. SGLT2 inhibitors and RAS inhibitors both induce
      glucose-independent renoprotective effects and improve renal outcome, seemingly via an at
      least partly equal mechanism, the dilation of the efferent glomerular arteriole resulting in
      an eGFR dip. The use of combination therapy with these agents could lead to an additive or
      even synergistic renoprotective effect in T2DM. As such, combined use of an SGLT2 inhibitor
      and RAS inhibitor may enhance individual benefits (e.g. reduction of glomerular pressure,
      activation of tubuloglomerular feedback, proximal and distal natriuresis, plasma volume
      contraction and reduction of blood pressure).
    

Intervention name(s): Empagliflozin 10 MG; Losartan 50Mg Tab; Placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): Empagliflozin 10 MG 7 days intervention period; Losartan 50 MG 7 days intervention period; Placebo 7 days intervention period
Other intervention name(s): Jardiance; Cozaar
Intervention MeSH terms: Empagliflozin; Losartan
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: A phase 4, monocenter, randomized, double-blind, placebo-controlled, 4-armed cross-over mechanistic intervention study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: RAS inhibition; Sodium Glucose Cotransport 2 inhibitors