Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study.
Condition: Type 2 Diabetes Mellitus; Diabetic Kidney Disease; Diabetic Nephropathy; Renal Hypoxia; Renoprotection; SGLT2 Inhibitor; Ertugliflozin
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Hypoxia
Study type: Interventional
Phase: Phase 4

Summary: 
      Current study will render insight in to the role of renal hypoxia in the diabetic kidney and
      is able to associate its finding with measurements of renal perfusion and glomerular
      filtration rate. Moreover, this research will focus on the effects of sodium-glucose
      cotransporter 2 inhibition on renal tissue oxygenation and oxygen consumption as well as a
      change in intrarenal hemodynamics and perfusion, and a shift of fuel metabolites. Elucidation
      the mechanisms underlying the effects of SGLT2 inhibition will advance our knowledge and
      contribute to their optimal clinical utilization in the treatment of chronic kidney disease
      in diabetes and possibly beyond.
    

Detailed description: 
      Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are a relatively new class of drugs in
      the treatment of diabetes and improve glycemic control by blocking SGLT-2 in the proximal
      tubule, the main transporter of coupled sodium-glucose reabsorption Three large
      cardiovascular outcome trials (EMPA-REG, CANVAS, DECLARE- TIMI 58) showed SGLT-2 inhibition
      to have a renoprotective effect, including on renal outcomes. Moreover, the recently
      publicized CREDENCE trial concluded early after the planned interim analyses showed a
      striking renoprotective effect of SGLT-2 inhibition in patients with T2DM and CKD. The
      mechanisms underlying their beneficial effects remain to be elucidated, as the small SGLT-2
      induced reduction in glucose level (0.5% HbA1c), bodyweight (about 3%), systolic blood
      pressure (about 4 mmHg), or uric acid (about 6%) are insufficient to fully account for the
      effect.

      The pathological mechanisms underlying DKD involve complex interactions between metabolic and
      haemodynamic factors which are not fully understood. However, accumulating evidence of
      foremost animal studies indicates that a chronic state of renal tissue hypoxia is the final
      common pathway in the development and progression of diabetic kidney disease. Therefore
      several hypothesis have been proposed on the alleviation of chronic tissue hypoxia following
      SGLT-2 inhibition: (1) A decrease in workload by a decrease in GFR. (2) A shift in renal fuel
      energetics by increasing ketone body oxidation, which renders high ATP/oxygen consumption
      ratio's compared to glucose or free fatty acids. (3) An improvement of cardiac function and
      systemic hemodynamics to lead to an increase in renal perfusion, and (4) an increase in
      erythropoietin (EPO) levels to stimulate oxygen delivery.

      Current study will examine the above hypothesis by researching renal oxygenation by BOLD-MRI,
      oxygen consumption by PET-CT, and hemodynamic kinetics by the Iohexol clearance
      method/contrast-enhance ultrasound/arterial spin labeling. Blood sampling will allow for the
      measurement of EPO and ketone bodies, as well as a resting energy expenditure will elucidate
      a shift in use of energy substrate metabolism. The research will be performed in T2DM without
      overt kidney disease (n=20) before and after a 4 week treatment with SGLT-2 inhibition
      (ertugliflozin), and will be compared the obtained results from healthy controls (n=20).
    

Intervention name(s): Ertugliflozin 15 mg
Intervention type(s): Drug
Intervention description(s): Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks
Other intervention name(s): Steglatro
Intervention MeSH terms: Ertugliflozin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention