Evaluating the Short-Term Renal and Systemic Effects of SGLT2 Inhibition in Non-Diabetic Patients at Risk of Accelerated GFR Decline Because of Glomerular Hyperfiltration: a Sequential OFF-ON-OFF Study With One-Month Empagliflozin Therapy Followed by One-Month Recovery Period
Overview
- Phase
- Phase 2
- Intervention
- Empagliflozin 10 MG
- Conditions
- Obesity
- Sponsor
- Mario Negri Institute for Pharmacological Research
- Primary Endpoint
- Measured Glomerular Filtration Rate (GFR)
- Status
- Withdrawn
- Last Updated
- 4 years ago
Overview
Brief Summary
Glomerular hyperfiltration is a major risk factor for accelerated glomerular filtration rate (GFR) decline and renal and cardiovascular events despite optimized conservative therapy with blood pressure and blood glucose (in diabetics) lowering medications and inhibitors of the Renin Angiotensin System (RAS) such as Angiotensin Converting Enzyme (ACE) inhibitors and/or Angiotensin Receptor Blockers (ARBs).
Progressive GFR decline initiated and sustained by glomerular hyperfiltration in subjects with diabetes, unhealthy obesity, hypertension and other risk factors, is paralleled by progressive glomerulosclerosis and loss of functioning nephrons.
The inhibition of the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubular segments of the nephrons appears to be an ideal, specific intervention to inhibit the tubulo-glomerular feedback and ameliorate glomerular hyperfiltration in subjects with absolute or relative hyperfiltration associated with unhealthy obesity or proteinuric chronic kidney disease (CKD). Indeed, by reducing tubular sodium reabsorption, SGLT2 inhibitors may enhance sodium chloride delivery to the macula densa, restore pre-glomerular resistances and therefore limit glomerular hyperperfusion and consequent hyperfiltration. Moreover, because of its natriuretic effects, SGLT2 inhibition therapy might reduce the sodium overload and volume expansion which, along with secondary hypertension, may further contribute to kidney hyperperfusion and glomerular hyperfiltration in obesity and CKD.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female ≥ 18 years old;
- •Increased risk of accelerated renal function loss because of absolute or relative hyperfiltration associated with unhealthy obesity or residual proteinuria defined as:
- •Unhealthy obesity:
- •BMI \>30 kg/m\^2 or waist circumference \>94 cm in males and \> 80 cm in females
- •Metabolic syndrome, defined as the presence of at least three of the following criteria:
- •Blood pressure\>140/90 mmHg or controlled blood pressure under current antihypertensive treatment
- •Triglyceride levels \>150 mg/dL
- •HDL\<40 mg/dL in males \<50 mg/dL in females
- •Fasting blood glucose \> 100 and \<125 mg/dL
- •Residual proteinuria:
Exclusion Criteria
- •Type 1or 2 diabetic patients;
- •Concomitant treatment with insulin or oral hypoglycemic agents;
- •Nephrotic syndrome of any etiology;
- •Patients with Autosomal Dominant Polycystic Kidney Disease;
- •Symptomatic urinary tract lithiasis or obstruction;
- •Ischemic kidney disease (because of possible excess risk of acute kidney injury upon SGLT2 inhibition associated reduction in sodium pool and kidney perfusion pressure);
- •Rapidly progressive kidney disease defined by impairment of renal function within 2 weeks - 3 months (for the cohort of patients with residual proteinuria only) ;
- •Active systemic autoimmune diseases;
- •Treatment for glomerulopathies or systemic diseases with steroids or any other immunosuppressive agent within one year;
- •Specific contraindication to SGLT2 inhibitor therapy;
Arms & Interventions
IMP
Intervention: Empagliflozin 10 MG
Outcomes
Primary Outcomes
Measured Glomerular Filtration Rate (GFR)
Time Frame: Changes from baseline to the end of one-month treatment period and one-month recovery period
GFR will be measured by the iohexol plasma clearance technique
Secondary Outcomes
- Fractional clearance of uric acid calculated by standard formulas(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Fractional clearance of free water calculated by standard formulas(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary glucose excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Fractional clearance of sodium calculated by standard formulas(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary urea excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary creatinine excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary output(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary protein excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary albumin excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary phosphate excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary sodium excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary potassium excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour urinary uric acid excretion(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Fractional clearance of total protein calculated by standard formulas(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Fractional clearance of albumin calculated by standard formulas(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Office blood pressure(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Indices of Quality of Life: questionnaire SF-36(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Glucose tolerance(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Fractional clearance of potassium calculated by standard formulas(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Glucose disposal rate(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour (day-time and night-time) blood pressure monitoring(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- 24 hour (day-time and night-time) heart rate monitoring(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Pulse wave velocity(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- other marker of vascular stiffness(Changes from baseline to the end of one-month treatment period and one-month recovery period)
- Office heart rate(Changes from baseline to the end of one-month treatment period and one-month recovery period)