SGLT2 Inhibitors in Glomerular Hyperfiltration

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Obesity, Non-diabetic Chronic Kidney Disease

Intervention / Treatment
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* Drug: Empagliflozin 10 MG


Participation Criteria
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Eligibility Criteria
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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: Urinary protein excretion >1g/24-h to <3g/24-h despite RAS inhibitor therapy with ACE inhibitors or ARBs; Blood pressure in recommended targets with or without blood pressure lowering medications; Estimated GFR > 60 ml/min/1.73m^2 (CKD-EPI formula); Female childbearing potential and non-sterile male must agree to use a method of contraception; Written informed consent 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; Heart failure with or without decreased systolic function; Uncontrolled hypertension or symptomatic hypotension; History of malignancy within 5 years of screening; Inability to fully understand the possible risks and benefits related to study participation; If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 90 days after last dose; or intending to donate ova during such time period; If male, the subject intends to donate sperm while on the study this study or for 90 days after last dose; Alcohol and drug abuse; Participation in another interventional clinical trial within the 4 weeks prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: OFF/ON/OFF design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMP<br> | Drug: Empagliflozin 10 MG<br>* Empagliflozin 10 mg/die for 28 days<br>* Other names: Jardiance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measured Glomerular Filtration Rate (GFR) | GFR will be measured by the iohexol plasma clearance technique | Changes from baseline to the end of one-month treatment period and one-month recovery period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hour urinary output | last of three consecutive collections | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary protein excretion | mean of the measurement in three consecutive 24-hour urine collection | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary albumin excretion | mean of the measurement in three consecutive 24-hour urine collection | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary urea excretion | last of three consecutive collections | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary phosphate excretion | last of three consecutive collections | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary sodium excretion | last of three consecutive collections | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary glucose excretion | last of three consecutive collections | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary potassium excretion | last of three consecutive collections | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary uric acid excretion | last of three consecutive collections | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| 24 hour urinary creatinine excretion | last of three consecutive collections | 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 | 
| Fractional clearance of sodium calculated by standard formulas |  | 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 | 
| 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 | 
| Glucose disposal rate | Performed by hyperinsulinemic euglycemic clamp and by standard oral glucose load and HOMA index; | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| Glucose tolerance | Performed by hyperinsulinemic euglycemic clamp and by standard oral glucose load and HOMA index; | 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 | 
| Office heart 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 | These parameters will be measured by tonometry | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| other marker of vascular stiffness | These parameters will be measured by tonometry | Changes from baseline to the end of one-month treatment period and one-month recovery period | 
| Indices of Quality of Life: questionnaire SF-36 | By submission of validate questionnaire | Changes from baseline to the end of one-month treatment period and one-month recovery period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GFR decline, Glomerular hyperfiltration, SGLT2 inhibitors, Residual proteinuria, Obesity