Effects of SGLT2 Inhibition Treatment on Different Levels of Albuminuria in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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Diabetic kidney disease has become the leading cause for ESRD worldwide.Albuminuria is a major risk factor for progression of diabetic nephropathy. SGLT2 inhibitors are the first antiglycaemic drugs with direct renoprotection, which are thought to protect the kidneys by lowering albuminuria, stimulating urinary glucose excretion ,reducing systemic blood pressure, while simultaneously improving multiple other risk factors in a glucose-independent manner. However, the precise mechanisms behind the renal beneficial effect of SGLT2 inhibitors are not entirely elucidated, although ongoing outcome trials will confirm these findings. This study is to assess the impact of three months of treatment with SGLT2 Inhibitions on different levels of albuminuria in patients with type 2 diabetes and to evaluate the effects of SGLT2 inhibition treatment on markers for podocyte damage , renal fibrosis, inflammation，oxidative stress and renin-angiotensin- aldosterone system.

Detailed Description
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Objective: The primary objective is to assess the impact of three months of treatment with SGLT2 Inhibition on Different levels of Albuminuria in Patients With type 2 diabetes and to seek the relationship of this influences to relevant risk markers in the pathology of diabetic renal disease. Design: prospective ，intervention， case-controlled , single center study. Treatment period: 12 weeks. Patient population: 60 patients with type 2 diabetes recruited from Zhongshan Hospital Xiamen University in accordance with the study in- and exclusion criteria. Intervention: Dapagliflozine 10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment. Endpoints: Primary outcome: evaluate the effects of SGLT2 inhibition treatment on on urinary albuminuria, kidney function and eGFR . Secondary endpoints To assess the effect of SGLT2 inhibition on markers for podocyte damage , renal fibrosis, inflammation，oxidative stress and renin-angiotensin- aldosterone system。 Timeframe: Recruiting planned from October 2019, inclusion over the following 12 months. Last patient is expected to be completed October 2020. Data analysis completed December 2020, publication autumn 2021.

Official Title
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Effects of SGLT2 Inhibition Treatment on Different Levels of Albuminuria in Patients With Type 2 Diabetes: a Prospective Interventional Study

Conditions
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Type 2 Diabetes, Diabetic Nephropathy

Intervention / Treatment
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* Drug: SGLT2 Inhibition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients between 18 -80 years of age with a diagnosis of type 2 diabetes (WHO criteria). HbA1c of 7-11 % eGFR equal to or above 45 ml/min/1.73 m2 The Trial included 20 normal albuminuria (Urinary albumin creatinine ratio [UACR]< 30 mg/g, with 20 moderately increased albuminuria UACR 30 300 mg/g, and 20 severely increased albuminuria UACR>30 0mg/g (in ≥2 out 3 morning spot urine collections prior to enrolment ).at baseline. Patients who agree to receive treatment with SGLT2 inhibitors. Patients must be on current stable hemodynamic profile , without dehydration. Patients must be on current stable antiglycaemic treatment with oral drugs (OAD) or insulin 4 weeks before start of study drug and throughout study duration. Patients must be on stable antihypertensive treatment (not include renin-angiotensin system blocking treatment) 4 weeks before start of study drug and throughout study duration. Exclusion Criteria: type 1 diabetes Patients who suffer from recent acute complications including diabetic ketoacidosis and hyperglycaemic hyperosmolar coma, which may be at risk for dehydration. Patients with hypertension who are not on stable antihypertensive treatment urinary tract or reproductive tract acute infection impaired liver function, defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN History of unstable or rapidly progressing renal disease impaired renal function ,eGFR: <45 mL/min (calculated by MDRD formula) Ongoing cancer treatment Recent Cardiovascular Events in a patient: 9.1. Acute Coronary Syndrome (ACS) within 2 months prior to enrolment 9.2.Hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment9. 3. Acute Stroke or TIA within two months prior to enrolment 9. 4. Less than two months post coronary artery revascularization Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure.. Pregnant or breastfeeding patients smoker.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: normal albuminuria<br>baseline urinary albumin creatinine ratio [UACR]< 30 mg/g | Drug: SGLT2 Inhibition<br>* Dapagliflozine 5-10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment<br>* Other names: Dapagliflozine,Empagliflozin,Canagliflozin;|
| Experimental: moderately increased albuminuria<br>baseline UACR 30 300 mg/g | Drug: SGLT2 Inhibition<br>* Dapagliflozine 5-10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment<br>* Other names: Dapagliflozine,Empagliflozin,Canagliflozin;|
| Experimental: severely increased albuminuria<br>baseline UACR>300mg/g | Drug: SGLT2 Inhibition<br>* Dapagliflozine 5-10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment<br>* Other names: Dapagliflozine,Empagliflozin,Canagliflozin;|
| No Intervention: blank Comparator<br>normal participant | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in urinary albuminuria | a clean-catch 24- hour urine sample and spot urine sample were collected to assess urinary albuminuria,which will be evaluated at week 0, and at end study week 12 (+/- 1 week) | Up to 12 weeks | 
| Change in eGFR | eGFR was calculated by modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. | Up to 12 weeks | 
| change in nephrin | To assess effect of SGLT2 inhibition intervention on glomerular podocyte injury by detecting the expression of renal nephrin. | Up to 12 weeks | 
| change in TGF-β1 | To assess effect of SGLT2 inhibition intervention on glomerular and tubulointerstitial fibrosis by detecting the expression of TGF-β1 | Up to 12 weeks | 
| change in IL-6 | To assess effect of SGLT2 inhibition intervention on inflammation biomarkers by detecting the levels of interleukin-6. | Up to 12 weeks | 
| change in TNFα | To evaluate the effects of SGLT2 inhibition treatment on inflammation, biomarkers by detecting the levels of tumor necrosis factor alpha. | Up to 12 weeks | 
| changes of AGEs | To evaluate the effects of SGLT2 inhibition treatment on oxidative stress index, the changes of AGEs. | Up to 12 weeks | 
| changes of 8-OH-dG | To evaluate the effects of SGLT2 inhibition treatment on oxidative stress index by detecting the levels of 8-OH-dG. Urinary 8-OH-dG concentrations were assayed using a competitive enzyme-linked immunosorbent assay | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in uric acid | To evaluate the levels of serum uric acid before and after SGLT2 inhibition treatment. | Up to 12 weeks | 
| Change in aldosterone | To evaluate the levels of aldosterone before and after SGLT2 inhibition treatment. | Up to 12 weeks | 
| Change in rennin | To evaluate the levels of rennin before and after SGLT2 inhibition treatment | Up to 12 weeks | 
| Change in angiotensin | To evaluate the levels of angiotensin before and after SGLT2 inhibition treatment | Up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, Diabetic Nephropathy, Albuminuria, SGLT2 inhibitor