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

Phase 4

• Conditions: Type 2 Diabetes; Diabetic Nephropathy
• Interventions: Drug: SGLT2 Inhibition

• Registration Number: NCT04127084
• Lead Sponsor: Zhongshan Hospital Xiamen University

Brief Summary

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

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.

Study Timeline

• Status Verified: 2019-10
• Study First Submitted: 2019-10-08
• Study First Submitted QC: 2019-10-11
• Study Start: 2019-10-15
• Study First Posted: 2019-10-15
• Last Update Submitted: 2019-10-16
• Last Update Posted: 2019-10-21
• Primary Completion: 2020-10
• Study Completion: 2021-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 70

Inclusion Criteria

1. Male or female patients between 18 -80 years of age with a diagnosis of type 2 diabetes (WHO criteria).
2. HbA1c of 7-11 %
3. eGFR equal to or above 45 ml/min/1.73 m2
4. 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.
5. Patients who agree to receive treatment with SGLT2 inhibitors.
6. Patients must be on current stable hemodynamic profile , without dehydration.
7. 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.
8. 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.

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Exclusion Criteria

1. type 1 diabetes

2. Patients who suffer from recent acute complications including diabetic ketoacidosis and hyperglycaemic hyperosmolar coma, which may be at risk for dehydration.

3. Patients with hypertension who are not on stable antihypertensive treatment

4. urinary tract or reproductive tract acute infection

5. impaired liver function, defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN

6. History of unstable or rapidly progressing renal disease

7. impaired renal function ,eGFR: <45 mL/min (calculated by MDRD formula)

8. Ongoing cancer treatment

9. 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

10. Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure..

11. Pregnant or breastfeeding patients

12. smoker.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
normal albuminuria	SGLT2 Inhibition	baseline urinary albumin creatinine ratio \[UACR\]\< 30 mg/g
moderately increased albuminuria	SGLT2 Inhibition	baseline UACR 30\~300 mg/g
severely increased albuminuria	SGLT2 Inhibition	baseline UACR\>300mg/g

Primary Outcome Measures

Name	Time	Method
Change in urinary albuminuria	Up to 12 weeks	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)
change in nephrin	Up to 12 weeks	To assess effect of SGLT2 inhibition intervention on glomerular podocyte injury by detecting the expression of renal nephrin.
Change in eGFR	Up to 12 weeks	eGFR was calculated by modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease.
change in TGF-β1	Up to 12 weeks	To assess effect of SGLT2 inhibition intervention on glomerular and tubulointerstitial fibrosis by detecting the expression of TGF-β1
change in IL-6	Up to 12 weeks	To assess effect of SGLT2 inhibition intervention on inflammation biomarkers by detecting the levels of interleukin-6.
change in TNFα	Up to 12 weeks	To evaluate the effects of SGLT2 inhibition treatment on inflammation, biomarkers by detecting the levels of tumor necrosis factor alpha.
changes of AGEs	Up to 12 weeks	To evaluate the effects of SGLT2 inhibition treatment on oxidative stress index, the changes of AGEs.
changes of 8-OH-dG	Up to 12 weeks	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

Secondary Outcome Measures

Name	Time	Method
Change in rennin	Up to 12 weeks	To evaluate the levels of rennin before and after SGLT2 inhibition treatment
Change in angiotensin	Up to 12 weeks	To evaluate the levels of angiotensin before and after SGLT2 inhibition treatment
Change in uric acid	Up to 12 weeks	To evaluate the levels of serum uric acid before and after SGLT2 inhibition treatment.
Change in aldosterone	Up to 12 weeks	To evaluate the levels of aldosterone before and after SGLT2 inhibition treatment.

Trial Locations

Locations (1)

Zhongshan Hospital Xiamen University; 🇨🇳 Xiamen, Fujian, China